BENZIMIDAZOLES, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS AND PROCESSES FOR PREPARING THEM

BENZIMIDAZOLES, COMPOSITIONS PHARMACEUTIQUES QUI EN CONTIENNENT ET LEURS MODES DE PREPARATION

English Abstract

The invention .relates to benzimidazoles of formula I
(see formula I)
their 1-, 3-isomer mixtures, and the salts thereof,
wherein the substituents R1, R2, R3 and R4 are preferably as
follows: R1 in the 6-position represents a 1-methylbenzimidazol-
2-yl, 3,4,5,6-tetrahydro-phthalimino, 2,3-diphenyl-maleic acid
imido, 2,3-dimethyl-maleic acid imido,
N-phenylmethanesulphonyl.-methylamino, 2-oxo-pyrrolidin-1-yl,
2-oxo-piperidin-1-yl, 2-oxo-hexamethyleneimino, 2-oxo-3,
4-tetramethylene-pyrrolidin-2-yl, 3,3-dimethylglutarimido,
N-methylaminocarbonyl-n-pentylamino, propanesultam-1-yl or
butanesultam-1-yl group; R2 represents a methyl, ethyl,
n-propyl or n-butyl group; R3 represents a carboxy or
1H-tetrazolyl group; and R4 represents a hydrogen atom. These
compounds have valuable properties, in particular as
angiotensin-II antagonists.

Claims

115

CLAIMS

1. A compound of formula I
Image
(wherein R1 represents a tetrahydrobenzimidazolyl or
imidazopyridinyl group,
a benzimidazolyl or benzoxazolyl group optionally substituted
in the phenyl nucleus by a fluorine, chlorine or bromine atom,
by a C1-3-alkyl group, by a C1-3-alkoxy or by a trifluoromethyl
group, and in which the NH-group of the above-mentioned
imidazole rings may additionally be substituted by a C1-6-alkyl
group or by a C3-7-cycloalkyl group,
an amino group substituted by a bicyclohexylcarbonyl or
biphenylcarbonyl group which may additionally be substituted at
the N-atom by a C1-3 alkyl group,
an aminocarbonylamino group substituted by a bicyclohexyl or
biphenyl group and optionally also substituted by one or two
C1-3-alkyl groups at the N-atom,
with the exception of the 2-oxo-3,4-tetramethylene-pyrrolidin-
1-yl group a 5-, 6- or 7-membered alkyleneimino or
alkenyleneimino group optionally substituted by one or two
C1-3-alkyl groups or by a tetramethylene or pentamethylene
group, in which a methylene group is replaced by a carbonyl or
sulphonyl group,
a 3,4,5,6-tetrahydro-2(1H)-pyrimidinone group optionally
substituted by a C1-3-alkyl or phenyl (C1-3-alkyl) group,



116
a malefic acid amido or malefic acid imido group optionally mono-
or disubstituted by a C1-3-alkyl group or by a phenyl group, in
which the substituents may be identical or different,
an imidazoline or imidazole group optionally substituted by a
C1-6-alkyl group or by a C3-7-cycloalkyl group,
an imidazolidinedione group optionally substituted by a
C1-3-alkyl group, by a phenyl (C1-3-alkyl) group or by a
tetramethylene, pentamethylene or hexamethylene group,
a C1-3-alkylamino or phenyl(C1-3-alkyl)amino group substituted by
a C4-6-alkylsulphonyl group or by a phenyl (C1-3-alkyl) sulphonyl
group,
an amino or C1-3-alkylamino group substituted by a
naphthalenesulphonyl group optionally substituted in the
naphthalene ring by a di(C1-3-alkyl)amino group or by one or two
C1-3-alkoxy groups,
a pyridazin-3-one or dihydro-pyridazin-3-one group optionally
substituted in the 2-position by an optionally phenyl-
substituted C1-3alkyl group and optionally additionally
substituted at a carbon atom by 1 or 2 C1-3 alkyl groups,
a pyrrolidino, piperidino or hexamethyleneimino group
substituted by two C1-3-alkyl groups,
a 7-nitrobenzofurazan-4-yl-amino (C2-3-alkanoyl)amino group,
a heptamethyleneimino, 1H,3H-quinazolin-2,4-dion-3-yl,
pentamethylene-oxazolin-2-yl, benzofuran-carbonylamino or
7-nitro-benzofurazan-4-yl-amino group, or
if R3 represents a carboxy group and R2 represents an n-butyl
group, R1 in the 6-position may also represent an



116a
amino group substituted by a phenylsulphonyl,
cyclohexylmethylaminocarbonyl, 2-carboxycyclohexyl-
methylcarbonyl, 2-tert.butoxycarbonyl-cyclohexylmethylcarbonyl,
2-carboxy-3,4,5,6-tetrahydrobenzoyl, N-methyl-



117
phenylaminocarbonyl or 3-cyclohexylpropyl group, a
methylamino group substituted by a propylsulphonyl,
phenylsulphonyl, methylphenylsulphonyl or chlorophenyl-
sulphonyl group, an n-pentylamino group substituted by a
phenylsulphonyl or methoxyphenylsulphonyl group, an n-
propylamino group substituted by a methylphenylsulphonyl
or methoxyphenylsulphonyl group, an isopropylamino group
substituted by a benzoyl or chlorophenylsulphonyl group,
an N-acetyl-cyclohexylmethylamino, 3,4,5,6-tetrahydro-
phthalimido, hexahydrohomophthalimido, N-
methanesulphonyl-2-phenylethylamino, N-chlorophenyl-
sulphonyl-benzylamino, piperidino, 4-methyl-piperidino
or hexamethyleneimino group, or
if R3 represents a carboxy group and R2 represents an n-
butyl group, R1 in the 5- or 6-position may also
represent a 2-oxo-1,2-dihydro-3,4-tetramethylene-
pyrrolidin-1-yl group, or
if R3 represents a carboxy group and R2 represents a
methyl, ethyl, n-propyl, n-butyl or methylmercapto
group, R1 in the 6-position may also represent a
pyrrolidino-carbonylamino group, or
if R3 represents a tetrazolyl group and R2 represents
an n-butyl group, R1 in the 5- or 6-position may also
represent an n-pentylamino group substituted by a
methyl-aminocarbonyl or cyclohexylaminocarbonyl group
and R1 in the 6-position may represent a 3,3-dimethyl-
glutaric acid imido or 4,4-tetramethylene-glutaric acid
imido group, or
if R3 represents a tetrazolyl group and R2 represents
an ethyl or n-propyl group, R1 in the 6-position may also
represent an N-benzenesulphonyl-methylamino group, or



118
if R3 represents a tert.butoxycarbonyl group and R2 represents
an n-butyl group, R1 in the 6-position may also represent a 2-
carboxycyclohexylmethylcarbonylamino or
pyrrolidinocarbonylamino group;
R2 represents a hydrogen atom or a straight-chained or branched
C1-5-alkyl group in which a methylene group may optionally be
replaced by a sulphur atom;
R3 represents a carboxy, cyano, 1H-tetrazolyl or
1-triphenylmethyl-tetrazolyl group or a (C1-4-alkoxy)carbonyl
group; and
R4 represents a hydrogen, fluorine, chlorine or bromine atom);
and isomers and salts thereof, and the compounds 4'-[[2-n-
butyl-6-(piperidin-1-yl)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid and 4'-[[2-n-butyl-6-(4-methylpiperidin-1-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid.
2. A compound of Formula I as claimed in claim 1 wherein
R1 represents a tetrahydrobenzimidazolyl or imidazopyridinyl
group,
a benzimidazolyl group optionally substituted in the phenyl
nucleus by a fluorine, chlorine or bromine atom, or by a
methyl, methoxy or trifluoromethyl group, and in which the
NH-group of the above-mentioned imidazole rings may
additionally be substituted by a C-16-alkyl group or by a C3-6-
cycloalkyl group,
a benzoxazol-2-yl group optionally substituted by a methyl
group,
an amino group substituted by a bicyclohexylcarbonyl,
biphenylcarbonyl or benzofuryl-2-carbonyl group, an



119
aminocarbonylamino group substituted in the 3-position by a
bicyclohexyl or biphenyl group,
a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group
optionally substituted by one or two methyl groups or by a
tetramethylene or pentamethylene group wherein a methylene
group is replaced by a carbonyl or sulphonyl group,
a 3,4,5,6-tetrahydro-2(1H)-pyrimidinone group optionally
substituted by a methyl or benzyl group,
a maleic acid amido or maleic acid imido group optionally
substituted by one or two substituents which may be the same or
different selected from methyl and phenyl groups,
an imidazolin-2-yl or imidazol-2-yl group substituted in the
1-position by a C1-6-alkyl group or by a C3-7-cycloalky group,
an imidazolidinedione group optionally substituted by a methyl,
benzyl, tetramethylene or pentamethylene group,
a methylamino or benzylamino group substituted by a
butanesulphonyl group or by a phenylmethanesulphonyl group,
an amino or methylamino group substituted by a
naphthalenesulphonyl group in which the naphthalene ring may be
substituted by a dimethylamino group or by 2 methoxy groups,
a pyridazin-3-one or dihydro-pyridazin-3-one group optionally
substituted by a methyl or benzyl group,
a pyrrolidino, piperidino or hexamethyleneimino group
substituted by two methyl groups,
a heptamethyleneimino, 1H,3H-quinazolin-2,4-dion-3-yl,



119a
4,5-pentamethylene-oxazolin-2-yl, 7-nitro-benzofurazan-4-yl-
amino or 7-nitro-benzofurazan-4-yl-aminopropionylamino group,
or if R3 represents a carboxy group and R2 represents an n-butyl
group, R1 in the 6-position may also represent an amino group
substituted by a phenylsulphonyl,
cyclohexylmethylaminocarbonyl, 2-carboxycyclohexyl-
methylcarbonyl, 2-tert.-butoxycarbonyl-
cyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6-tetrahydrobenzoyl,
N-methyl-phenylaminocarbonyl or 3-cyclohexylpropyl group, a
methylamino group substituted by a propylsulphonyl,
phenylsulphonyl, 4-methylphenylsulphonyl or
4-chlorophenylsulphonyl group, an n-pentylamino group
substituted by a phenylsulphonyl or 4-methoxyphenylsulphonyl
group, an propylamino group substituted by a



-120-
4-methylphenylsulphonyl or 4-methoxyphenylsulphonyl
group, an isopropylamino group substituted by a benzoyl
or 4-chlorophenylsulphonyl group, an N-acetyl-
cyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido,
hexahydrohomophthalimido, N-methanesulphonyl-2-
phenylethylamino, N-(4-chlorophenylsulphonyl)-
benzylamino, piperidino, 4-methyl-piperidino or
hexamethyleneimino group, or
if R3 represents a carboxy group and R2 represents an
n-butyl group, R1 in the 5- or 6-position may also
represent a 2-oxo-1,2-dihydro-3,4-tetramethylene-
pyrrolidin-1-yl group, or
if R3 represents a carboxy group and R2 represents a
methyl, ethyl, n-propyl, n-butyl or methylmercapto
group, R1 in the 6-position may also represent a
pyrrolidino-carbonylamino group, or
if R3 represents a tetrazolyl group and R2 represents
an n-butyl group, R1 in the 5- or 6-position may also
represent an n-pentylamino group substituted by a
methylaminocarbonyl or cyclohexylaminocarbonyl group and
R1 in the 6-position may also represent a 3,3-dimethyl-
glutaric acid imido or 4,4-tetramethylene-glutaric acid
imido group, or
if R3 represents a tetrazolyl group and R2 represents
an ethyl or n-propyl group, R1 in the 6-position may also
represent an N-benzenesulphonyl-methylamino group, or
if R3 represents a tert.butoxycarbonyl group and R2
represents an n-butyl group, R1 in the 6-position may
also represent a 2-carboxy-cyclohexylmethylcarbonylamino
or pyrrolidinocarbonylamino group;



121
R2 represents a hydrogen atom or a straight-chained or
branched C1-4-alkyl group in which a methylene group may
be replaced by a sulphur atom;
R3 represents a carboxy, cyano, 1H-tetrazolyl or 1-
triphenylmethyl-tetrazolyl group or a (C1-4 alkoxy)-
carbonyl group; and
R4 represents a hydrogen, fluorine, chlorine or bromine
atom;
and the 1-, 3-isomer mixtures and salts thereof with
organic or inorganic acids or bases.
3. A compound of formula I as claimed in claim 1 or
claim 2 wherein
R1 in the 6-position represents a 1-methylbenzimidazol-2-
yl, 3,4,5,6-tetrahydro-phthalimino, 2,3-diphenyl-maleic
acid imido, 2,3-dimethyl-maleic acid imido, N-phenyl-
methanesulphonyl-methylamino, 2-oxo-pyrrolidin-1-yl, 2-
oxo-piperidin-1-yl, 2-oxo-hexamethyleneimino, 2-oxo-3,4-
tetramethylene-pyrrolidin-2-yl, 3,3-dimethylglutarimido,
N-methylaminocarbonyl-n-pentylamino, propanesultam-1-yl
or butanesultam-1-yl group;
R2 represents a methyl, ethyl, n-propyl or n-butyl group;
R3 represents a carboxy or 1H-tetrazolyl group; and
R4 represents a hydrogen atom;
and the salts thereof with organic or inorganic acids or
bases.
4. A compound as claimed in any one of claims 1 to 3
being



-122-
4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid;
4'-[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid;
4'-[[2-n-butyl-6-(2,3-diphenyl-maleic acid imido)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid;
4'-[[2-n-butyl-6-(2,3-dimethyl-maleic acid imido)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid;
4'-[[2-n-butyl-6-(N-phenylmethanesulphonyl-methylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid;
4'-[[2-n-butyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-y1)-biphenyl;
4'[[2-n-butyl-6-(2-oxo-pyrralidin-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl;
4'-[[2-n-butyl-6-(2-oxo-hexamethyleneimino)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl;
4'-[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazol-
1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl;
4'-[[2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl;
4'-[[2-n-butyl-6-(cyclohexylaminocarbonyl-n-
pentylamino)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-
yl)-biphenyl;
4'-[[2-n-butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-1-
yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid;



-123-
4'-[[2-n-butyl-6-(propanesultam-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl;
4'-[[2-n-propyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl;
4'-[[2-n-butyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl;
4'-[[2-n-propyl-6-(1-methyl-benzimidazol-2-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl;
or
4'-[[2-n-propyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl:
or a salt thereof with an organic or inorganic acid or
base.
5. A compound as claimed in any one of claims 1 to 4
being a physiologically acceptable salt of a compound of
formula I.
6. A process for the preparation of compounds as claimed
in any one of claims 1 to 5, said process comprising at least.
one of the following steps:
a) cyclising a compound of formula II
Image
(wherein
R1 is as defined in any one of claims 1 to 4;



-124-



one of the groups X1 or Y1 represents a group of formula

Image

and the other group X1 or Y1 represents a group of
formula

Image

R2, R3 and R4 are as defined in any one of claims 1 to 4,
R5 represents a hydrogen atom or an R2CO group:
Z1 and Z2, which may be the same 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 imino group optionally substituted by a C1-3-alkyl
group, or a C2-3-alkylenedioxy or C2-3alkylenedithio group,
with the proviso that one of the groups X1 or Y1 must
represent a group of formula

Image



-125-



Image

or an N-oxide thereof
and optionally subsequently reducing a cyclized N-oxide
thus obtained;
b) reacting a benzimidazole of formula III

Image

(wherein
R1 and R2 are as defined in any one of claims 1 to 4),
with a biphenyl compound of formula IV

Image

(wherein
R3 and R4 are as defined in any one of claims 1 to 4; and
Z3 represents a nucleophilic leaving group);
c) (to prepare a compound of formula I wherein R3
represents a carboxy group)
converting a compound of formula V

Image




-126-



(wherein
R2 and R4 are as defined in any one of claims 1 to 4;
R1' is a group R10 as defined in any one of claims 1 to 4
or a 3-((C1-3alkoxy)carbonyl)propionyl or 3-((C1-3-
alkoxy)carbonyl)-2-methylpropionyl group; and
R3' represents a group which may be converted into a
carboxy group by hydrolysis, thermolysis or
hydrogenolysis) unto a corresponding carboxy compound:
or
d) (to prepare a compound of formula T wherein R3
represents a 1H-tetrazolyl group) cleaving a protecting
group from a compound of formula VI

Image

(wherein
R1, R2 and R4 are as defined in any one of claims 2 to 4:
and
R3" represents a 1H-tetrazolyl group protected in the 1-
or 3-position by a protecting group);
e) (to prepare a compound of formula I wherein R3
represents a 1H-tetrazolyl group) reacting a compound of
formula VII

Image



-127-


(wherein
R1, R2 and R4 are as defined in any one of claims 1 to 4)
with hydrazoic acid or a salt thereof:
f) (to prepare compounds of formula I wherein R1
represents a pentamethylene-oxazolin-2-yl group)
reacting a compound of formula VIII

Image

(wherein
R2, R3 and R4 are as defined in any one of claims 1 to
with 1-aminomethyl-cyclohexanol in the presence of an
acid-activating agent:
g) (to prepare a compound of formula I wherein R1
represents a 2-oxo-3,4-tetramethylene-pyrrolidin-1-yl
group) hydrogenating a compound of formula IX

Image

(wherein
R2, R3 and R4 are as defined in any one of claims 1 to
4);
h) (to prepare compounds of formula I wherein R1
represents an amino group substituted by a



