-60-
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Benzimidazoles of general formula
<IMG>
wherein
R1 represents a fluorine, chlorine or bromine atom, an
alkyl, cycloalkyl, fluoromethyl, difluoromethyl or
trifluoromethyl group and
R2 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 the
benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl
-61-
group may additionally be substituted by a fluorine atom or by
a methyl or trifluoromethyl group, R2 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 C3-5-cycloalkyl
group and
R4 represents a carboxy or 1H-tetrazolyl group,
and the salts thereof with inorganic or organic acids or
bases,
whilst, unless otherwise specified, an alkyl moiety as
mentioned hereinbefore may in each case contain 1 to 3 carbon
atoms and a cycloalkyl moiety mentioned hereinbefore may
contain from 3 to 7 carbon atoms.
2. Benzimidazoles of general formula I according to
claim 1, wherein
R1 represents a chlorine atom, or a C1-3-alkyl or a
trifluoromethyl group,
-62-
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
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
C1-6-alkyl or by a cycloalkyl group, whilst the phenyl nucleus of
the benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl
group may additionally be substituted by a fluorine atom or by
a methyl or trifluoromethyl group, or R2 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
R4 represents a carboxy or 1H-tetrazolyl group,
and the salts thereof with inorganic or organic acids or
bases.
-63-
3. Benzimidazoles of general formula I according to
claim 1, 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
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 the benzimidazol-2-yl
or 4,5,6,7-tetrahydro-benzimidazol-2-yl group may
additionally be substituted by a fluorine atom, or R2 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.
4. The following benzimidazoles of general formula I
according to claim 1:
-64-
(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-
methylbenzimidazol-1-yl]methyl]-biphenyl-2-carboxylic
acid,
(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,
-65-
(k) 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid,
(1) 4'-([2-ethyl-4-methyl-6-(butanesultam-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,
(m) 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl,
(n) 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid,
(o) 4'-([2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl,
(p) 4' - [[2-n-propyl-4-methyl-6- (imidazo [2, 1-b]thiazol-6-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl,
(q) 4'-[(2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-
benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-
carboxylic acid, and
(r) 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, and the salts thereof with
inorganic or organic acids or bases.
5. 4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid and
the salts thereof with inorganic or organic acids or bases.
-66-
6. 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 and the salts thereof with
inorganic or organic acids or bases.
7. Physiologically acceptable salts of the compounds
according to any one of claims 1 to 6 with inorganic or
organic acids or bases.
8. Pharmaceutical compositions containing a compound
according to any one of claims 1 to 6 or a physiologically
acceptable salt according to claim 7 together with an inert
carrier or diluent.
9. Use of a compound according to any one of claims 1
to 7 for preparing a pharmaceutical composition with an
angiotensin-antagonist activity.
10. Use of a compound according to any one of claims 1
to 6 or a physiologically acceptable salt thereof as an
angiotensin-antagonist.
11. Use of a compound according to any one of claims 1
to 6 or a physiologically acceptable salt thereof in the
manufacture of a pharmaceutical composition for use as an
angiotensin-antagonist.
-67-
12. Use of a compound according to any one of claims 1
to 6 or a physiologically acceptable salt thereof for the
treatment of hypertension, pulmonary diseases, cardiac
insufficiency, ischaemic peripheral circulatory disorders,
myocardial ischaemia (angina), diabetic nephropathy, glaucoma,
gastrointestinal and bladder diseases or to prevent the
progession of cardiac insufficiency after myocardial
infarction.
13. Use of a compound according to any one of claims 1
to 6 or a physiologically acceptable salt thereof for the
treatment of depression, Alzheimer's disease, Parkinson
syndrome, bulimia, disorders of cognitive function as well as
other central nervous system disorders.
14. Use of a compound according to any one of claims 1
to 6 or a physiologically acceptable salt thereof in the
manufacture of a pharmaceutical composition for use in the
treatment of hypertension, pulmonary diseases, cardiac
insufficiency, ischaemic peripheral circulatory disorders,
myocardial ischaemia (angina), diabetic nephropathy, glaucoma,
gastrointestinal and bladder diseases or to prevent the
progession of cardiac insufficiency after myocardial
infarction.
15. Use of a compound according to any one of claims 1
to 6 or a physiologically acceptable salt thereof in the
manufacture of a pharmaceutical composition for use in the
-68-
treatment of depression, Alzheimer's disease, Parkinson
syndrome, bulimia, disorders of cognitive function as well as
other central nervous system disorders.
16. Process for preparing a pharmaceutical composition
according to claim 8, characterised in that a compound
according to any one of claims 1 to 7 is incorporated in an
inert carrier or diluent by a non-chemical method.