-128-



bicyclohexylcarbonyl or biphenylcarbonyl group, which
may additionally be substituted at the N-atom by a
alkyl group, an aminocarbonylamino group substituted by
a bicyclohexyl or biphenyl group and optionally
additionally substituted by one or two C1-3-alkyl groups
at the N-atom, a maleic acid amido or maleic acid imido
group optionally mono- or disubstituted by substituents
selected from C1-3-alkyl and phenyl groups, a C1-3-
alkylamino or phenyl (C1-3alkyl) amino substituted by a C4-6-
alkylsulphonyl group or by a phenyl(C1-3-alkyl)sulphonyl
group, an amino or C1-3alkylamino group substituted by a
naphthalenesulphonyl group and optionally substituted in
the naphthalene ring by a di(C1-3alkyl)amino group or by
one or two C1-3-alkoxy groups, a 7-nitro-benzofurazan-4-
yl-amino(C2-3alkanoyl)amino group, a benzofurancarbonyl-
amino or 7-nitro-benzofurazan-4-yl-amino group, or
if R3 represents a carboxy group and R2 represents an
n-butyl group, R1 in the 6-position may also represent an
amino group substituted by a phenylsulphonyl,
cyclohexylmethylaminocarbonyl, 2-carboxycyclo-
hexylmethylcarbonyl, 2-tert.-butoxycarbonyl-
cyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6-
tetrahydrobenzoyl, N-methyl-phenylaminocarbonyl or 3-
cyclohexylpropyl group, a methylamino group substituted
by a propylsulphonyl, phenylsulphonyl,
methylphenylsulphonyl or chlorophenylsulphonyl group, an
n-pentylamino group substituted by a phenylsulphonyl or
methoxyphenylsulphonyl group, an n-propylamino group
substituted by a methylphenylsulphonyl or methoxyphenyl-
sulphonyl group, an isopropylamino group substituted by
a benzoyl or chlorophenylsulphonyl group, an N-acetyl-
cyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido,
hexahydrohomophthalimido, N-methanesulphonyl-2-
phenylethylamino or N-chlorophenylsulphonyl-benzylamino
group, or


-129-



if R3 represents a carboxy group and R2 represents an
n-butyl group, R1 in the 5- or 6-position may also
represent a 2-oxo-1,2-dihydro-3,4-tetramethylene-
pyrrolidin-1-yl group, or
if R3 represents a carboxy group and R2 represents a
methyl, ethyl, n-propyl, n-butyl or methylmercapto
group, R1 in the 6-position may also represent a
pyrrolidino-carbonylamino group, or
if R3 represents a tetrazolyl group and R2 represents
an n-butyl group, R1 in the 5- or 6-position may also
represent an n-pentylamino group substituted by a
methylamino-carbonyl or cyclohexylaminocarbonyl group
and R1 in the 6-position may also represent a 3,3-
dimethyl-glutaric acid imido or 4,4-tetramethylene-
glutaric acid imido group, or
if R3 represents a tetrazolyl group and R2 represents
an ethyl or n-propyl group, R1 in the 6-position may also
represent an N-benzenesulphonyl-methylamino group, or
if R3 represents a tert.-butoxycarbonyl group and R2
represents an n-butyl group, R1 in the 6-position may
also represent a 2-carboxy-cyclohexylmethylcarbonylamino
or pyrrolidinocarbonylamino group) reacting a compound
of formula X

Image
(wherein



-130-



R2, R3 and R4 are as defined in any one of claims 1 to 4;
and
R6 represents a hydrogen atom, an n-pentyl, cyclohexyl-
methyl, C1-3-alkyl or phenyl (C1-3alkyl) group) with a
compound of formula XI

Z4 - W - R7 (XI)

(wherein
Z4 represents a nucleophilic leaving group;
W represents a -CO- or -SO2- group; and
R7 represents a 2-hydroxycarbonyl-ethenyl group wherein
the ethenyl moiety is mono- or disubstituted by
substituents selected from C1-3-alkyl and phenyl groups,
a C3-6-alkyl group, a phenyl (C1-3alkyl) group, a
naphthalene group optionally substituted by a di(C1-3-
alkyl)amino group or by one or two C1-3alkoxy groups, a
methyl, phenyl, methylphenyl, methoxyphenyl,
chlorophenyl, biphenyl, bicyclohexyl, 2-carboxy-
cyclohexylmethyl, 2-carboxy-3,4,5,6-tetrahydrophenyl, 3-
carboxy-1,1-dimethyl-propyl, 3-carboxy-2,2-
tetramethylene-propyl, 7-nitro--benzofurazan-4-yl-
aminomethyl or 7-nitro-benzofurazan-4-yl-aminoethyl
group, arid
where W represents a -CO- group, R7 may also represent an
R8NR9 group wherein
R8 represents a hydrogen atom or a C1-3-alkyl group,
R9 represents a methyl, cyclohexyl,
cyclohexylmethyl, phenyl, biphenyl or bicyclohexyl
group, or
R8 and R9 together with the nitrogen atom between
them represent a pyrrolidino group, or



-131-



Z4 together with R9 represents another carbon-
nitrogen bond, and
R7 together with W may also represent a 7-nitro-
benzofurazan-4-yl-amino group) or with a reactive
derivative of a carboxylic acid of formula XI;
i) (to prepare compounds of formula I wherein R1
represents a tetrahydrobenzimidazolyl or
imidazopyridinyl group, a benzimidazolyl group
optionally substituted in the phenyl nucleus by a
fluorine, chlorine or bromine atom, by a C1-3-alkyl
group, by a C1-3-alkoxy group or by a trifluoromethyl
group, and in which the NH-group of the above-mentioned
imidazole rings may additionally be substituted by a
C1-6-alkyl group or by a C3-7-cycloalkyl group, a
hydroxy(C5-7-cycloalkyl)aminocarbonyl group, which may
additionally be substituted at the N-atom by a C1-3-alkyl
group, or a straight-chained or branched hydroxy(C4-6-
alkyl)aminocarbonyl group) reacting a compound of
formula XII

Image

(wherein
R2, R3 and R4 are as defined in any one of claims 1 to 4)
or a reactive derivative thereof with an amine of
formula XIII

Image


-132-



(wherein
R10 represents a hydrogen atom, a cycloalkyl group or a
C1-6-alkyl group; and
R11 represents a C4-6-hydroxyalkyl group, a C5-7 hydroxy-
cycloalkyl group or a 2-aminophenyl group which may be
substituted in the phenyl nucleus by a fluorine,
chlorine or bromine atom, by a C1-3-alkyl group, by a C1-3-
alkoxy group or by a trifluoromethyl group, a 2-
aminocyclohexyl or 2-aminopyridyl group) optionally with
simultaneous decarboxylation;
j) (to prepare compounds of formula I wherein R1
represents a dihydro-pyridazin-3-one or pyridazin-3-one
group which may be substituted in the 2-position by an
optionally phenyl-substituted C1-3-alkyl group or at a
carbon atom by one or two C1-3-alkyl groups) reacting a
carboxylic acid of formula XIV

Image

(wherein
R1, R2, R3 and R4 are as defined in any one of claims 1 to
4; and
A represents an ethylene or ethenylene group optionally
substituted by one or two C1-3-alkyl groups) or a
reactive acid derivative thereof with a hydrazine of
formula XV

H2N-NHR12 (XV)

(wherein
R12 represents a hydrogen atom or an optionally phenyl-
substituted C1-3-alkyl group);



133



(k) resolving a 1-, 3-isomer mixture of a compound of
formula I thus obtained by isomer separation into the 1- and
3-isomers thereof;
(l) converting a compound of formula I thus obtained
into a salt thereof or a salt of a compound of formula I into
the free compound; and
(m) carrying out a reaction according to any one of
said steps (a) to (l) in which one or more groups are protected
by a protecting group and subsequently removing any protecting
group used.
7. A pharmaceutical composition comprising a compound of
formula I as claimed in any one of claims 1 to 4 or a
physiologically acceptable salt thereof with the proviso that
each of R1, R2, R3 and R4 is not a tert.butoxycarbonyl group, a
cyano group or a 1-triphenylmethyl-tetrazolyl group, together
with at least one pharmaceutical carrier or exipient.
8. Use of a compound of formula I as claimed in any one
of claims 1 to 4 or a physiologically acceptable salt thereof
with the proviso that each of R1, R2, R3 and R4 is not a
tert.butoxycarbonyl group, a cyano group or a 1-
triphenylmethyl-tetrazolyl group, for the manufacture of a
therapeutic agent for the treatment of hypertension, cardiac
insufficiency, ischaemic peripheral circulatory disorders,
myocardial ischaemia (angina), for the prevention of cardiac
insufficiency progression after myocardial infarct, or for the
treatment of diabetic nephropathy, glaucoma, gastrointestinal
diseases and bladder diseases.
9. Use of a compound of formula I as claimed in any one
of claims 1 to 4 or a physiologically acceptable salt thereof
with the proviso that each of R1, R2, R3 and R4 is not a
tert.butoxycarbonyl group, a cyano group or a 1-


134

triphenylmethyl-tetrazolyl group, for the treatment of
hypertension, cardiac insufficiency, ischaemic peripheral
circulatory disorders, myocardial ischaemia (angina) cardiac
insufficiency progression following myocardial infarction,
diabetic nephropathy, glaucoma, gastrointestinal diseases and
bladder diseases.

Description

- 1 -
56-779.532
Benzimidazoles
The present invention relates to new benzimidazoles,
processes for their preparation and pharmaceutical..,
compositions containing them.
US-A-4,880,804 describes inter alia 4'-[(2-alkyl-
benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acids
and 4'-[(2-alkyl-benzimidazol-1-yl}-methyl]-2-(2H-
tetrazol-5-yl)-biphenyls which are substituted in the
benzimidazole ring by an alkanoylaminomethyl group and
which are angiotension-II antagonists.
It has now been found that certain new benzimidazoles
are even more useful angiotensin antagonists,
particularly angiotensin-II antagonists.
Thus, according to one aspect the present invention
provides compounds of formula I
,, N
Rt \ ~ / R2 ( I )
N R3
R4
1
(wherein
R~ represents a tetrahydrobenzimidazolyl or imidazo-
pyridinyl group, a benzimidazolyl or benzoxazolyl group
optionally substituted in the phenyl nucleus by a
fluorine, chlorine or bromine atom, by a C~_3-alkyl
group, by a C~_3-alkoxy group or by a trifluoromethyl
group, and in which the NH-group of the above-mentioned
imidazole rings may additionally be substituted by a
C~_b-alkyl group or by a C3_7-cycloalkyl group, an amino


CA 02047496 2001-O1-19
27169-190
2
group substituted by a bicyclohexylcarbonyl or biphenylcarbonyl
group, which may additionally be substituted at the N-atom by a
C1_3 alkyl group, an aminocarbonylamino group substituted by a
bicyclohexyl or bipheny_L group and optionally also substituted
by one or two C1_3-alkyl ~~roups at the N-atom, with the
exception of the 2-oxo-3,4-tetramethylene-pyrrolidin-1-yl
group, a 5-, 6- or 7-mernbered alkyleneimino or alkenyleneimino
group optionally substit=uted by one or two C1_3-alkyl groups or
by a tetramethylene or pentamethylene group, in which a
methylene group is replacJed by a carbonyl or sulphonyl group, a
3,4,5,6-terahydro-2(1H)--pyrimidinone group optionally
substituted by a C1_,3-alkyl or phenyl (C1_3-alkyl) group, a
malefic acid amido or ma:~E~ic acid imido group optionally mono-
or disubstituted by a C1_3-alkyl or by a phenyl group, in which
the substituents may be identical or different, an imidazoline
or imidazole group optionally substituted by a C1_6-alkyl group
or by a C3_~-cycloalkyl group, an imidazolidinedione group
optionally substituted by a C1_3-alkyl group, by a phenyl
(C1_3-alkyl) group or by a tetramethylene, pentamethylene or
hexamethylene group, a C:z_3-alkylamino or phenyl
(C1_3-alkyl) amino group :>ubstituted by a C4_6-alkylsulphonyl
group or by a phenyl (Cl_3-alkyl)sulphonyl group, an amino or
C1_3-alkylamino group substituted by a naphthalenesulphonyl
group optionally substituted in the naphthalene ring by a
di (C1_3-alkyl) amino group or by one or two C1_3-alkoxy groups, a
pyridazin-3-one or dihydro-pyridazin-3-one group optionally
substituted in


CA 02047496 2001-O1-19
27169-190
3
the 2-position by an optionally phenyl-substituted C
alkyl group and optionally additionally substituted at a
carbon atom by 1 or 2 C~_3-alkyl groups, a pyrrolidino,
piperidino or hexamethyleneimino group substituted by
two C~_3-alkyl croup:>, a 7-nitrobenzofurazan-4-yl-
amino(C2_3-alkanoyl)amino group, a heptamethyleneimino,
1H,3H-quinazolin-2,4-dion-3-yl, pentamethylene-oxazolin-
2-yl, benzofuran-carbonylamino or 7-nitro-benzofurazan-
4-yl-amino group, or
if R3 represents a carboxy group and RZ represents an
n-butyl group, R~ i.n the 6-position may also represent an
amino group substitu~t~ed by a phenylsulphonyl,
cyclohexylmethylaminocarbonyl, 2-carboxycyclohexyl-
methy.lcarbonyl, 2-te~rt.butoxycarbonyl-cyclohexylmethyl-
carbonyl, 2-carboxy-3,4,5,6-tetrahydrobenzoyl, N-methyl-
phenylaminocarbonyl or 3-cyclohexylpropyl group, a
methylamino group substituted by a propylsulphonyl,
phenylsulphonyl, methylphenylsulphonyl or chlorophenyl-
sulphonyl group, an n-pentylamino group substituted by a
phenylsulphonyl or methoxyphenylsulphonyl group, an n-
propylamino group substituted by a methylphenylsulphonyl
or methoxyphenylsulp:honyl group, an isopropylamino group
substituted by a benzayl or chlorophenylsulphonyl group,
an N-acetyl-cyclohexylmethylamino, 3,4,5,6-tetrahydro-
phthalimido, hexahyd:rohomophthalimido,
N-methanesulphonyl-2-phenylethylamino, N-chlorophenyl-
sulphonyl-benzylamino, piperidino, 4-methyl-piperidino
or hexamethyleneimino group, or
if Rj represents a carboxy group and R2 represents an
n-butyl group, R~ in the 5- or 6-position may also
represent a 2-oxo-1,?.-dihydro-3,4-tetramethylene-
pyrrolidin-1-yl group, or
if R3 represents a carboxy group and RZ represents a


CA 02047496 2001-O1-19
27169-190
4
methyl, ethyl, n-propyl, n-butyl, or methylmercapto group, R1 in
the 6-position may also represent a pyrrolidino-carbonylamino
group, or
if R3 represent=s a tetrazolyl group and R2. represents
an n-butyl group, R1 in t=he 5- or 6-position may also represent
an n-pentylamino group substituted by a methyl-aminocarbonyl or
cyclohexylaminocarbonyl_ group., and R1 in the 6-position may also
represent a 3,3-dimethyl-gl.utaric acid imido or
4,4-tetramethylene-gluta:ric acid imido group, or
if R3 represent:: a tetrazolyl group and RZ represents
an ethyl or n-propyl group, R1 in the 6-position may also
represent an N-benzenesu:l:phonyl-methylamino group, or
if R3 represents a tert.butoxycarbonyl group and RZ
represents an n-butyl group, R1 in the 6-position may also
represent a 2-carboxycyc:iohexylmethylcarbonylamino or
pyrrolidinocarbonylamino !group;
R2 represents a hydrogen atom or a straight-chained or
branched C1_5-alkyl group in which a methylene group may
optionally be replaced by a sulphur atom;
R3 represents a. carboxy, cyano, 1H-tetrazolyl or
1-triphenylmethyl-tetrazolyl group or a (C1_4-alkoxy)carbonyl
group; and
R4 represents a hydrogen, fluorine, chlorine or
bromine atom); and isomers, especially the 1-, 3-isomer
mixtures, and salts thereof, in particular, for pharmaceutical
use the physiologically acceptable salts thereof with organic
or inorganic acids or bares, and the compounds 4'-[[2-n-butyl-
6- (piperidin-1-yl) -benzirn_idazol-1-yl] methyl] biphenyl-2-


CA 02047496 2001-O1-19
27169-190
4a
carboxylic acid and 4'-[[2-n-butyl-6-(4-methylpiperidin-1-yl)-
benzimidazol-1.-yl]methyl]biphenyl-2-carboxylic acid. The
following are examples of the definitions of the




- 5 -
groups R~ and RZ as mentioned hereinbefore:
R~ may represent a 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-n-pentyl-benzimidazol-2-
yl, 2-n-hexyl-benzimidazol-2-yl, 1-cyclopropyl-
benzimidazol-2-yl, 1-cyclopentyl-benzimidazol-2-yl, 1-
cyclohexyl-benzimidazol-2-yl, 1-cycloheptyl-
benzimidazol-2-yl, 1,5-dimethyl-benzimidazol-2-yl, 1,6-
dimethyl-benzimidazol-2-yl, 1-methyl-5-methoxy-
benzimidazol-2-yl, 1-methyl-5-fluoro-benzimidazol-2-yl,
1-methyl-5-chloro-benzimidazol-2-yl, 1-methyl-5-bromo-
benzimidazol-2-yl, 1-methyl-5-trifluoromethyl-
benzimidazol-2-yl, tetrahydro-benzimidazol-2-yl, 1-
methyl-tetrahydro-benzimidazol-2-yl, 1-ethyl-tetrahydro-
benzimidazol-2-yl, 1-n-propyl-tetrahydro-benzimidazol-2-
yl, 1-isopropyl-tetrahydro-benzimidazol-2-yl, 1-n-butyl-
tetrahydro-benzimidazol-2-yl, 1-n-pentyl-tetrahydro-
benzimidazol-2-yl, 7.-n-hexyl-tetrahydro-benzimidazol-2-
yl, 1-cyclopropyl-tetrahydro-benzimidazol-2-y1, 1-
cyclopentyl-tetrahydro-benzimidazol-2-yl, 1-cyclohexyl-
tetrahydro-benzimidazol-2-yl, 1-cycloheptyl-tetrahydro-
benzimidazol-2-yl, benzoxazol-2-yl, 5-methyl-benzoxazol-
2-yl, 5-methoxy-benzoxazol-2-yl, 5-trifluoromethyl-
benzoxazol-2-yl, 5-fluoro-benzoxazol-2-yl, 5-chloro-
benzoxazol-2-yl, 5-bromo-benzoxazol-2-yl, 4-biphenylyl-
carbonylamino, 4-cyclohexylcarbonylamino, N-methyl-4-
biphenylylcarbonylamino, N-ethyl-4-cyclohexylcarbonyl-
amino, N-n-propyl-4-biphenylylcarbonylamino, N-
isopropyl-4-cyclohexylcarbonylamino, 2-hydroxy-
cyclopentylamino, 2-hydroxy-cyclohexylamino, 2-hydroxy-
cycloheptylamino, 3-hydroxy-cyclopentylamino, 3-hydroxy-
cyclohexylamino, 3-hydroxy-cycloheptylamino, ~-hydroxy-
cyclohexylamino, 4-hydroxy-cycloheptylamino, N-methyl-2-
hydroxy-cyclopentylamino, N-ethyl-2-hydroxy-
cyclahexylamino, N-~.sopropyl-2-hydroxy-cycloheptylamino,




a ~~ ~ ~.~ f,
'::i e3
- 6 -
N-methyl-3--hydroxy-cyclopentylamino, N-ethyl-3-hydroxy-
cyclohexylamino, N-n-propyl-3-hydroxy-cycloheptylamino,
N-methyl-4-hydroxy-cyclohexylamino, N-ethyl-4-hydroxy-
cycloheptylamino, 4-biphenylylaminocarbonylamino, 4-
bicyclohexylaminacarbonylamina, N-(4-biphenylylamino-
carbonyl)-methylamino, N-(4-bicyclohexylaminocarbonyl)-
methylamino, N-(methyl-4-biphenylylaminocarbonyl)-
methylamino, N-(methyl-4-bicyclohexylaminocarbonyl)-
methylamino, N-(4-?aiphenylylaminocarbonyl)-ethylamino,
N-(4-bicyclohexylaminocarbonyl)-isopropylamino, N-
(ethyl-4-biphenylylaminocarbonyl)-methylamino, N-
(methyl-4-bicyclohexylaminocarbonyl)-ethylamino,
pyrrolidin-2-on-1-y1, piperidin-2-on-2-yl,
hexamethyleneimino-2-on-1-yl, propanesultam-1-y1,
butanesultam-1-yl, pentanesultam-1-yl, 3,4,5,6-
tetrahydro-2(1H)-pyrimidon-1-yl, 3-methyl -3,4,5,6-
tetrahydro-2(1H)-pyrimidon-1y1, 3-ethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidon-1-yl, 3-n-propyl-3,4,5,6-
tetrahydro-2(1.H)-pyrimidon-1-yl, 3-isopropyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidon-1-yl, 3-benzyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidon-1-yl, 3-(2-phenylethyl)-
3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl, 3-(3-
phenylpropyl)-3,4,5,6-tetrahydro'-2(1H)-pyrimidon-1-yl;
4-hydroxybutylamino, 5-hydroxypentylamino, 6-hydroxy-
hexylamino, malefic acid imido, 2-methyl-malefic acid
imido, 2-phenyl-malefic acid imido, 2,3-dimethyl-malefic
acid imido, 2,3-Biphenyl-malefic acid imido, 2-methyl-
malefic acid amido, 3-methyl-malefic acid amido, 2,3-
dimethyl-malefic acid amido, 2-phenyl-malefic acid amido,
3-phenyl-malefic acid amido, 2,3-Biphenyl-malefic acid
amido, 3-methyl-2-phenyl-malefic acid amido, 2-methyl-3-
phenyl-malefic acid amido, imidazolin-2-yl, 1-methyl -
imidazolin-2-yl, 1-ethyl-imidazolin-2-yl, 1-propyl-
imidazolin-2-yl; imidazolidin-2,4-dion-3-yl, 5-methyl-
imidazolidin-2,4-lion-3-yl, 5-ethyl-imidazolidin-2,4-
dion-3-yl, 5-n-propyl-imidazolidin-2,4-dion-3-yl, 5-
benzyl-imidazolidin-2,4-dion-3-yl, 5-(2-phenylethyl)-




- ~ _ ~~~~~E~~~
imidazolidin-2,4-lion-3-yl, 5-(3-phenylpropyl)-
imidazolidin-2,4-dion-3-y1, 5,5-tetramethylene-
imidazolidin-2,4-dion-3-yl, 5,5-pentamethylene-
imidazolidin-2,4-dion-3-yl, 5,5-hexamethylene-
imidazolidin-2,4-dion-3-yl, 5,5-dimethyl-imidazolidin-
2,4-dion-3-yl, 5,5-diethyl-imidazolidin-2,4-dion-3-yl,
methanesulphonyloxy, ethanesulphonyloxy,
propanesulphonyloxy, butanesulphonyloxy, pentane-
sulphonyloxy, hexanesulphonyloxy, benzenesulphonyloxy,
p-toluenesulphonyloxy, N-n-butanesulphonyl-methylamino,
N-n-pentanesulphonyl-methylamino, N-n-hexanesulphonyl-
methylamino, N-phenylmethanesulphonyl-methylamino, N-(2-
phenylethanesulphonyl)-methylamino, N-(3-phenylpropane-
sulphonyl)-methylamino, N-n-butanesulphonyl-ethylamina;
N-n-pentanesulphonyl-isopropylamino, N-n-
hexanesulphonyl-ethylamino, N-phenylmethanesulphonyl-
ethylamino, N-(2-phenylethanesulphonyl)-n-propylamino,
N-(3-phenylpropanesulphonyl)-ethylamino, naphthalen-1-
sulphonylamino, naphthalen-2-sulphonylamino, 5-
dimethylamino-naphthalen-1-sulphonylamino, N-
(naphthalen-1-sulphonyl)-methylamino, N-(naphthalen-2-
sulphonyl)-ethylamino, N-(5-dimethylamino-naphthalen-1-
sulphonyl)-methylamino, N-(5-methoxynaphthalen-1-
sulphonyl)-methylamino, N-(5,6-dimethoxy-naphthalen-2-
sulphonyl)-ethylamino, 3-(imidazol-3-yl)-propoxy, 4-
(imidazol-1-yl)-butoxy, 5-(imidazol-1-yl)-pentoxy, 2-
(benzimidazol-1-yl)-ethoxy, 3-(benzimidazol-1-yl)-
propoxy, 4-(benzimidazol-1-yl)-butoxy, 5-(benzimidazol-
1-yl)-pentoxy, 2-(tetrahydrobenzimidazol-1-yl)-ethoxy,
3-(tetrahydrobenzimidazol-1-yl)-propoxy, 4-(tetrahydro-
benzimidazol-1-yl)-butoxy, 5-(tetrahydrobenzimidazol-1-
yl)-pentoxy, 4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-
methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-ethyl-4,5-
dihydro-2H-pyridazin-3-on-6-yl, 2-n-propyl-4,5--dihydro-
2H-pyridazin-3-on-6-yl, 2-isopropyl-4,5-dihydro-2H-
pyridazin-3-on-6-yl, 2-benzyl-4,5-dihydro-2H-pyridazin-
3-on-6-yl, 2-(2-phenylethyl)-4,5-dihydro-2H-pyridazin-3-



_ g
on-6-yl, 2-(3-phenylpropyl)-4,5-dihydro-2H-pyridazin-3-
on-6-yl, 4-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 5-
methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 4,4-dimethyl-
4,5-dihydro-2H-pyridazin-3-on-6-yl, 5,5-dimethyl-4,5-
dihydro-2H-pyridazin-3-on-6-yl, 4,5-dimethyl-4,5- -
dihydro-2H-pyridazin-3-on-6-yl, 2,4-dimethyl-4,5-
dihydro-2H-pyridazin-3-on-6-yl, 2,5-dime~thyl-4,5-
dihydro-2H-pyridazin-3-on-6-yl, 2,4,5-trimethyl-4,5-
dihydro-2H-pyridazin-3-on-6-yl, 2,4,4-trimethyl-4,5-
dihydro-2H-pyridazin-3-on-6-yl, 2,5,5-trimethyl-4,5-
dihydro-2H-pyridazin-3-on-6-yl, 2H-pyridazin-3-on-6-yl,
2-methyl-2H-pyridazin-3-on-6-yl, 2-ethyl-2H-pyridazin-3-
on-6-yl, 2-n-propyl-2H-pyridazin-3-on-6-yl, 2-isopropyl-
2H-pyridazin-3-on-6-yl, 2-benz~l-2H-pyridazin-3-on-6-yl,
2-(2-phenylethyl)--2H-pyridazin-3-on-6-yl, 2-(3-
phenylpropyl)-2H-pyridazin-3-on-6-yI, 4-methyl-2H-
pyridazin-3-on-6-yl, 5-methyl-2H-pyridazin-3-on-6-yl,
4,5-dimethyl-2H-pyridazin-3-on-6-yl, 2,4-dimethyl-2H-
pyridazin-3-on-6-yl, 2,5-dimethyl-2I-i-pyridazin-3-on-6-
yl, 2,4,5-trimethyl-2H-pyridazin-3-on-6-yl, 3,3-
dimethyl-pyrrolidino, 3,4-dimethyl-pyrrolidino, 3,3-
dimethyl-piperidino, 3,4-dimethylpiperidino, 4,4-
dimethyl-piperidino, 3,3-dimethyl-hexamethyleneimino,
3,4-dimethyl-hexamethyleneimino, 4,4-dimethylhexa-
methyleneimino, 3,5-dimethyl-hexamethyleneimino,
phenylsulphonylamino, cyclohexylmethylaminocarbonyl-
amino, 2-methylamino-benzoylamino, 2-carboxy-cyclohexyl-
methylcarbonylamino, 2-tert.butoxycarbonyl-
cyclohexylmethylcarbonylamino, 2-carboxy-3,4,5,6-
tetrahydrobenzaylamino, 3-cyclohexylpropylamino, N-
propylsulphonyl-methylamino, N-phenylsulphonyl-
methylamino, N-(4-methylphenylsulphonyl}-methylamino, N-
(4-chlorophenylsulphonyl)-methylamino, N-phenyl--
sulphonyl -n-pentylamino, N-(4-methoxyphenylsulphonyl)-n-
pentylamina, N-(4-methylphenylsulphonyl)-n-propylamino,
N-(4-methoxyphenylsulphonyl)-n-propylamino, N-benzoyl-
isopropylamino, N-(4-chlorophenylsulphonyl)-isopropyl-


CA 02047496 2000-11-29
27169-190
- g _
amino, N-acetyl-cyclohexylmethylamino, 3,4,5,6-
tetrahydrophthalimido, hexahydrophthalimido, N-methane-
sulphonyl-2-phenylethylamino, N-chlorophenylsulphonyl-
benzylamino, piperidino; 4-methyl-piperidino,
hexamethyleneimino, pyrrolidinocarbonylamino, N-
methylaminocarbonyl-n-pentylamino, N-cyclohexylamino-
carbonyl-n-pentylamino, 3,3-dimethyl-glutaric acid
imido, 4,4-tetramethylene-glutaric acid imido, 2-
carboxy-cyclohexylmethylcarbonylamino, 1-n-butyl-
imidazolin-2-yl, 1-n-pentyl-imidazolin-2-yl, 1-n-hexyl-
imidazolin-2-yl, 1-cyclopropyl-imidazolin-2-yl, 1-
cyclobutyl-imidazolin-2-yl, 1-cyclohexyl-imidazolin-2-
yl, 1-cycloheptyl-imidazolin-2-yl, imidazol-2-yl, 1-
methyl-imidazol-2-yl, 1-ethyl-imidazol-2-yl, 1-propyl-
imidazol-2-yl, 1-n-butyl-imidazol-2-yl, 1-n-pentyl-
imidazol-2-yl, 1-n-hexyl-imidazol-2-yl, 1-cyclopropyl-
imidazol-2-yl, 1-cyclobutyl-imidazol-2-yl, 1-cyclohexyl-
imidazol-2-yl or 1-cycloheptyl-imidazol-2-yl group; and
R2 may represent a hydrogen atom, a methyl, ethyl, n-
propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-
pentyl, 1-methylpropyl, 1-methylbutyl, 2-methylbutyl, 3-
methylbutyl, 1-ethylpropyl, 1,1-diethylethyl,
methylmercaptomethyl, 2-methylmercapto-ethyl, 3-
methylmercaptopropyl or 4-methylmercaptobutyl group.
Preferred compounds according to the invention include
those of formula I wherein
R~ represents a tetrahydrobenzimidazolyl or
imidazopyridinyl group, a benzimiaazolyl group
optionally substituted in the phenyl nucleus by a
fluorine, chlorine or bromine atom or by a methyl,
methoxy or trifluoromethyl group, and in which the NH-
group of the above-mentioned imidazole rings may
additionally be substituted by a C~_b-alkyl group or by a


CA 02047496 2000-11-29
27169-190
- 10 -
C3-6-cycloalkyl group, a benzoxazol-2-yl group optionally
substituted by a methyl group, an amino group
substituted by a bicyclohexylcarbonyl, biphenylcarbonyl
or benzofuryl-2-carbonyl group, an aminocarbonylamino
group substituted in the 3-position by a bicyclohexyl or
biphenyl group, a 5-, 6- or 7-membered alkyleneimino or
alkenyleneimino group optionally substituted by one or
two methyl groups or by a tetramethylene or
pentamethylene group wherein a methylene group is
replaced by a carbonyl or sulphonyl group, a 3,4,5,6-
tetrahydro-2(1H)-pyrimidinone group optionally
substituted by a methyl or~benzyl group, a malefic acid
~mido or malefic acid imido group optionally substituted
by one or two substituents which may be the same or different
selectea from methyl :end phc~tyl groups, an imidazolin-2-yl
or imidazol-2-yl group substituted in the 1-position by a
C~-6-alkyl group or by a C3-~-cycloalkyl group, an
imidazolidinedione group optionally substituted by a
- methyl, benzyl, tetramethylene or pentamethylene group,
a methylamino or benzylamino group substituted by a
butanesulphonyl group or by a phenylmethanesulphonyl
group, an amino or methylamino group~substituted by a
naphthalenesulphonyl group in which the naphthalene ring
may be substituted by a dimethylamino group or by 2
methoxy groups, a pyridazin-3-one or dihydro-pyridazin-
3-one group optionally substituted by a methyl or benzyl
group, a pyrrolidino, piperidino or hexamethyleneimino~
group substituted by two methyl groups, a
,heptamethyleneimino, 1H,3H-quinazolin-2,4-dion-3-yl,
4,5-pentamethylene-oxazolin-2-yl, 7-nitro-benzofurazan-
4-yl-amino, or 7- nitro-benzofurazan-4-yl-aminopropionylamino
group, or
if R3 represents a carboxy group and R2 represents an
n-butyl group, R~ in the 6-position may also represent an
amino group substituted by a phenylsulphonyl,


CA 02047496 2000-11-29
27169-190
- 11 -
cyclohexylmethylaminocarbonyl, 2-carboxycyclohexyl-
methylcarbonyl, 2-tert.-butoxycarbonyl-cyclohexyl-
methylcarbonyl, 2-carboxy-3,4,5,6-tetrahydrobenzoyl, N-
methyl-phenylaminocarbonyl or 3-cyclohexylpropyl group,
a methylamino group substituted by a propylsulphonyl,
phenylsulphonyl, 4-methyiphenylsulphonyl or 4-
chlorophenylsulphonyl group, an n-pentylamino group
substituted by a phenylsulphonyl or 4-methoxyphenyl-
sulphonyl group, an n-propylamino group substituted by a
4-methylphenylsulphonyl or 4-methoxyphenylsulphonyl
group, an isopropylamino group substituted by a benzoyl
or 4-chlorophenylsulphonyl group, an N-acetyl--
cyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido,
hexahydrohomophthalimido, N-methanesulphonyl-2-
phenylethylamino, N-(4-chlorophenylsulphonyl)-
benzylamino, piperidino, 4-methyl-piperidino or
hexamethyleneimino group, or
if R3 represents a carboxy group and R2 represents an
n-butyl group, R~ in the 5- or 6-position may also
represent a 2-oxo-1,2-dihydro-3,4-tetramethylene-
pyrrolidin-1-yl, group, or
if R3 represents a carboxy group and R2 represents a
methyl, ethyl, n-propyl, n-butyl or methylmercapto
group, R~ in the 6-position may also represent a
pyrrolidino-carbonylamino group, or
if R3 represents a tetrazolyl group and RZ represents
an n-~utyl group, R~ in the 5- or 6-position may also
represent an n-pentylamino group substituted by a
methylaminocarbonyl or cyclohexylaminocarbonyl group and
R1 in the 6-position may also represent a 3,3-dimethyl-
glutaric acid imido or 4,4-tetramethylene-glutaric acid
imido group, or


CA 02047496 2001-O1-19
27169-190
12
if R3 represents a tetrazolyl group and RZ represents
an ethyl or n-propyl group, R~ in the 6-position may also
represent an N-benzenesulphonyl-methylamino group, or
if R3 represents a tert.butoxycarbonyl group and R2
represents an n-butyl group, R~ in the 6-position may
also represent a 2-carboxy-cyclohexylmethylcarbonylamino
or pyrrolidinocarbonylamino group;
Rz represents a hydrogen atom or a straight-chained or
branched C~_4-alkyl group in which a methylene group may
be replaced by a su:Lphur atom;
R3 represents a carboxy, cyano, 1H-tetrazolyl or 1-
triphenylmethyl-tetrazolyl group or a (C~_4-alkoxy)-
carbonyl group; and
R4 represents a hydrogen, fluorine, chlorine or bromine
atom;
and isomers and sali~s thereof, especially the 1-, 3-
isomer mixtures thereof, and particularly the
physiologically acceptable salts thereof with organic or
inorganic acids or bases.
Particularly preferred compounds according to the
invention include those of formula I wherein
R~ in the 6-position represents a 1-methylbenzimidazol-2-
yl, 3,4,5,6-tetrahydro-phthalimino, 2,3-diphenyl-malefic
acid imido, 2,3-dimethyl-malefic acid imido, N-phenyl-
methanesulphonyl-met:hylamino, 2-oxo-pyrrolidin-1-yl, 2-
oxo-piperidin-1-yl, ?.-oxo-hexamethyleneimino, 2-oxo-3,4-
tetramethylene-pyrrolidin-2-yl, 3,3-dimethylglutarimido,
N-methylaminocarbonyl-n-pentylamino, propanesultam-1-yl
or butanesultam-1-yl. group;