17. Process for preparing a benzimidazole according to
any one of claims 1 to 7, characterised in that
a) a compound of general formula
<IMG>
wherein
R1 and R2 are defined as in any one of claims 1 to 6,
one of the groups X1 or Y1 represents a group of general
formula
<IMG>
and the other group X1 or Y1 represents a group of the
general formula
-69-
<IMG>
wherein
R2 and R4 are defined as in any one of claims 1 to 6,
R8 represents a hydrogen atom or an R3CO- group, wherein
R3 is as defined in any one of claims 1 to 6,
Z1 and Z2, 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 Z2 together represent an oxygen or sulphur atom,
an optionally C1-3-alkyl substituted imino group, an
alkylenedioxy or alkylenedithio group, each having 2 or 3
carbon atoms, but one of the groups X1 or Y1 must represent a
group of general formula
<IMG>
or
<IMG>
is cyclised and a corresponding N-oxide which might thus
be obtained is reduced or
-70-
b) a benzimidazole of general formula
<IMG>
wherein
R1 to R3 are as defined in any one of claims 1 to 6, is
reacted with a biphenyl compound of general formula
<IMG>
wherein
R4 is as defined in any one of claims 1 to 6 and
Z3 represents a nucleophilic leaving group, or
c) in order to prepare a compound of general formula I
wherein R4 represents a carboxy group, a compound of general
formula
-71-
<IMG>
wherein
R1 to R3 are as defined in any one of claims 1 to 6 and
R4' represents a group which may be converted into a carboxy
group by hydrolysis, thermolysis or hydrogenolysis, is
converted into a corresponding carboxy compound or
d) in order to prepare a compound of general formula I
wherein R4 represents a 1H-tetrazolyl group, a protecting
group is split off from a compound of general formula
<IMG>
wherein
R1, R2 and R3 are defined as hereinbefore and
R4" represents a 1H-tetrazolyl group protected in the 1- or
3- position by a protecting group, or
-72-
(e) in order to prepare a compound of general formula I
wherein R4 represents a 1H-tetrazolyl group, a compound of
general formula
<IMG>
wherein
R1 to R3 are defined as hereinbefore, is reacted with
hydrazoic acid or the salts thereof or
(f) in order to prepare compounds of general formula I
wherein R2 represents one of the 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 mentioned hereinbefore,
a compound of general formula
<IMG>
wherein
-73-
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 methine and the -C=D- group
represents a sulphur atom,
is reacted with a compound of general formula
<IMG>
wherein
R1, R3 and R4 are as defined in any one of claims 1 to 6
and Z4 represents a nucleophilic leaving group or
g) in order to prepare compounds of general formula I
wherein R2 represents one of the 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 mentioned in
any one of claims 1 to 6,
a compound of general formula
-74-
<IMG>
wherein
none, one or two of the groups A1, B1, C1 or D1
represents a nitrogen atom and
the remaining groups A1, B1, C1 or D1 represent methine
groups,
R11 represents a hydrogen or fluorine atom or a methyl or
trifluoromethyl group,
one of the groups X2 or Y2 represents an R13-NH- group
and the other X2 or Y2 group represents a group of general
formula
<IMG>
wherein
R1, R3, and R4 are as defined in any one of claims 1 to
6, one of the groups R13 or R14 represents a hydrogen atom and
-75-
the other R13 or R14 group represents a hydrogen atom, a
C1-6-alkyl group or a C3-7-cycloalkyl group,
Z5 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
Z5 and Z6 together represent an oxygen or sulphur atom,
an optionally C1-3-alkyl-substituted imino group, an
alkylenedioxy or alkylenedithio group each having 2 or 3
carbon atoms,
is cyclised and any corresponding N-oxide which is thus
obtained is reduced and a compound thus obtained is
subsequently hydrolysed, if required, and
if necessary a protecting group used during the reactions
a) to g) in order to protect reactive groups is cleaved and
if required, an isomer mixture thus obtained is resolved
into its isomers, and
if required a compound of general formula I thus obtained
is converted into a salt thereof.
18. A process according to claim 17 which includes the
step of converting an obtained compound of formula I into a
physiologically acceptable salt thereof.
19. A process according to claim 17(f) or 18 wherein Z4
represents a chlorine or bromine atom.
20. A commercial package containing, as active
ingredient, a compound according to any one of claims 1 to 6,
-76-
or a physiologically acceptable salt thereof, together with
instructions for its use for the treatment of hypertension,
pulmonary diseases, cardiac insufficiency, ischaemic
peripheral circulatory disorders, myocardial ischaemia
(angina), diabetic nephropathy, glaucoma, gastrointestinal and
bladder diseases or to prevent the progression of cardiac
insufficiency after myocardial infarction.
21. A commercial package containing, as active
ingredient, a compound according to any one of claims 1 to 6,
or a physiologically acceptable salt thereof, together with
instructions for its use for the treatment of depression,
Alzheimer's disease, Parkinson syndrome, bulimia, disorders of
cognitive function as well as other central nervous system
disorders.