CA 02047496 2001-O1-19
27169-190
13
R2 represents a methyl, ethyl, n-propyl or n-butyl group;
R3 represents a carboxy or 1H-tetrazolyl group; and
R4 represents a hydrogen atom;
and the isomers and salts, especially the 1-,3- isomer
mixtures thereof and particularly the physiologically
acceptable addition salts thereof with organic or
inorganic acids or bases.
Although the present: invention relates to new compounds
of formula I, the corresponding cyano, tert.-
butoxycarbonyl and t:riphenylmethyl compounds, in
particular, represent: valuable intermediates which can
readily~be convertedi to one of the pharmacologically
active compounds.
According to a further aspect the invention also
provides a process for the preparation of compounds of
the invention, said process comprising at least one of
the following steps:
a~ cyclising a compound of formula II
Xt
Rt r . III)
'_'~ \ Y
t
(wherein
R~ is as hereinbeforc~ defined;
one of the groups X~ or Y~ represents a group of formula




_ 1q _
R3
R4
-_
N
~5
and the other group X~ or Y~ represents a group of
formula
_ NH Z~\~~ZZ Rz ;
RZ, R3 and R4 are as hereinbefore defined;
RS represents a hydrogen atom or an R2CO group;
Z~ and Z2, which may be the same or different, represent
optionally substituted amino groups or hydroxy or
mercapto groups optionally substituted by lower alkyl
(e.g. C~_b-alkyl) groups, or
Z~ and ZZ together represent an oxygen or sulphur atom,
an imino group optionally substituted by a C1_3-alkyl
group, or a CZ_3-alkylenedioxy or CZ_3alkylenedithio group,
with the proviso that one of the groups X~ or Y~ must
represent a group of formula
R3
R4
N
COR2
or
- NH - \Cf - Rz ) or an N-oxide thereof



-- 15 -
and subsequently if necessary reducing the cyclized N-
axide product:
b) reacting a benzimidazole of formula III
N
(ill)
N
N
(wherein
R~ and RZ are as hereinbefore defined) with a biphenyl
compound of formula IV
(IY)
z3
(wherein
R3 and R4 are as hereinbefore defined: and
Z3 represents a nucleophilic leaving group such as a
halogen atom, e.g. a chlorine, bromine or iodine atom,
or ~ substituted sulphonyloxy group, e.g. a
methanesulphonyloxy, phenylsulphonyloxy or p-
toluenesulphonyloxy group):
c) (to prepare a compound of formula I wherein R3
represents a carboxy group) converting a compound of
formula V
N
i '~--R
Rn \ 2 ~Y)
N R3'
R4




(wherein
RZ and R4 are as hereinbefore defined;
R~' is a group R~ as hereinbefore defined or a 3-((C~_3-
alkoxy)carbonyl)propionyl or 3-((C~_3-alkoxy)carbonyl)-2-
methylpropionyl group; and
R3' represents a group which may be canverted into a
carboxy group by hydrolysis, thermalysis or
hydrogenolysis) into a corresponding carboxy compound;
d) (to prepare a compound of formula T 'wherein R3
represents a 1H-tetrazolyl group) cleaving a protecting
group from a compound of formula VI
r N
Rt \ I N/ R2 , (VI)
R ~'
Rt
(wherein
R~, ~tz and R4 are as hereinbefore defined; and
R3°' represents a 1H-tetrazolyl group protected in the 1-
or 3-position by a protecting group);
e) (to prepare a compound of formula I wherein R3
represents a 1H-tetrazolyl group) reacting a compound of
formula VII
N
Rt ~ ~~R2
N (VII)
CN
R4



'~ ,;~ g"~ r~
- 17 -
(wherein
R,, Rz and R4 are as hereinbefore defined} with hydrazoic
acid or a salt thereof:
f) (to prepare compounds of formula I wherein R~
represents a pentamethylene-oxazolin-2-yl group)
reacting a compound of formula VIII
N
HOOC ~ I \~R
2
N R3
R~
(wherein
R2, R3 and R4 are as hereinbefore defined) with 1-
aminomethyl-cyclohexanol in the presence of an acid-
activating agent:
g) (to prepare a compound of formula I wherein R~
represents a 2-oxo-3,4-tetramethylene-pyrrolidin-1-yl
group) hydrogenating a compound of formula IX
O x7
4
(wherein
RZ, R3 arid R,~ are as hereinbefore defined) :
h) (to prepare compounds of formula I wherein R~
represents an amino group substituted by a
bicyclohexylcarbonyl or biphenylcarbonyl group, which




- 18 -
may additionally be substituted at the N-atom by a C~_3-
alkyl group, an aminocarbonylamino group substituted by
a bicyclohexyl or biphenyl group and optionally
additionally substituted by one or two C1_3alkyl groups
at the N-atom, a malefic acid amido or malefic acid imido
group optionally mono- or disubstituted by substituents
selected from C~_3-alkyl and phenyl groups, a (C~_3-
alkyl)amino or phenyl(C~_~-alkyl)amino group substituted
by a C4_b-alkylsulphonyl group or by a phenyl(C~_3-
alkyl)sulphonyl group, an amino or C~_3-alkylamino group
substituted by a naphthalenesulphonyl group and
optionally substituted in the naphthalene ring by a
di (C1_3-alkyl) amino group or by one or two Ct_3-alkoxy
groups, a 7-nitro-benzofurazan-4-yl-amino(CZ_3-
alkanoyl)amino group, a benzofurancarbonyl-amino or 7-
nitro-benzofurazan-4-yl-amino group, and
where R3 represents a carboxy group and RZ represents an
n-butyl group, R~ in the 6-position may also represent an
amino group substituted by a phenylsulphonyl,
cyclohexylmethylamino-carbonyl, 2-
carboxycyclohexylmethylcarbonyl, 2-tart.-butoxycarbonyl-
cyclahexylmethylcarbonyl, 2-carboxy-3,4,5,6-
tetrahydrobenzoyl, N-methyl-phenylaminocarbonyl or 3-
cyclohexylpropyl group, a methylamino group substituted
by a propylsulphonyl, phenylsulphonyl,
methylphenylsulphonyl or ch~orophenylsulphonyl group, an
n-pentylamino group substituted by a phenylsulphonyl ar
methoxyphenylsulphonyl group, an n-propylamino group
substituted by a methylphenylsulphonyl or methoxyphenyl-
sulphonyl group, an isopropylamino group substituted by
a benzoyl or chlorophenylsulphonyl group, an N-acetyl-
cyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido,
hexahydrohomophthalimido, N-methanesulphonyl-2-
phenylethylamino or N-chlorophenylsulphonyl-benzylamino
group, and




- 19 -
where R3 represents a carbaxy group and RZ represents an
n-butyl group, R1 in the 5- or 6-position may also
represent a 2-oxo-1,2-dihydro-3,4-tetramethylene-
pyrrolidin-1-yl group, and
where R3 represents a carboxy group and RZ represents a
methyl, ethyl, n-propyl, n-butyl or methylmercapto
group, R1 in the 6-position may also represent a
pyrrolidino-carbonylamina group, and
where R3 represents a tetrazolyl group and R2 represents
an n-butyl group, R~ in the 5- or 6-position may also
represent an n-pentylamino group substituted by a
methylamino-carbonyl or cyclohexylaminocarbonyl group
and R~ in the 6-position may also represent a 3,3-
dimethyl-glutaric acid imido or 4,4-tetramethylene-
glutaric acid imido group, and
where R3 represents a tetrazalyl group and R2 represents
an ethyl or n-propyl group, R1 in the 6-position may also
represent an ~I-benzenesulphonyl-methylamino group, and
where R3 represents a tert.-butoxycarbonyl group and RZ
represents an n-butyl group, Ry in the 6-position may
also represent a 2-carboxy-cyclohexylmethylcarbanylamino
or pyrrolidinocarbonylamino group) reacting a compound
of formula X
H
R
(X)
4
(wherein




c~ n
.~,
~t:~ ~t~~~
- 20 -
R2, R3 and R4 are as hereinbefore defined; and
R6 represents a hydrogen atom, an n-pentyl, cyclohexyl-
methyl, C~_3-alkyl or phenyl(C~_~-alkyl) group) with a
compound of formula XI
Z4 _ W - R7 (XI)
(wherein
Z4 represents a nucleophilic leaving group:
W represents a -CO- or -SOZ- group; and
R7 represents a 2-hydroxycarbonyl-ethenyl group wherein
the ethenyl moiety is mono- or disubstituted by
substituents selected from C~_3-alkyl and phenyl groups,
a C3_6-alkyl group, a phenyl (C~_3-alkyl} group, a
naphthalene group optionally substituted by a di(C~_3-
alkyl}amino group or by one or two C1_3-alkoxy groups, a
methyl, phenyl, methylphenyl, methoxyphenyl,
chlorophenyl, biphenyl, bicyclohexyl, 2-carboxy-
cyclohexylmethyl, 2-carboxy-3,4,5,6-tetrahydrophenyl,
carboxy-1,1-dimethyl-propy3,~3-carboxy-2,2-
tetramethylenepropyl, 7-nitro-benzofurazan-4-yl-
aminomethyl or 7-nitrowbenzofurazan-4-yl-aminoethyl
group, and
where W represents a -CO- group, R~ may also represent an
R$NR9 group wherein
R8 represents a hydrogen atom or a C1_3-alkyl group,
R9 represents a methyl, cyclohexyl,
cyclohexylmethyl, phenyl, biphenyl or bicyclohexyl
group, or
R8 and Rq together with the nitrogen atom between
them represent a pyrrolidino group, or
Z4 together with Rp represents another carbon-



r .~ rra
a ~ ~ ~~ r_
vl ~8 . ~ ". ~P
- 21 -
nitrogen bond, and
R~ together with W may also represent a 7-nitro-
benzofurazan-4-yl-amino group) or a reactive derivative
of a carboxylic acid of formula XI:
i) (to prepare compounds of formula I wherein R1
represents a tetrahydrobenzimidazolyl or
imidazopyridinyl group, or a benzimidazolyl group
optionally substituted in the phenyl nucleus by a
fluorine, chlorine or bromine atom, by a C1_3-alkyl
group, by a C1_3-alkoxy group or by a trifluoromethyl
group, and in which the NH-group of the above-mentioned
imidazole rings may additionally be substituted by a
C1_g-alkyl group or by a C3_7-cycloalkyl group, a
hydroxy(C5_7-cycloalkyl)aminocarbonyl group, which may
additionally be substituted at the N-atom by a C1_3-alkyl
group, or a straight-chained or branched hydroxy(C4_6-
alkyl)aminocarbonyl group) reacting a compound of
formula XII
N
HOOC ~ ~ \~'R2 ( X 1 1 }
N R3
R~
(wherein
R2, R3 and R4 are as hereinbefore defined) or a reactive
derivative thereof, for example an acid halide, ester,
amide, anhydride or nitrile, with an amine of formula
XIII
R10
~/ N - H (XIII)
R11'




r~t~'~~.
22 -
(wherein
Rio represents a hydrogen atom, a cycloalkyl group or a
Ci_b-alkyl group; and
R» represents a C4_6-hydroxyalkyl group, a C5_~-hydroxy-
cycloalkyl group or a 2-aminophenyl group which may be
substituted in the phenyl nucleus by a fluorine,
chlorine or bromine atom, by a C~_3-alkyl group, by a Ct.3-
alkoxy group or by a trifluoromethyl group, a 2-
aminocyclohexyl or 2-aminopyridyl group) optionally with
simultaneous decarboxylation;
j) (to prepare compounds of formula I wherein R~
represents a dihydro-pyridazin-3-one or a pyridazin-3-
one group which may be substituted in the 2-position by
an optionally phenyl-substituted C1,3-alkyl group or at a
carbon atom by one or two C~.3-alkyl groups) reacting a
carboxylic acid of formula XIV
r "
Haoc-a-c ~ ~ ~~~z (xiv)
N
~ R~
(wherein
R~, RZ, R3 and R4 are as hereinbefore defined: and
A represents an ethylene or ethenylene group optionally
substituted by one or two C~_3-alkyl groups) or a
reactive acid derivative thereof, for example an ester,
amide ar halide thereof, with a hydrazine of formula XV
HZN - NHR~2 ( XV )
(wherein
R~2 represents a hydrogen atom or an optionally phenyl-
substituted C~_3-alkyl group) ;


_ 23 _
A S" ~ E4 ~
~3 '~' ~ .'._: z~ ~
k) resolving a 1-,3- isomer mixture of a compound of
formula I by isomer separation into the 1- and 3-
isomers thereof:
1) converting a compound of formula I into an addition
salt thereof, more particularly, for pharmaceutical use
into a physiologically acceptable salt thereof with an
organic or inorganic acid or base or converting a salt
of a compound of formula I into the free compound: and
m) carrying out a reaction according to any one of steps
(a) to (1) above in which one or more groups are
protected by a protecting group and subsequently
removing any protecting group used.
Tn the reactions described above, any reactive groups
present.such as hydroxy, amino or alkylamino groups may
optionally be protected during the reaction by
conventional protecting groups which are split off again
after the reaction.
Hxamples of suitable protecting groups for a hydroxy
group era trimethylsilyl, acetyl, benzoyl, methyl,
ethyl, tert.-butyl, benzyl or tetrahydropyranyl groups
and suitable protecting groups for an amino, alkylamino
or imino group include 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, conveniently at
temperatures between 0 and 100°C, preferably at the
boiling temperature of the reaction mixture. However, a
L



- 24 -
benzyl group is preferably removed 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, conveniently at temperatures between
0 and 50°C, but preferably at ambient temperature, under
a hydrogen pressure of 1 to 7 bar, preferably 3 to
bar.
The cyclisation of step (a) may conveniently be 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
formula II, e.g. in the corresponding nitrile,
anhydride, acid halide, ester or amide. The reaction is
conveniently effected at temperatures between 0 and
250°C, preferably at the boiling temperature of the
react~.on 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
or 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.
It is particularly advantageous to carry out the
reaction of step (a) by preparing a compound of 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 RZCOOH, or by
acylating a corresponding o-diamino compound. When the
r




- 25 --
reduction of the nitro group is broken off at the
hydraxylamine stage, the N-oxide of a compound of
formula I is obtained in the subsequent cyclisation.
The resulting N-oxide is then converted by reduction
into a corresponding compound of formula I. The
subsequent reduction of the N-oxide of formula I
obtained is 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 ar 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, preferably at
ambient temperature.
The reaction of step (b) may conveniently be carried out
in a solvent or mixture of solvents such as methy:Lene
chloride, diethylether, tetrahydrofuran, dioxane,
dime~thyl.-sulphoxide, dimethylformamide or benzene,
optionally in the presence of an acid binding agent such
as sodium carbonate, potassium carbonate, sodium
hydroxide, potassium tart.-butoxide, triethylamine or
pyridine, whilst the latter two may simultaneously also
be used as solvent, conveniently at temperatures between
0 and x.00°C, preferably at temperatures between ambient
temperature and 50°C. A mixture of the 2- and 3-
isomers is preferably obtained.
In step (c) functional derivatives of the carboxy group
such as optionally substituted amides, esters,
thiolesters, orthoesters, iminoethers, amidines and
anhydrides, and nitrile and tetrazolyl groups may be
converted by hydrolysis into a carboxy group, esters
with tertiary alcohols, e.g. tert.butylesters, may be




~~sf
- 26 -
converted by thermolysis into a carboxy group and esters
with aralkanols, e.g. benzyl esters, may be converted by
hydrogenolysis into a carboxy group.
The hydrolysis of step ~c) is conveniently carried out
either in the presence of an acid such as hydrochloric,
sulphuric, phosphoric, trichloroacetic or
trifluoroacetic acid or 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, preferably 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 a
trifluoroacetoxy group.
If R3' in a compound of formula V represents a cyano or
aminocarbonyl group, such a group 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 simultaneously also be used as solvent,
at temperatures between 0 and 50°C.
If R3' in a compound of 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 acid such as p-
toluenesulphonic, sulphuric, phosphoric or
polyphosphoric acid, conveniently at temperatures
between 40°C and 100°C, preferably at the boiling
temperature of the solvent used.



If R3' in a compound of 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, more preferably 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 the
amino group, a benzyl'oxy group to the 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.
If R~ in a compound of formula V represents one of the
above mentioned hydrolysable groups, it may be converted
during the reaction into a corresponding carboxy or
amino compound.
Suitable protecting groups for use in step (d) include,
for example, triphenylmethyl, tributyl tin arid triphenyl
tin groups.
The cleaving of a protecting group is preferably carried
out in the presence of a hydrohalic acid, more 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, conveniently
at temperatures between 0 and 100°C, 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




~~~""l!~~~
- 28 -
150°C, preferably at temperatures between 120 and 140°C.
The reaction of step (e) is preferably carried out in a
solvent such as benzene, toluene or dimethylformamide at
temperatures between 80 and 150°C, preferably at 125°C.
Appropriately, either the hydrazoic acid is liberated
during the reaction from an alkali metal azide, e.g.
sodium azide in tha presence of a weak acid such as
ammonium chloride, or the tetrazolide salt obtained in
the reaction mixture from 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.
The reaction of step (f) is preferably carried out in a
solvent such as tetrahydrofuran ar dioxane in the
presence of an acid activating agent such as
carbonylimidazole at temperatures between 0 and 50°C,
preferably at ambient temperature.
The catalytic hydrogenation of step (g} is conveniently
carried out 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
at temperatures between 0 and 50°C, preferably at
ambient temperature, under a hydrogen pressure of 1 to 7
bar, preferably 3 to 5 bar.
Examples of nucleophilic leaving groups for Z4 in step
(h) include chlorine or bromine atoms, alkoxy or
phenylalkoxy groups such as methoxy, ethoxy or benzyloxy
groups or, if R~ represents a hydrocarbon group, a
hydroxy group.



- 29 -
The reaction of step (h) may conveniently be carried out
in a solvent such as methylene chloride, chloroform,
carbon tetrachloride, ether, tetrahydrofuran, dioxane,
benzene, toluene, acetonitrile or dimethylformamide,
optionally in the presence of an acid activating agent
or a dehydrating agent, e.g. in the presence of ethyl
chloroformate, thionyl chloride, phosphorus trichloride,
phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,
N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole or
triphenylphosphine/carbon tetrachloride, or an agent
which activates the amino group, e.g. phosphorus
trichloride, and optionally in the presence of an
inorganic base such as sodium carbonate or a tertiary
organic base such as triethylamine or pyridine, which
may simultaneously be used as solvents, conveniently at
temperatures between -25 and 150°C, preferably at
temperatures between -10°C and the boiling temperature
of the solvent used.
If Z4 represents a hydroxy group, however, it is
particularly advantageous to carry out the reaction of
step (h) with the reactive derivatives of a carboxylic
acid of general formula XI, e.g. with the esters,
thioesters, halides, anhydrides or imidazolides.
The reaction of step (i) may conveniently be carried
out in a solvent such as methylene chloride, chloroform,
carbon tetrachloride, ether, tetrahydrofuran, dioxane,
benzene, toluene, acetonitrile or dimethylformamide,
optionally in the presence of an acid activating agent
or a dehydrating agent, e.g. in the presence of ethyl
chloroformate, thionyl chloride, phosphorus trichloride,
phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,
N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole or
triphenylphosphine/carbon tetrachloride, or an agent
r



- s0 -
which activates the amino group, e.g. phosphorus
trichloride, and optionally in the presence of an
inorganic base such as sodium carbonate or a tertiary
organic base such as triethylamine or pyridine, which
may simultaneously be used as solvents, conveniently at
temperatures between -25 and 150°C, but preferably at
temperatures between -10°C and the boiling tennperature
of the solvent used.
An ortho-benzamido compound optionally obtained in this
way can then, if necessary, be converted into the
desired benzimidazole compound by heating, preferably in
a solvent or mixture of solvents such as ethanol,
isopropanol, glacial acetic acid, benzene,
chlorobenzene, toluene, xylene, glycol, glycol-
monomethylether, diethyleneglycol-dimethylether,
sulpholane, dimethylformamide or tetraline, optionally
in the presence of a condensing agent such as phosphorus
oxychloride, thionyl chloride, sulphuryl chloride,
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, this
cyclisation may also be carried out without a solvent
and/or condensing agent.
The reaction of step (j) may conveniently be carried out
in a solvent such as methanol, ethanol, isopropanol,
glacial acetic acid or propionic acid and/or in an
excess of the hydrazine or hydrazine hydrate used, at
temperatures between 0 and 200°C, preferably at
temperatures between 20 and 150°C, more preferably at
the boiling temperature of the reaction mixture, and
optionally in the presence of an acid such as sulphuric
or p-toluenesulphonic acid as a condensing agent. The
reaction may, however, also be carried out without a
s



- 31 --
solvent.
The isomer separation of step (k) is preferably carried.
out by chromatography using a substrate such as silica
gel or aluminium oxide. w
The compounds of formula I obtained may, if desired, be
converted into the acid addition salts thereof, mare
particularly for pharmaceutical use the physiologically
acceptable salts thereof with inorganic or organic
acids. Suitable acids for this purpose include
hydrochloric, hydrobromic, sulpriuric, phosphoric,
fumaric, succinic, lactic, citric, tartaric and malefic
acid.
Furthermore, the new compounds of formula I thus
obtained, if they contain a carboxy or 1H-tetrazolyl
group, may, if desired, subsequently be converted into
the salts thereof with inorganic ar organic bases, more
particularly for pharmaceutical use into the
physiologically acceptable salts thereof. Suitable
bases for this purpose include sodium hydroxide,
potassium hydroxide, cyclohexylamine, ethanolamine,
diethanolamine and triethanolamine.
Some of the compounds of general formulae II to XV used
as starting materials are known from the literature.
Otherwise these compounds may be obtained by methods
known from the literature.
Thus, for example, a compound of general formula II may
be obtained by alkylation of a corresponding o-amino-
nitro compound and subsequent reduction of the nitro
group.
Compounds of general formulae III, V, VI, VII, VIII, IX,
X, XII or XIV used as starting materials may be obtained




r~~t~"'l ~~.
- 32 -
by alkylation of a corresponding o-phenylenediamine or a
corresponding o-amino-vitro compound, followed by
reduction of the vitro group and subsequent cyclisation
of an o-diamino-phenyl compound thus obtained,
optionally followed by. cleaving any protecting group
used 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-392317.
The new compounds of general formula I and the
physiologically acceptable salts thereof have valuable
pharmacological properties. They are angiotensin
antagonists, in particular, angiotensin-II-antagonists.
Thus in a further aspect the present invention provides
a pharmaceutical composition comprising a compound of
formula I or a physiologically acceptable salt thereof
together with at least one pharmaceutical carrier or
excipient.
In a still further aspect the present invention provides
the use of a compound of formula I or a physiologically
acceptable salt thereof for the manufacture of a
therapeutic agent for the treatment of hypertension,
cardiac insufficiency, ischaemic peripheral circulatory
disorders, myocardial ischaemia (angina), for the
prevention of cardiac insufficiency progression after
myocardial infarct, or for the treatment of diabetic
nephropathy, glaucoma, gastrointestinal diseases and
bladder diseases.
In a still yet further aspect the present invention
provides a method of treatment of the human or non-human
animal body to combat hypertension, cardiac
insufficiency, ischaemic peripheral circulatory
r




- 33 -
disorders, myocardial ischaemia (angina), cardiac
insufficiency progression following myocardial
infarction, diabetic nephropathy, glaucoma,
gastrointestinal diseases and bladder diseases, said
method comprising administering to said body a compound
of formula I or a physiologically acceptable salt
thereofa
By way of example, the following compounds:
A = 4'-[(2-n-propyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid;
B = 4°-([2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid-
dihydrate;
C = 4'-((2-n-butyl-6-(2,3-diphenyl-malefic acid imido)-
benzimidazol-1-yl]methyl]biphenyl-2-carbaxylic acid;
D = 4'-([2-n-butyl-6-(2,3-dimethyl-malefic acid imido)-
benzimidazol-~.-yl]methyl]biphenyl-2-carboxylic acid;
E = 4°-[[2-n-butyl-6-(N-phenylmethanesulphonyl-
methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid:
F = 4'-[(2-n-butyl-6-(2-oxo-piperidin-1-yl)-
benzimidazol-Z-yl]methyl]-2-(1H-tetrazol-5-yl)-
biphenyl;
G = 4'-[[2-n-butyl-6-(2-oxo-pyrrolidin-1-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-
biphenyl;
H = 4'-([2-n-butyl-6-(2-oxo-hexamethyleneimino)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-


- 34 -
biphenyl;
I = 4'-[[2-n-butyl-6-(3,3-dimethylglutarimido)-
benzimidazol-1-yl]methyl]-2-(lT~i-tetrazol-5-yl)-
biphenyl;
J = 4'-[[2-n-butyl-6-(N-methylaminocarbonyl-n-
pentylamino)-benzimidazol-1-yl]methyl]-2-(1H-
tetrazol-5-yl)-biphenyl;
K = 4°-[[2-n-butyl-6-(cyclohexylaminocarbonyl-n-
pentylamino)-benzimidazol-2-yl]methyl]-2-(1H-
tetrazol-5-yl)-biphenyl hydrate; and
L = 4'-[[2-n-butyl-6-(2-oxo-3,4-tetramethylene-
pyrrolidin-1-yl)-benzimidazol-1-yl]methyl]biphenyl-
2-carboxylic acid
were tested for their biological effects as follows:
Rats (male, 180-220 g) are anaesthetised with sodium
hexobarbital (150 mg/kg i.p.). After they have become
unconscious, a tracheal cannula is inserted, the animals
are pithed and then immediately artificially respirated
with a ventilator pump. The arterial blood pressure is
recorded by means of a cannula in the carotid artery
using a Bell & Howell pressure recorder. The substances
are administered in the jugular vein through a cannula.
Test substances are administered in three doses (10, 20
and 30 mg/kg i.v.), with one dose of substance being
tested on each animal. Three minutes after the
intravenous administration of the test substance,
angiotensin-II is administered intravenously in
increasing doses and in this way a cumulative dose-
activity relationship is achieved for angiotensin-II in
the presence of the test substances. The increase in



- 35 -
arterial blood pressure is measured.
These dose-activity curves are compared with standard
curves for angiotensin-II without the use of any test
substances. Using a computer program, the shift ~o the
right in the dose-activity curves for angiotensin-II as
a result of the administration of the test substances
are determined and corresponding pAz-values are
calculated for the test substances.
The pAz values of the above-mentioned test compounds A to
L are between 6.0 and 7.5.
Moreover, when the above-mentioned compounds were
administered in a dose of 30 mg/kg i.v. no toxic side
effects, e.g. negative isotropic effects or heart rhythm
disorders, were observed. Accordingly, the compounds
are well tolerated.
The new compounds arid their physiologically acceptable
salts are suitable for the treatment of hypertension and
cardiac insufficiency and also for treating ischaemic
peripheral circulatory disorders, myocardial ischaemia
(anginaj, for the prevention of the progression of
cardiac insufficiency after myocardial infarct and for
treating diabetic nephropathy, glaucoma,
gastrointestinal diseases and bladder diseases.
The new compounds and the physiologically acceptable
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




~~~f~"~!?.
- 36 -
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 is
canveniently, when administered intravenously, 20 to
200 mg, preferably 30 to 70 mg, and, when administered
orally, 50 to 200 mg; preferably 75 to 1.50 mg, 1 to 3
times a day. For this purpose, the compounds of formula
I and salts thereof, optionally in conjunction with
other active substances such as antihypertensives,
diuretics and/or calcium channel blockers, may be
incorporated together with one or more inert
conventional carriers and/or diluents, for example with
corn starch, lactose, glucose, microcrystalline
cellulose, magnesium stearate, polyvinylpyrrolidone,
citric acid, tartaric acid, water, water/ethanol,
water/glycerol, water/sorbitol,
water/polyethyleneglycol, 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.
Suitable active ingredients for the above-mentioned
combinations include for example atenolol,
bendroflumethiazide, chlorothiazide, (di)hydralazine
hydrochloride, hydrochlorothiazide, metoprolol,
prazosin, propranolol, spironolactone, benzthiazide,
cyclothiazide, ethacrinic acid, furosemide, diltiazem,
felodipine, nicardipine, nifedipine, nisoldipine and
nitrendipine. The individual dosages for these
ingredients can range from about one-fifth of the
usually minimal recommended dosage up to the maximum
recommended dosage, for example from 15 to 200 mg of




- 37 -
hydrochlorothiazide, from 125 to 2000 mg of
chlorothiazide, from 15 to 200 mg of ethacrinic acid,
from 5 to 80 mg of furosemide, from 20 to 480 mg of
propranolol, from 5 to 60 mg of felodipine, from 5 to 60
mg of nifedipine or from 5 to 60 mg of nitrendipine.
The following non-limiting Examples are provided to
illustrate the invention. Unless otherwise specified
all percentages and ratios given are by weight:



Example 1
4'-[[2-n-Propyl-5-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid and
4'-[[2-n-Propyl-6-(2-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid'
a) Methyl-2-n-propyl-benzimidazole-5-carboxylate
A solution of 23.9 g (100 mMol) of methyl 3,4-diamino-
benzoate dihydrochloride and 11.7 g (110 mMol) of
butyric acid chloride in 100 ml of phosphorus
oxychloride is refluxed for 2 hours. Then about 80 ml
of phosphorus axychloride are distilled off and the
residue is mixed with about 150 ml of water. The oily
crude product precipitated is extracted three times with
50 ml of ethyl acetate and after evaporation purified by
column chromatography (600 g of silica gel: eluant:
methylene chloride/methanol (30:1 by volume)).
Yield: 15.0 g of oil (69A of theory)
b) 2-n-Propyl-benzimidazole-5-carboxylic acid-
hemisuluhate
A solution of 15.0 g (73 mMol) of methyl 2-n-propyl-
benzimidazole-5-carboxylate and 8 g (200 mMol) of sodium
hydroxide in 200 ml of water and 400 ml of ethanol is
refluxed for 2 hours. Then the alcohol is distilled
off, the aqueous solution is acidified with dilute
sulphuric acid (pH 4-5) and evaporated using a rotary
evaporator. The product crystallising out is suction
filtered, washed with 50 ml of acetone and 50 ml of
diethylether and dried.
Yield: 9.1 g (610 of theory),
Melting point: > 220°C.
C~1H12N202 x 1/2 HZS04 (253.26)
Calculated: C 52.17 H 5.17 N 11.06 S 6.33


- 39 --
Found: 51.87 5.23 11.11 6.41
c) 2-n-Propyl-5-(1-methylbenzimidazol-2-yl~
benzimidazole
A solution of 6.7 g (25 mMol) of 2-n-propyl-
benzimidazole-5-carboxylic acid-hemisulphate and 4.9 g
(25 mMol) of 2-methylaminoaniline-dihydrochloride in
200 g of polyphosphoric acid is stirred for 5 hours at
150°C, then poured onto 600 ml of water and made
alkaline with concentrated ammonia whilst cooling with ,
ice. The resulting solution is extracted three times
with 200 ml of ethyl acetate, the crude product thus
obtained is purified by column chromatography (300 g of
silica geld eluant: methylene chloride/methanol = 15:1
by volume).
Yield: 2.8 g of oil (390 of theory),
C~$H~8N4 (290.37)
Calculated: C 74.46 H 6.25 N 9.29
Found: 73.92 6.32 18.96
d) Tert.-butyl 4'-[[2-n-propyl-5-(1-methylbenzimidazol-
2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic
acid and
tert.-butyl 4'-j[2-n-propyl-6-(1-methylbenzimidazol-
2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic
A solution of 2.0 g (6.9 mMol) of 2-n-propyl-5-(1-
methylbenzimidazol-2-yl)-benzimidazole and 0.91 g
(7.5 mMol) of potassium tert.-butoxide in 50 ml of
dimethylsulphoxide is stirred for 90 minutes at ambient
temperature, then 2.6 g (7.5 mrlol) of tert.-butyl 4'-
bromomethyl-biphenyl-2-carboxylate are added and the
mixture is stirred for a further 15 hours at ambient
temperature. The mixture is then poured onto 300 ml of
water and extracted three times with 50 ml of ethyl
acetate. The crude product obtained after evaporation
i



~!~ '~~~.~
- 40 -
of the organic phase is purified by column
chromatography (300 g silica gel; eluant: methylene
chloride/methanol = 30:1 by volume). In this way, 2.7 g
(70% of theory) of an isomer mixture are obtained, which
when analysed by NMR spectroscopy, contains abo~xt 1.18 g
of tert.-butyl 4'-[(2-n-propyl-5-(1-methylbenzimidazol-
2-yl}-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate
and about 1.52 g of tert.-butyl 4'-[(2-n-propyl-6-(1-
methylbenzimidazol-2-yl)-benzimidazol-1-yl}-methyl]-
biphenyl-2-carboxylate.
Rf value: 0.43 (methylene chloride/methanol = 19:1 by
volume)
e) 4'-[[2-n-Propyl-5-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
and
4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyllbiphen~l-2-carboxylic acid
2.70 g of the isomer mixture obtained in Example 1d are
dissolved in 100 m1 of methylene chloride, mixed with
40 ml of trifluoroacetic acid and stirred for 4 hours at
ambient temperature. The mixture is then evaporated to
dryness in vacuo, the residue is dissolved in 100 ml of
2N sodium hydroxide solution, the solution is washed
with 50 ml of diethylether and the product mixture is
precipitated by acidifying the aqueous phase with acetic
acid. By column chromatography (400 g of silica gel,
eluant: methylene chloride/methanol = 15:1 by volume} of
the solid thus obtained, 0.7 g (58% of theory} of 4'-
[[2-n-propyl-5-(1-methylbenzimidazol-2-yl}-benzimidazol-
1-yl]methyl]-biphenyl-2-carboxylate are obtained,
melting point 219-220°C
C32H2sN4~z (500.60)
Calculated: C 76.78 H 5.64 N 11.19
Found: 76.54 5.57 11.01
Rf value: 0.15 (methylene chloride/methanol = 9:1 by
volume}
and 0.9 g (74% o'f theory) of 4'-[[2-n-propyl-6-(1-


_ ~~ -
methylbenzimidazol-2-yl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylate are obtained, melting
point 217-218°C
CszHzaN4~z (500.60)
Calculated: C 76.78 ~I 5.64 N 11.29
Found: 76.63 5.55 11.29
Rf value: 0.40 (methylene chloride/methanol = 9:1)
The following compounds are obtained analogously:
4'-[[2-n-propyl-6-(1,6-dimethyl-benzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-butyl-6-(1-methyl-5-bromo-benzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-butyl-6-(1-methyl-5-methoxy-benzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-butyl-6-(1-n-butyl-5-trifluoromethyl-
benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
4'-[[2-n-butyl-6-(1-n-hexyl-5-methyl-benzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-propyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-propyl-6-(1-methyl-5-chloro-benzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid



_ 42 -
Example 2
4'-[[2 -n-Butyl-6-(1-methylbenzimidazol-2-y1)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid ,
Prepared analogously to Example 1 from tert.-butyl 4'-
(~[2-n-butyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-
1-y1]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid in methylene chloride.
Yield: 43% of theory,
Melting point: amorphous
C33H3oN4~z ( 514 . 6 0 )
Calculated: C 77.02 H 5.88 N 10.89
Found: ?6.88 5.83 10.55
Rf value: 0.42 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Mass spectrum: (M + H)+ - 515
Example 3
4'-[[6-(Biphenyl-4-carbonylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid x
0 . 2 5 H20
Prepared analogously to Example 1 from tert.-butyl 4'-
[[6-(biphenyl-4-carbonylamino)-2-n-butyl-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid in methylene chloride.
Yield: 70. f% of theory,
Melting point: 316-317°C
C38H33N3~3 x 0 ~ 2 5 Hz0 ( 5 8 4 . 2 0 )
Calculated: C 78.13 H 5.78 N 7.19
Found: 78.12 5.79 7.08
Rf value: 0.25 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)



- 43 -
Example 4
4'-[[6-(Biphenylyl-4-aminocarbonylam~.no)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
trifluoroacetate-semihydrate w
Prepared analogously to Example 1 from tert.-butyl 4'-
[[6-(biphenylyl-4-aminocarbonylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 97.0% of theory,
Melting point: 171-172°C
C38H34NG03 x CF3COOH x 1/ 2 H20 ( 717 . 7 4 )
Calculated: C 66.94 H 5.06 N 7.81
Found: 67.13 4.99 7.76
Rf value: 0.25 (silica gel: eluant: ethyl
acetate/ethanol/ammonia = 80:40x2 by volume)
Examt~le 5
4'-[(6-Benzenesulphonamido-2-n-butyl--benzimidazol-1-yl)-
methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from test.-butyl 4°-
[(6-benzenesulphonamido-2-n-butyl-benzimidazol-1-yl)-
methyl]biphenyl-2-carboxylate and trifluproacetic acid
in methylene chloride.
Yield: 75.0% of theory,
Melting point: 251-252°C
C~~Hz9N~04S (539.65)
Calculated: C 69.00 H 5.42 N 7.79 S 5.94
Found: 68.96 5.52 7.82 5.86
Rf value: 0.50 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 50:45:5)




- 44 -
Example 6
4'-[[6-(N-Benzenesulphonyl-methylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[6-(N-benzenesulphonyl-methylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 70.0% of theory,
Melting point: 211-212°C
C3ZH3~N304S ( 553 . 68 }
Calculated: C 69.42 H 5.64 N 7.59 S 5.79
Found: 69.24 5.66 7.53 6.02
Rf value: 0.55 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 50:45:5 by volume}
Example 7
4'-[[2-n-Butyl-6-(cyclohexylmethylaminocarbonylamino}-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid-
trifluoroacetate
Prepared analagously to Example 1 from tart.-butyl 4°-
[[2-n-butyl-6-(cyclohexylmethylaminocarbonylamino}-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 91.10 of 'theory,
Melting point: 149-150°C
C~3H3sN403 x CF3COOH ( 652 . 71 )
Calculated: C 64.41P H 6.02 N 8.58
Found: 64.23 6.09 8.73
Rf value: 0.25 (silica gel: eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)



'~ 3.3
- 45 _
Examgle 8
4'-[[2-n-Butyl-6-(N-cyclohexylmethyl-acetamido)-
benzimidazol-1-yl]methylJbiphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-butyl-6-(N-cyclohexylmethyl-acetamido)-
benzimidazol-1-yl]methyl)biphenyl-2-carboxylate and
trifluoroaceti.c acid in methylene chloride.
Yield: 78.6 of theory,
Melting point: 185-187°C
C34H39N303 ( 5 3 7 . 7 0 )
Calculated: C 75.95 H 7.31 N ?.81
Found: ?5.75 7.40 7.65
Rf value: 0.45 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 50:45:5 by volume)
Example 9
4'-[[6-(Bicyclohexyl-4-carbonylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
trifluoroacetate
Prepared analogously to Example 1 from tert.-butyl 4'-
[[6-(bicyclohexyl-4-carbanylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 93.3% o'f theory,
Melting point: 104-106°C
C38H4SN303 X CF3COOH ( 7 05 . 8 2 )
Calculated: C 68.07 H 6.57 N 5.95
Found: 68.38 6.64 5.80
Rf value: 0.30 (silica geld eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)




4 6 lb '" ri~ ~~ ~~ e3
Example 10
4'-[[6-(Bicyclohexyl-4-aminocarbonylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
semitrifluoroacetate-monohydrate
Prepared analogously to Example 1 from tert.-butyl 4'-
[[6-(bicyclohexyl-4-aminocarbonylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 94.9% of theory,
Melting point: 119-120°C
C3sHa6Na03 x 1/2 CF3 COON x H20 ( 681. 83 )
Calculated: C 68.70 H 7.17 N 8.22
Found: 68.32 6.91 7.81
Rf value: 0.30 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)
Example 11
4'-[[2-n-Butyl-6-(3,4,5,6-tetrahydro-phthalimino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
dihydrate
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-butyl -6-(3,4,5,6-tetrahydro-phthalimino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 14.7% of theory,
Melting point: 119-122°C
C33H3tN304 x 2 H20 ( 53 3 . 63 )
Calculated: C 69.58 H 6.19 N 7.38
Found: 69.77 6.34 7.65
Rf value: 0.45 (silica gel: eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)




<~~~'~~
- 47 -
Example 12
4'-[[2-n-Butyl-6-(5-dimethylamino-naphthalen-1-
sulphonami_no)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid-semitrifluoroacetate
Prepared analogously to Example 1 from tart.-butyl .4'-
[[2-n-butyl-6-(5-dimethylamino-naphthalen-1-
sulphonamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylate and trifluoroacetic acid in methylene
chloride.
Yield: 92.3% of theory,
Melting point: 148-150°C
C37H36H404S x 1/2 CF3COOH ( 689 . 78 )
Calculated: C 66.17 H 5.33 N 8.12 S 4.64
Found: 65.40 5.33 7.92 5.19
Example 13
4'-[[2-n-Butyl-6-(2,3-diphenyl-malefic acid imido)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(2,3-diphenyl-malefic acid imido)-
benzimidazol-1-y1]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 82.6% of theory,
Melting point: 236-237°C
C4 t H33N304 ( 6 31. 7 3 )
Calculated: C 77.95 H 5.27 N 6.65
Found: 77.66 5.24 6.56
Rf value: 0.65 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 50:45:5 by volume)




i~y~~
_ 48 -
Example 14
4'-[[2-n-Butyl-6-(N-methanesulphonyl-2-phenylethyl-
amino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic
acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(N-methanesulphonyl-2-phenylethylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chlaride.
Yield: 71.40 of theory,
Melting point: 215-216°C .
C34H35N3~4 (581.73)
Calculated: C 70.20 H 6.06 N 7.22 S 5.51
Found: 69.99 6.14 7.23 5.55
Rf value: 0.25 (silica gel: eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)
Example 15
4'-[[2-n-Butyl-6-(2,3-d_i.methyl-malefic acid imido)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(2,3-dimethyl-malefic acid imido)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 69.6% of theory,
Melting point: 289-290°C
C3~H~N304 ( 507 . 59 )
Calculated: C 73.35 H 5.76 N 8.28
Found: 73.14 5.90 8.20
Rf value: 0.55 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 50:45:5 by volume)



- 49 -
Example 16
4'-[[6-(N-Benzenesulphonyl-n-pentylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[6-(N-benzenesulphonyl-n-pentylamino)-2-n-butyl-
benzimidazol-2-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
'Yield: 83.9 of theory,
Melting point: 243-244°C
C36H39N3~4S C 6 0 9 . 7 8 )
Calculated: C 70.91 H 6.45 N 6.89 S 5.26
Found: 70.92 6.21 6.98 5.19
Rf value: 0.45 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume}
Example 17
4'-[[2-n-Butyl-6-(N-4-methoxybenzenesulphonyl-n-
pentylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
Prepared analogously to Example 1 from tert,-butyl 4'-
[[2-n-butyl-6-(N-4-methoxybenzenesulphonyl-n-
pentylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylate and trifluoroacetic acid in methylene
chloride.
Yield: 84.6% of theory,
Melting point: 207-208°C
C37H41N3~5S (639.81)
Calculated: C 69.46 H 6.46 N 6.57 S 5.01
Found: 69.31 6.50 6.77 5.21
Rf value: 0.50 (silica gel: eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)




a
Example 18
4'-[[2-n-Butyl-6-(N-4-chlorobenzenesulphonyl-
methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-butyl-6-(N-4-chlorobenzenesulphonyl-methylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 84.8% of theory,
Melting point: 240-241°C
C3zH3oC1N304S ( 588 .12 )
Calculated: C 65.35 H 5.14 N 7.14 C1 6.03 S 5.45
Found: 65.02 5.30 7.17 6.21 5.46
Example 19
4a_[[2_n_Butyl-6-(N-phenylmethanesulphanyl-methylamino)-
benzimidazol-1-y1]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-butyl-6-(N-phenylmethanesulphonyl-methylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 54.9% of theory,
Melting point: 208-209°C
C33~33N3~4~ ( 5 67 . 7 0 )
Calculated: C 69.82 H 5.86 N 7.40 S 5.65
Found: 69.54 5.79 7.47 5.59




- 51 -
Example 20
4'-[[2-n-Butyl-6-(N-4-methylbenzenesulphonyl--
methylamino)-benzimidazol-1-yl]methyl)biphenyl-2-
carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(N-4-methylbenzenesulphonyl-methylamino)-
benzimidazol-1-yl)methyl)biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 92.5% of theory,
Melting point: 259-260°C
C33H33N3~4s ( 5 6 7 . 7 0 )
Calculated: C 69.82 H 5.86 N 7.40 S 5.65
Found: 69.70 5.90 7.44 5.68
Rø value: 0.25 (silica gel; eluant: ethyl
acetate/ethano2/ammonia = 80:40:2 by volume)
Example 21
4'-[[2-n-Butyl-6-(N-n-propylsulphonyl-methylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(N-n-propylsulphonyl-methylamino)-
benzimidazol-1-y1)methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 67.3% of theory,
Melting point: 222-223°C
C2sH33N3C4s ( 519 . 6 6 )
Calculated: C 67.03 H 6.40 N 8.09 S 6.17
Found: 67.02 6.49 8.04 6.1&
Rf value: 0.20 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)
r




52
Example 22
4'-[[2-n°Butyl°6-(N-4-methoxybenzenesulphonyl-n-
propylamino)-benzimidazal-1-yl)methyl]biphenyl-2-
carboxylic acid -
Prepared analagously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(N-4-methoxybenzenesulphonyl-n-
propylamino)-benzimidazol-1-yl]methyl)biphenyl-2-
carboxylate and trifluoroacetic acid in methylene
chloride.
Yield: 86.40 of theory,
Melting point: 227-228°C
C35H37N305S ( 611. 7 5 )
Calculated: C 68.?2 H 6.10 N 6.87 S 5.24
Found: 68.54 6.20 6:88 5.25
Rf value: 0.25 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)
Example 23
4'-[[2-n-Butyl-6-(N-4-methylbenzenesulphonyl-n-
propylamino)-benzimidazol-1-yl]methyl)biphenyl-2-
carboxylic acid
Prepared analogously to Example 2 from tart.-butyl 4'-
[[2-n-butyl-6-(N-4-methylbenzenesulphonyl-n-
propylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid and trifluoroacetic acid in methylene
chloride.
Yield: 82.8% of theory,
Melting point: 223-224°C
C35H37N3C4S ( 59 5 . 7 6 )
Calculated: C 70.56 H 6.26 N 7.05 S 5.38
Faund: 70.25 6.20 7.24 5.62
Rf value: 0.28 (silica gel: eluant: ethyl
acetate/ethanal/ammonia = 80:40:2 by volume)



-- 53 -
Example 24
4°-[[2-n-Butyl-6-(N-4-chlorobenzenesulphonyl-
isopropylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-butyl-6-(N-4-chlorobenzenesulphonyl-
isopropylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylate and trifluoroacetic acid in methylene
chloride.
Yield: 82.1% of theory,
Melting point: 260-261°C
C34H34C1N304S ( 616 .17 )
Calculated: C 66.28 H 5.56 N 6.82 C1 5.75 S 5.20
Found: 66.05 5.77 7.05 5.87 5.34
Rf value: 0.30 (silica gelo eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)
Example 25
4°-[[6-(N-Benzoy2-isopropylamino)-2-n-butyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[6-(N-benzoyl-isopropylamino)-2-n-butyl-benzimidazol-1-
yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic
acid in methylene chloride.
Yield: 58.3% of theory,
Melting point: 209-210°C
C35H35N3~3 ( 54 5 . 68 )
Calculated: C 77.04 H 6.46 N 7.70
Found: 76.66 6.57 7.65
Rf value: 0.20 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)




54 -
Example 26
4'-[[2-n-Butyl-6-(1H,3H-quinazolin-2,4-dion-3-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
hemihydrate
Prepared analogously to Example 1 from tart.-butyl 4°-
[[2-n-butyl-6-(1H,3H-quinazolin-2,4-dion-3-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 53.1% of theory,
Melting point: 338-340°C
C33HzaN4o4 x 1/ 2 HZO ( 5 5 3 . 61 )
Calculated: C 71.59 H 5.28 N 10.12
Found: 71.19 5.33 10.22
Example 27
4'-[[2-n-Butyl-6-(N-4-chlorobenzenesulphonyl-
benzylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
Prepared analagously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(N-4 -chlorobenzenesulphonyl-benzylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 64.50 of theory,
Melting point: 212-213°C
C3sH34C1N304S ( 664 . 2 2 )
Calculated: C 68.72 H 5.16 N 6.33 C1 5.34 S 4.83
Found: 68.76 5.27 6.39 5.62 4.81
Rf value: 0.28 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)




- 55 -
Example 28
4'-[[2-n-Butyl-6-(N-n-butanesulphonyl-benzylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-butyl-6-(N-n-butanesulphanyl-benzylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 66.40 of theory,
Melting point: I93-194°C
C3bH39N3~4s (609.78)
Calculated: C 70.92 H 6.45 N 6.89 S 5.26
Found: 70.76 6.54 6.94 5.40
Rø value: 0.25 (silica gels eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume)
Example 29
4'-[[2-n-Butyl-6-(N-6,7-dimethoxynaphthalen-2-sulphonyl-
methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-butyl-6-(N-6,7-dimethoxynaphthalen-2-sulphonyl-
methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylate and trifluoroacetic acid in methylene
chloride.
Yield: 87.0% of theory,
Melting point: 261-262°C
C38H37N3~6S ( 6 6 3 . 7 9 )
Calculated: C 68.76 H 5.62 N 6.33 S 4.83
Found: 69.00 6.00 6.15 5.07
Rf value: 0.23 (silica gel; eluant: ethyl
acetate/ethanol/ammonia = 80:40:2 by volume}




- 56 - ~~ ~:e~'4'~
Example 30
4'-[j2-n°Butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-1-
yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-1-
yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 38.0% of theory,
Melting point: 146-148°C
C33H33N3~3 ( 519 . 65 )
Rf value: 0.30 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Example 31
4'-[[2-n-Butyl-5-(2-oxo-3,4-tetramethylene-pyrrolidin-1-
yl)-benzimidazol-1-y1]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[(2-n-butyl-5-(2-oxo-3,4-tetramethylene-pyrrolidin-1-
yl)-banzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 15.5% of theory,
Melting point: amorphous
C33B33N3C3 ( 519 . 65 )
Rf value: 0.20 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)



~~~x~~~
- 57 -
Example 32
4'-[[2-n-Butyl-6-(3,3-dimethylpiperidin-1-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(3,3-dimethylpiperidin-1-yl)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid in methylene chloride.
Yield: 860 of theory,
Melting point: from 120°C (sintering)
C32H37N3~2 ( 4 9 5 . 7 0 )
Calculated: C 77.54 H 7.52 N 8.48
Found: 77.54 7.24 8.19
Rf value: 0.35 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Example 33
4'-[(2-n-Butyl-6-heptamethyleneimino-benzimidazol-1-yl~-
methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-heptamethyleneimino-benzimidazol-1-yl]-
methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 71% of theory,
Melting point: 195-198°C
C32H37N3~2 ( 4 9 5 . 6 0 )
Calculated: C 77.55 H 7.52 N 8.48
Found: 77.40 7.66 8.23
Rf value: 0.40 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)


~~~~'~~ ~
- 58 -
Examgle 34
4°-[[2-n-Butyl-6-(piperidin-1-yl)-benzimidazol-1.-
yl)methyl)biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(piperidin-1-yl)-benzimidazol-1-
yl)methyl)biphenyl-2-carboxylate and trifluoroacetic
acid.
Yield: 840 of theory,
Melting point: 199-200°C
C3oH33N3~2 ( 4 6? . 6 0 ) .
Calculated: C 77.06 H 7.11 N 8.99
Found: 76:85 7.28 9.02
Rf value: 0.40 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Examgle 35
4'-[[2-n-Butyl-6-(4-methylpiperidin-1-yl)-benzimidazol-
1-yl)methyl)biphenyl-2-carbaxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(4-methyl-piperidin-1-yl)-benzimidazol-1-
yl)methyl]biphenyl-2-carboxylate and trifluoroacetic
acid.
Yield: 82% of theory,
Melting point: 162-165°C
C31H35~3~2 (481.60)
Calculated: C 7?.31 H 7.33 N 8.?3
Found: 77.20 ?.19 8.63
Rf value: 0.40 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)




- 59 -
Examgle 36
4°-[[2-n-Butyl-6-hexamethyleneimina-benzimidazol-1-yl]-
methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[(2-n-butyl-6-hexamethyleneimino-benzimidazol-1-yl)-
methyl]-biphenyl-2-carboxylate and trifllaoroacetic acid.
Yield: 34% of theory,
Melting point: 197-199°C
~'3tH3sN3~z (481.60)
Calculated: C 77.31 H 7.33 N 8.73
Found: 76.99 7.35 8.62
Rf value: 0.40 (silica geld eluant: methylene
chloride/ethanol = 9:1 by volume)
Examgle 37
4'-[[2-n-Propyl-6-(2--oxo-piperidin-1-yl)-benzimidazol-1-
yl]methyl]biphenyl-2 -carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-propyl-6-(2-oxo-piperidin-1-yl)-benzimidazal-1-
yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid.
Yield: 600 of theory,
Melting point: 208-210°C
Cz9Hz9Ns~3 ( 4 6 7 . 6 0 )
Calculated: C 74.49 H 6.25 N 8.99
Found: 74.00 6.29 8.90
Rf value: 0.50 (silica gel: eluant: methylene
chloride/ethanol = 9:1 by volume)



- 60 -
Example 38
4°-[[2-n-Propyl-6-(prapanesultam-1-yl)-benzimidazol-1-
yl)methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4°-
[[2-n-propyl-6-(propanesultam-1-yl)-benzimidazol-1-
yl)methyl)biphenyl-2-carboxylate and trifluoraacetic
acid.
Yield: 49% of theory,
Melting paint: amorphous
C27H27N3~45 ( 4 8 9 . 58 ) '
Calculated: C 66.23 H 5.56 N 8.56 S 6.55
Found: 66.08 5.50 8.37 6.52
Rf value: 0.47 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Mass spectrum: (M + H)~' = 490
Example 39
4°-[[2-n-Propyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4°-
[[2 -n-propyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid.
Yield: 57% of theory,
Melting point: amorphous
CZ8H29N3~4S ( 503 : 63 )
Calculated: C 66.77 H 5.80 T1 8.34 S 6.37
Found: 66.59 5.7? 8.18 6.33
Rf value: 0.51 (silica gel; eluant: methylene
chlaride/ethanol = 9:1 by volume)
Mass spectrum: (M + H)~ - 504



-- 61
Example 40
4'-[[2-n-Butyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-butyl-6-(butanesultam--1-yl)-benzimidazol-1--
yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid.
Yield: 51% of theory,
Melting point: 203-205°C
C29H3~N30~S (517.63)
Calculated: C 67.29 H 6.04 N 8.12 S 6.19
Found: 67.22 5.97 7.97 6.10
Rf value: 0.52 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Mass spectrum: (M + H)'" -- 518
Example 41
4'-[[2-n-Butyl-6-(benzoxazol-2-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
a} 2-n-Butyl-5-fbenzoxazol-2-yl?-benzimidazole
1.43 g (12 mMol) of thionyl chloride are added dropwise
at 10°C with stirring to a suspension of 2.52 g
(10 mMol) of 2-n-butyl-benzimidazole-5-carboxylic acid
in 15 ml of N-methylpyrrolidinone. The mixture is
stirred for a further 15 minutes at ambient temperature,
then 1.31 g (11 mMol) of 2 -aminophenol are added and the
mixture is heated to 140°C for 2 hours. The mixture is
then poured onto about 50 g of ice and 5 ml of 30%
sodium hydroxide solution are added with stirring. The
crude product precipitated is suction filtered and
purified by column chromatography (300 g of silica gel;
eluant: methylene chloride + 3% ethanol}.
<.




- 62 -
Yield: 1.2 g (41a of theory),
Melting point: 118-120°C
Ct8H17N3C (291.36)
Calculated: C 74.20 H 5.88 N 14.42
Found: 73:98 5.97 14.20
b) Isomer mixture of
4°-[[2-n-butyl-6-(benzoxazol-2-yl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylic acid nitrite and
4'-[[2-n-butyl-5-(benzoxazol-2-yl)-benzimidazol-1-
yllmethyl]biphenyl-2-carboxylic acid nitrite
A solution of 1 g (3.43 mMol) of 2-n-butyl-5-
(benzoxazol-2-yl)-benzimidazole and 0.98 g (3.60 mMol)
of 4°-bromomethyl-biphenyl-2-carboxylic ac~.d nitrite in
20 ml dimethylsulphoxide is mixed with 0.41 g (3.6 mMol)
of potassium tert.-butoxide and stirred for 48 hours ast
ambient temperature. the mixture is then poured onto
300 ml of water, saturated with sodium chloride and
extracted three times with 30 ml of ethyl acetate. By
column chromatography (200 g of silica gel; eluant:
ethyl acetate/petroleum ether (1:1 by volume)) 1.4 g
(850 of theory) of a mixture of the isomers is obtained
in the retie l:1 and this mixture begins to sinter from
130°C.
C32H26N4~ ( 4 8 2 . 5 9 )
Calculated: C 79.64 H 5.43 N 11.61
Found: 79.64 5.36 11.59
c) 4'-[[2-n-Butyl-6-(benzoxazol-2-yl)-benzimidazol-1-
Yl l methyl,] -2- ( 1H-tetrazol-5-yl~~ -biphenyl
A solution of the (1:1) isomer mixture of 4'-[[2-n-
butyl-6-(benzoxazol-2-yl)-benzimidazal-3-yl)methyl]-
biphenyl-2-carboxylic acid nitrite and 4'-[[2-n-butyl-5-
(benzoxazol-2-yl)-benzimidazol-:1-yl)methyl]biphenyl-2-
carboxylic acid nitrite in 20 ml of dimethylformamide is
mixed with 2 g of ammonium chloride and 2 g of sodium
azide and heated to 120-130°C for 4 hours. After a
further 2 g of ammonium chloride and 2 g of sodium azide
have been added''and the mixture has been heated to



- 63 -
120-130°C for a further 18 hours, it is poured onto
100 ml of water. The product mixture precipitated is
suction filtered and separated by column chromatography
(300 g of silica gel, eluant: methylene chloride + 3%
ethanol).
Yield: 100 mg (20% of theory) in amorphous form.
C32H27N7a ( 5 2 5 . 6 2 )
Calculated: C 73.12 H 5.18 N 18.66
Found: 73.10 5.50 18.42
Rf value: 0.75 (silica gel; eluant: methylene
chlaride/ethanol = 9:1 by volume)
The following compounds are obtained analogously to
Example 41:
4°-[[2-n-butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5 -yl)-biphenyl
4'-[[2-n-propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-butyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-
1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-propyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-
1-yl]methyl)-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-ethyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-y1)-biphenyl
4' - [ [ 2-n-propyl-6- ( 2-methyl-4 , 5-dihydro-pyridaz in-3-an-
6-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
4'-[[2-n-propyl-6-(2-benzyl-4,5-dihydro-pyridazin-3-an-
6-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-




- 64 -
biphenyl
4'-[[2-n-butyl-6-(1-methyl-imidazolin-2-yl)-
benzimidazol-1-y1]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-propyl-6-(1-n-hexyl-imidazolin-~-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-((2-n-butyl-6-(1-n-butyl-imidazolin-2-yl)-
benzimidazol-1-yl]methyl]-2-(1I-I-tetrazol-5-yl)-biphenyl
4'-[[2-n-propyl-6-(1-cyclopropyl-imidazolin-2-yl)--
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[(2-n-propyl-6-(~.-cyclohexyl-imidazolin-2-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[(2-n-propyl-6-(1-methyl-imidazol-2-y1)-benzimidazol-
1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-([2-n-butyl-6-(1-methyl-imidazol-2-yl)-benzimidazol-
1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[(2-n-propyl-6-(1-n-propyl-imidazol-~-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-propyl-6-(1-n-hexyl-imidazol-2-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-butyl-6-(2-n-butyl-imidazol-2-yl)-benzimidazal-
1--yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[(2-n-propyl-6-(1-cyclopropyl-imidazol-2-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-propyl-6-(1-cyclohexyl-imidazol-2-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl




d~,~ '~ !~!.
- 65 -
Example 42
4'-[[2-n-Propyl-5-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
and
4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from a mixture of 4'-
[[2-n-propyl-5-(1-methylbenzimidazol-2-yl)-benzimidazol-
1-yl]-methyl]biphenyl-2-carboxylic acid nitrite and 4'-
[[2-n-propyl-6-(Z-methylbenzimidazol-2-yl)-benzimidazol-
1-yl]-methyl]biphenyl-2-carboxylic acid nitrite and
sodium azide in dimethylformamide.
5-isomer:
Yield: 29% of theory,
Melting point: amorphous
C32H2sNa ( 524 . 61 )
Calculated: C 73.26 H 5.38 N 22.36
Found: 73.03 5.22 21.26
Mass spectrum: (M f H)+ - 525
6-isomer:
Yield: 340 of theory,
Melting point: 198-200°C
C32H28N$ ( 5 2 4 . 61 )
Calculated: C 73.26 H 5.38 N 21.36
Found: 73.11 5.27 21.19
Mass spectrum: (M + H)+ - 525




66 -
Exempla 43
4°-[[2-n-Butyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4°-[[2-n-butyl-
6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-
methyl]biphenyl-2-carboxylic acid nitrile arid sodium
azide in dimethylformamide.
Yield: 28~ of theory,
Melting point: 224 -226°C
C33H3oN8 ( 5 3 8 . 6 3 )
Calculated: C 73.58 H 5.61 N 20.81
Found: 73.31 5.73 19.99
Rf value: 0.76 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Mass spectrum: (M ~- H)+ = 539
Example 44
4'-[[2-n-Butyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-n-butyl-
6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-
methyl]biphenyl-2-carboxylic acid nitrile and sodium
azide in dimethylformamide.
Yield: 20% of theory,
Melting point: amorphous
C3oH3~N~0 (505.63)
Calculated: C 67:94 H 6.23 N 17.33
Found: 67.67 6.13 17.52
Rf value: 0°30 (silica gel: eluant: methylene
chloride/ethanol = 9:1 by volume.)




,r ~
~ ~Z~ t~ c~ ti., '~.
._ 67 - f,~ ~ -; ~ !3 z:s .3
Example 45
4'-[[2-n-Butyl-6-(3,3-dimethylpiperidin-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4°-[[2-n-butyl-
6-(3,3-dimethylpiperidin-1-yl)-benzimidazol-1-yl]-
methyl]-2-carboxylic acid nitrile and sodium azide in
dimethylformamide.
Yield: 8~ of theory,
Melting point: sintering from 148°C
C32H37N7 x HC1 ( 519 . 7 0 ) .
Mass spectrums (M + H)+ - 520
Example 46
4'-[[2-n-Butyl-6-(4,4-tetramethyleneglutarimido)-
benzimidazol-1-yl]-methyl]-4-chloro-2-(1H-tetrazol-5-
yl)-biphenyl
Prepared analogously to Example 41 from 4°-[[2-n-butyl-
6-(4,4-tetramethyleneglutarimido)-benzimidazol-1-yl]-
methyl]-4-chloro-biphenyl-2-carboxylic acid nitrile and
sodium azide in dimethylformamide.
Yield: 40% of theory,
Melting point: sintering from 160°C
C34H34N7~2C1 ( 608 . 16 )
Calculated: C 67.15 H 5.64 N 16.12
Found: 66.90 5.86 15.86
Rf value: 0.50 (silica gel: eluant: methylene
chloride/ethanol = 9:1 by volume)
Example 47
4'-[[2-n-Butyl-6-(propanesultam-1-yl)-benzimidazol-1-
yl]-methyl)-2-(1H-tetrazol-5-y1)-biphenyl
Prepared analogously to Example 41 from 4°-[[2-n-butyl-
6-(propanesultam-1-yl)-benzimidazol-1-yl]-
methyl]biphenyl =2-carboxylic acid nitrite and




' P lF' Et'Q 's
fd ~z ~ °~?w.J 's~
- 68
dimethylformamide.
Yield: 46% of theory,
Melting point: 203-205°C
CzaHzvN7~zS ( 527 . ? 0 )
Calculated: C 63.73 H 5.54 N~7:8.58 S 6.08
Found: 62.52 5.56 18.40 6.00
Rf value: 0.35 (silica gal; eluant: methyl.ene
chlaride/ethanal = 9:1 by volume)
Example 48
4'-[[2-n-Butyl-6-(butanesultam-1-yl)-benzimidazol-1-y1]-
methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-n-butyl-
6-(butanesultam-1-yl)-benzimidazol-1-yl]-
methyl]biphenyl-2-carboxylic acid nitrile and sodium
azide in dimethylformamide.
Yield: 30% of theory,
Melting point: 189-191°C
CzvH3tN7CzS (541.70)
Calculated: C 64.30 H 5.95 N 18.10 S 5.92
Found: 64.40 5.75 17.90 5.85
Rf value: 0.37 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Example 49
4'-[[2-n-Propyl-6-(butanesultam-1-yl)-benzimidazol-I-
yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-n-propyl-
6-(butanesultam-1-yl)-benzimidazol-1-yl]-
methyl]biphenyl-2-carboxylic acid nitrile and sodium
azide in dimethylformamide.
Yield: 37% of theory,
Melting point: 204-206°C
Cz8Hz9N~O2S ( 527 . 63 )
Calculated: C 63.73 H 5.54 N 18.58 S 6.08




- ~~~:~ g~t.~~~i~
Found: 63.70 5.49 18.37 6.19
Rf value: 0.36 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Mass spectrum: m/e = 527
Exam~ole 50
Mixture of
4'-[[2.-n-butyl-6-(2-hydroxy-cycloheatylamin~ocarbonyl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
and
4'-[[2-n-butyl-5-(2-hydroxy-cyclohexylaminocarbonyl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 4l from a mixture of 4'-
([2-n-butyl-6-(2~-hydroxy-cyclohexylaminocarbonyl)-
benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid
nitrile and 4'-[[2-n-butyl-5-(2-hydroxy-cyclohexylamino-
carbonyl)-benzimidazol-1-yl]-methyl]biphenyl-2-
carboxylic acid nitrite and sodium azide in
dimethylformamide.
Yield: 8% of theory,
Melting point: 198-200°C
C32H35N7~z ( 5 4 9 . 7 0 )
Rf value: 0.30 silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Mass spectrum: (M + H)+ - 550
Example 51
4'-[[2-n-Butyl-6-(2-oxo-pyrrolidin-1-yl)-benzimidazol-1-
yl]-methyl]-2-(1~I-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-n-butyl-
6-(2-oxo-pyrrolidin-1-yl)-benzimidazol-Z-yl.]methyl]-
biphenyl-2-carboxylic acid nitrite and sodium azide in
dimethylformamide.
Yield: 15% of theory,
Melting point: 153-155°C




- 70 - ~.,~~.~~
C29H29N7C ( 4 91. 6 0 )
Calculated: C 70.85 H 5.95 N 19.95
Found: 70.79 6.17 19.71
Rf value: 0.45 (silica gel; eluant: methylene
chloride/ethanal = 9:1 by walume)
Mass spectrum: (M + H)* - 492
Example 52
Mixture of
4'-[[2-n-butyl-6-(1,1-dimethyl-2-hydroxy-ethylamino-
carbonyl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-
yl)-biphenyl and
4'-[[2-n-butyl-5-(1,1-dimethyl-2-hydroxy-ethylamino-
carbonyl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-
yl)-biphenyl
Prepared analogously to Example 41 from a mixture of 4°-
[[2-n-butyl-6-(1,1-dimethyl-2-hydroxy-ethylamino-
carbonyl)-benzimidazol-1-yl]-methyl]biphenyl-2-
carboxylic acid nitrite and 4"-[[2-n-butyl-5-(1,1-
dimethyl-2-hydroxy-ethylamino-carbonyl)-benzimidazol-1-
ylJ-methyl]biphenyl-2-carboxylic acid nitrite and sodium
azide in dimethylformamide.
Yield: 14% of theory,
Melting point: amorphous
C3oH33N702 ( 5 2 3 . 6 0 )
Rf value: 0.30 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Mass spectrum: (M + H)* -- 524




P
- 71 --
Example 53
4'-[[2-n-Butyl-6-(2-oxo-hexamethyleneimino)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-n-butyl-
6-(2-oxo-hexamethyleneimino)-benzimidazol-1-yl}-
methyl}biphenyl-2-carboxylic acid nitrile and sodium
azide in dimethylformamide.
Yield: 340 of theory,
Melting point: amorphous
C31 H33N7d ( 519 . 7 0 )
Calculated: C 71.65 H 6.40 N 18.87
Found: 70.99 6.32 18.75
R~ value: 0.15 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Example 54
4'-[[2-n-Propyl-6-(2-oxo--piperidin-1-yl)-benzimidazol-1-
yl}-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-n-propyl-
6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl}-
methyl}biphenyl-2-carboxylic acid nitrite and sodium
azide in dimethylformamide.
Yield: 14.50 of theory,
Melting point: sintering from 125°C
C29Hz9N7~ ( 4 91 ~ 6 0 )
Rf value: 0.25 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Mass spectrum: (M + H)+ = 492
a




_ ~2 ~~ ~~'~ ~~
Example 55
4'-[[2-n-Butyl-6-(3,3-dimethylglutarimido)-benzimidazol-
1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
a) 4'[[2-n-Butyl-6-(3,3-dimethylglutarimido)-
benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-
tetrazol-5-vl)-biphem~l
1.8 g (3.3 mMol) of 4°-bromomethyl-2-(1-triphenylmethyl-
tetrazol-5-y1)-biphenyl are added to a solution of
1.04 g (3.3 mMol) of 2-n-butyl-5-(3,3-dimethyl- .
glutarimido)-benzimidazole and 425 mg (3.8 mMol) of
potassium tert.-butoxide in 25 ml of dimethylsulphoxide.
The mixture is stirred for 3 hours at ambient
temperature, then stirred into 150 ml of water,
extracted three times with 30 ml of ethyl acetate, then
the organic extracts are dried and concentrated by
evaporation. The residue obtained is purified by column
chromatography (300 g of silica gel; eluant: ethyl
acetate/petroleum ether (2:1 by volume)).
'Yield: 400 mg (15% of theory),
Rf value: 0.38 (ethyl acetate/petroleum ether = 6:1)
b) 4'-[[2-n-Butyl-6-(3,3-dimethylglutarimido)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
A solution of 400 mg (0.5 mMol) of 4'-[[2-n-butyl-6-
(3,3-dimethylglutarimido)-benzimidazol-1-yl]-methyl]-2-
(1-triphenylmethyl-tetrazol-5-yl)-biphenyl in 10 ml of
methanol is mixed with 1.5 ml of methanolic hydrochloric
acid and stirred for 2 hours at ambient temperature,
then concentrated by evaporation, the residue is mixed
with 15 ml of water and made alkaline with concentrated
ammonia, whereupon the product goes into solution. By
acidification with glacial acetic acid, the crude
product is precipitated and 'then purified by column
chromatography (150 g of silica gel; eluant: methylene
r


~~~~~r~.~~
- 73 -
chloride + 5% ethanol).
Yield: 150 mg (55% of theory),
Melting point: 184-186°C
C32H33N7~2 ( 5 4 7 . 7 0 )
Calculated: C 70.18 H 6.07 N 17.90
Found: 69.98 6.20 17.67
Example 56
4°-[[2-n-Butyl°6-(N-methylaminocarbonyl-n-pentylamino)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 55 from 4'-[[2-n-butyl-
6-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-
yl)methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl
and hydrochloric acid in ethanol.
Yield: 53.80 of theory,
Melting point: 124-126°C
C33H38N~0 ( 5 5 0 . 71 )
Rf value: 0.25 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)
Calculated: C 69.79 H 6.95 N 20.35
Found: 69.78 ?.05 20.31
Mass spectrum: (M + H)~ - 492
Example 57
4'-[[2-n-Butyl-5-(N-methylaminocarbonyl-n-pentylamino)-
benzimidazol-1-yl]methyl.]-2-(1H-tetrazol-5-yl)-biphenyl-
dihydrate
Prepared analogously to Example 55 from 4'-[[2-n-butyl-
5-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-
yl)methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl
and hydrochloric acid in ethanol.
Yield: 76.2% of theory,
Melting point: 201-203°C
C32H38N80 x 2 H20 ( 5 8 6 . 7 4 )



~~~~E~v~
- 74 -
Calculated: C 65.50 H 7.21 N 19.09
Found: 65.43 7.07 19.12
Examt~le 58
4'-[[2-n-Butyl-6-(N-cyclohexylaminocarbonyl-n-
pentylamino)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-
yl)-biphenyl-hydrate
Prepared analogously to Example 55 from 4'-[[2-n-butyl-
6-(N-cyclohexylaminocarbonyl-n-pentylamino)-
benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-
5-yl)-biphenyl and hydrochloric acid in ethanol.
Yield: 95.2% of theory,
Melting point: 128-132°C
C37H46N80 x H20 ( 6 3 6 . 8 4 )
Calculated: C 69.78 H 7.59 N 17.59
Found: 69.61 7.71 1?.41
Rf value: 0.45 (silica gel; eluant: ethanol/ammonia -
80:40:2 by volume)
Example 59
4'-[[2-n-Butyl-5-(N-cyclohexylaminocarbonyl-n-
pentylamino)-benzimidazol-1-yl]methyl]-Z-(1H-tetrazol-5-
yl)-biphenyl-hydrate
Prepared analogously to Example 55 from 4'-[[2-n-butyl-
5-(N-cyclohexylaminocarbonyl-n-pentylamino)-
benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-
5-yl)-biphenyl and hydrochloric acid in ethanol.
Yield: 88.6% of theory,
Melting point: 117-120°C
C3~Ha6N8C x H20 ( 63 6 . 84 )
Calculated: C 69.78 H 7.59 N 17.59
Found: 70.06 7.58 17.56
Rf value: 0.45 (silica gel; eluant: ethanol/ammonia -
80:40:2 by volume)



S~ a~a
~~1,~ ~ra~k
- ?5 -
Examt~le 60
4'-[[2-n-Butyl-6-(5-dimethylaminonaphthalen-1-
sulphonamino)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-
5-yl)-biphenyl-hydrate
Prepared analogously to Example 55 from 4°-[[2-n-butyl-
6-(5-dimethylaminonaphthalen-1-sulphonamino)-
benzimidazol-1-yl]methyl]-2-(2-triphenylmethyl-tetrazol-
5-yl)-biphenyl and hydrochloric acid in ethanol.
Yield: 44.7% of theory,
C37H36NaozS x H20 ( 67 4 . 81 ) .:
Calculated: C 65.85 H 5.67 N 16.60 S 4.75
Found: 65.80 5.46 16.42 4.90
Example 61.
4'-[[2-n-Butyl-6-(2-oxo-8,4-tetramethylene-pyrrolidin-1-
yl)-benzimidazol--1-yl]methyl]biphenyl-2-carboxylic acid
420 mg (0.81 mMol) of 4'-[[2-n-butyl-6-(2-oxo-1,2-
dihydro-3,4-tetramethylene-pyrrol-1-yl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylic acid are dissolved in
60 ml of methanol and 60 ml of ethyl acetate and
hydrogenated with the addition of 200 mg of palladium on
charcoal (100) under 5 bar of hydrogen pressure and at
40°C. The catalyst is removed by suction filtering, the
solvent is evaporated off and the crude product is
purified by column chromatography (200 g of silica gel;
eluant: methylene chloride + 3o ethanol).
Yield: 260 mg (62% of theory),
Melting point: amorphous
C33H35N3C3 ( 521. 67 )
Calculated: C 75.98 H 6.76 N 8.06
Found: 75.75 6.62 8.24




- 76 - ~~'~~
Example 62
Mixture of
4'-[[2-n-butyl-6-(5,5-pentamethylene-oxazolin-2-yl)-
benzimidazol-1-yl)-methyl]-2-(3.H-~tetrazol-5-yl)-biphenyl
and
4'-[[2-n-butyl-5-(5,5-pentamethylene-oxazolin-2-yl)-
benzimidazol-1-y1)-methyl)-2-(1H-tetrazol-5-yl)-biphenyl
A solution of 930 mg (2 mMol) of an isomer mixture of
4'-[[2-n-butyl-6-earboxy-benzimidazol-1-yl]-methyl]-2-
(1H-tetrazol-5-yl)-biphenyl arid 4°-[[2-n-butyl-5-
carboxy-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl and 356 mg (2.2 mMol) of carbonyldiimidazole in
30 ml of tetrahydrofuran is stirred for 30 minutes at
ambient temperature. Then 332 r~, (2 mMol) of 1-
(aminomethyl)-cyclohexanol-dihydrochloride are added and
the mixture is stirred for a further 15 hours at ambient
temperature. The mixture is then concentrated by
evaporation, 2 ml of thionyl chloride are slowly added
dropwise, the mixture is stirred for one hour, the
thionyl chloride is distilled off and the residue is
mixed with 5 ml of ice water. The insoluble crude
product is purified by column chromatography (150 g of
silica gel: eluant: methylene chloride + 5n ethanol).
In this way, 25 mg (2% of theory) of a mixture of 4'-
[[2-n-butyl-6-(5,5-pentamethylene-oxazolin-2-yl)-
benzimidazol-1-yl)-methyl)-2-(1H-tetrazol-5-yl)-biphenyl
and
4'-[[2-n-butyl-5-(5,5-pentamethylene-oxazolin-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
is obtained.
Melting point: from 2.15°C (decomp.)
C33H35N7~ ( 5 ~ 5 . 6 7 )
Mass spectrum: (M + H)* - 546




- 77 -
ExamQle 63
4'-[[2-n-Butyl-6-(N-methyl-phenylaminocarbonylamino)-
benzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid
A solution of 0.8 g (2.00 mMol) of 4'-[(2-n-butyl-6-
aminobenzimidazol-1-yl]-methyl]biphenyl-2-carboxylic
acid and 0.9 g of N-methyl-isatoic acid anhydride in
3 m1 of pyridine is refluxed for 48 hours, then
evaporated to dryness, the residue is suspended in about
ml of methylene ehloride, suction filtered, washed
with a further 5 ml of methylene chloride and dried. .
Yield: 0.66 g (62% of theory),
Melting point: 274-276°C
C33H32N4~3 ( 5 3 2 . 6 0 )
Calculated: C 74.41 H 6.06 N 10.57
Found: 74.23 5.94 10.66
Example 64
4'-[[2-n-Butyl-5-(3-carboxy-propionyl)-benzimidazol-1-
yl]-methyl]biphenyl-2-carboxylic acid
A solution of 200 mg (0.39 mMol) of methyl 4'-[[2-n-
butyl-5-(3-methoxycarbonyl-propionyl)-benzimidazol-1-
yl]-methyl]biphenyl-2-carboxylate and 0.75 ml of sodium
hydroxide solution in 4 ml of ethanol is stirred for 2
hours at 75°C, then mixed with 40 ml of water and
acidified with glacial acetic acid. The alcohol is then
distilled off, the resulting mixture is stirred for one
hour at ambient temperature, tha product precipitated is
suction filtered, washed with 10 ml of water and dried.
Yield: 120 mg (64% of theory),
Melting point: 200-202°C
C29H2sN2~a ( 4 8 4 . 6 0 )
Calculated: C 71.88 H 5.83 N 5.78
Found: 71.66 5.86 5.63




- 78
Example 65
4'-[[2-n-Butyl-6-(3-carboxy-2-methyl-propionyl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid x
0 . 2 5 H20
Prepared analogously to Example 64 from methyl 4°-[[2-n-
butyl-6-(3-methoxycarbonyl-2-methyl-propionyl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
sodium hydroxide solution in ethanol.
Yield: 18a of theory,
Melting point: 193-194°C
C30H30~2~5 x ~-/ 4 H20 ( 4 9 8 . 6 0 )
Calculated: C 71.62 H 6.11 N 5.56
Found: 71.72 6.09 5.68
Rf value: 0.37 (silica gel; eluant: methylene
chloride/ethanol/glacial acetic acid = 28:1:0.05 by
volume)
Example 66
4°-[[2-n-Butyl-6-(3-carboxy-propionyl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 64 from methyl 4'-[[2-n°
butyl-6-(3-methoxycarbonyl-propionyl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylate and sodium hydroxide
solution in ethanol.
Yield: 97% of theory,
Melting point: 240-242°C
C29H2sN2Q5 ( 4 8 4 . 6 0 )
Calculated: C 71.88 H 5.83 N 5.78
Found: 71.74 6.07 5.93




Example 67
4'-[[2-n-Butyl-6-(2,3-dimethylmaleic acid imino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
52.5 mg (0.1 mMol) of 4'-[[2-n-butyl-6-(2,3-
dimethylmaleic acid amino)-benzimidazol-1-yl]-methyl]-
biphenyl-2-carboxylate are heated to boiling for one
hour in 2 ml of bis-(2-methoxy-ethyl)-ether. The
solvent is removed by distillation and the oily residue
is distributed in ethyl acetate/water. The organic
phase is washed twice more with water, dried with
magnesium sulphate and concentrated by rotary
evaporation. The residue is triturated in 1 ml of
acetone, suction filtered, washed with ether and dried
in vacuo at 75°C.
Yield: 29.0 mg (57.2a of theory),
Melting point: 289-291°C
C~~I329N304 ( 507 . 59 )
Calculated: C 73.35 H 5.76 i~ 8.29
Found: 73.50 5.64 8.10
Example 68
4°-[[2-n-Butyl-6-(3,4,5,6-tetrahydro-phthalimino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid-
hydrate
0.275 g (0.5 mMal) of 4°-[[2-n-butyl-6-(2-carboxy-
3,4,5,6-tetrahydrobenzamino)-benzimidazol-1-yl]-
methyl]biphenyl-2-~carboxylate are refluxed for 4 hours
in 5 ml of pyridine. The mixture is evaporated to
dryness in vacuo by rotary evaporation and the crude
product is recrystallised from acetone. It is suction
filtered, washed with acetone and dried in vacuo at
70°C.
Yield: 0.2 g (72.4% of theory),
Melting point: 226-228°C




-8~-
C30H31N3~4 x Hzp (551.64)
Calculated: C 71.85 ~I 6.03 N 7.62
Found: 71.83 5.90 7.61
Example 69
Tert.-butyl 4'-[[2-n-butyl-6-(pyrrolidinocarbonylamino)-
benzimidazol-1-yl)methyl)biphenyl-2-carboxylate
2.0 g (15 mMol) of pyrrolidinocarbonyl chloride are
placed in 50 ml of dry chloroform and 2.3 g (6 mMol) of
tert.-butyl 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)- .
methyl]biphenyl-2-carboxylate dissolved in 50 m1 of dry
pyridine are added dropwise for one hour. The reaction
solution is stirred for a further 24 hours and then
concentrated by rotary evaporation. The oily residue is
distributed in ethyl acetate and 10% sodium hydrogen
carbonate solution, the organic phase is separated off '
and, after drying with magnesium sulphate, concentrated
by rotary evaporation. Purification is carried out
using a silica gel column (particle size: 0.063 -
0.2 mm), eluting with petroleum ether/ethyl acetate =
3:7. The corresponding column fractions are
concentrated by rotary evaporation and dried in_ vacuo at
50°C.
Yield: 1.7 g (61.8% of theory),
Melting point: 68-70°C (amorphous)
~3~HGON4C3 (552.72)
Rf value: 0.35 (silica gel; eluant: ethyl acetate/ethanol
- 19:1 by volume)
Example 70
4'-[[2-n-Butyl-6-(pyrrolidinocarbonylamino)--
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
trifluoroacetate-monohydrate
Prepared analogously to Example 1 from tert.-butyl 4'-
a




_ g1 _
[[2-n-butyl-6-(pyrralidinocarbonylamino)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid/methylene chloride.
Yield: 91.7 of theory,
Melting point: 233-234°C
C3oH32N403 x CF3COOH x H20 ( 62 8 . 2 5 )
Calculated: C 61.14 H 5.61 N 8.91
Found: 61.25 5.62 9.09
Rf value: 0.48 (silica gel: eluant: ethyl
acetate: ethanol: ammonia = 50:45:5 by volume)
Example ?1
4'-[[2-n-Butyl-6-(2,3-dimethylmaleic acid imino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
314 mg (0.5 mMol) of 4"-[(6-amino-2-n-butyl-
benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid
trifluoroacetate are refluxed together with 76 mg
(0.6 mMol) of 2,3-dimethylmaleic acid anhydride in 10 m1
of pyridine for 18 hours. The solvent is then removed
by rotary evaporation and the oily substance is
distributed in ethyl acetate and loo sodium hydrogen
carbonate solution. The organic phase is separated off,
dried with magnesium sulphate and concentrated by rotary
evaporation after being filtered. By trituration with
acetone and ether, a white crystalline product is
obtained which is dried at 50°C in vacuo after suction
filtering.
Yield: 165 mg (65.0% of theory),
Melting point: 288-290°C
C31H29N304 ( 507 . 59 )
Calculated: C 73.35 H 5.76 N 8.29
Found: 73.14 5.94 8.32




~~~~'~~~.
_ 82 -
Example 72
4°-[(2-n-Butyl-6-hexahydrohomophthalimino-benzimidazol-
1-yl)-methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 71 from 4°-[(6-amino-2-
n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic
acid and hexahydrohomophthalic acrd anhydride in
pyridine.
Yield: 15.3% of theory,
Melting point: 183-185°C
C34H35N3o4 ( 5 4 9 . 6 7 )
Calculated: C 74.29 H 6.49 N 7.64
Found: 74.09 6.47 7,80
Example 73
4'-[[2-n-Butyl-6-(benzofuran-2-carbonylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 71 from 4'-[(6-amino-2-
n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic
acid and benzofuran-2-carboxylic acid anhydride in
pyridine.
Yield: 80a7o of theory,
Melting point: 321-323°C
~34H39N3~4 ( 5 4 3 . 6 2 )
Calculated: C 75.12 H 5.38 N 7.73
Found: 74.92 5.45 7.87
Example 74
4'-[[2-n-Butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinon-1-yl)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
Prepared analogously to Example 1 from tert.,-butyl 4'-
[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinon-1-yl)-benzimidazol-1-yl]-methyl]biphenyl-2-
carboxylate andttrifluoroacetic acid in methylene



- 83 -
chloride.
Yield: 42.20 of theory,
Melting point: 119-122°C
C36H~N403 X H20 ( 5 9 0 . 7 2 )
Calculated: C 73.20 H 6.48 N 9.48
Found: 73.11 6.50 9.67
Example 75
4'-[[2-n-Butyl-6-(2-carboxy-cyclohexylmethylcarbonyl-
amino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic
acid hydrate
a) Tert.-butyl 4'-[[2-n-butyl-6-(2-carboxy-
cyclohexylmethylcarbonylamino)-benzimidazol-7.-yl]-
methyllbighenyl-2-carboxylate
1.3 g (2.86 mMol) of tert.-butyl 4'-[(6-amino-2-n-butyl-
benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate, 0.6 g
(5.35 mMol) of hexahydrohomophthalic acid anhydride and
ml of pyridine are refluxed with stirring for 3 hours.
Then the pyridine is removed by rotary evaporation in
vacuo, the residue is crystallised from acetone, washed
with acetone and dried in vacuo at 70°C.
Yield: 0.67 g (37.6% of theory),
Melting point: 227-229°C
C38H45N3~5 (623.79)
Calculated: C 73.17 H 7.27 N 6.?4
Found: 72.93 ?.15 6.94
b) 4'-[[2-n-butyl-6-(2-carboxy-cyclohexylmethylcarbonyl-
amino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic
0.6 g (0.06 mMol) of tert.-butyl 4'-[[2-n-butyl-6-(2-
carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylate, 30 ml of methylene
chloride and 10 ml of trifluoroacetic acid are stirred
for 3 hours at ambient temperature. The mixture is
diluted with 20 3n1 of methylene chloride, extracted with




R" !~ ~ i~
- 84 -
water, the organic phase is dried aver sodium sulphate
and evaporated to dryness. The residue is dissolved in
ethanol and made alkaline by the addition of ammonia.
The solvent is distilled off in vacuo. The remaining
aqueous solution is acidified with acetic acid, the
product which crystallises out is suction filtered,
washed with water and dried in vacuo at 70°C.
Yield: 0.55 g (98.2% of theory),
Melting point: 160-162°C
C34H37"3Q5 x H2~ (585.68)
Calculated: C 69.72 H 6.71 N 7.17
Found: 69.63 6.64 7.33
Example 76
4~-[[2-n-Butyl-6-(2-carboxy-3,4,5,6-tetrahydro-
benzamino)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
0.4 g (1 mMol) of 4'-[(6-amino-2-n-butyl-benzimidazal-1-
yl)-methyl]biphenyl-2-carboxylic acid, dissolved in 7 ml
of pyridine, are mixed with 0.34 g (1.1 mMal) of 1-
cyclohexene-1,2-dicarboxylic acid anhydride at ambient
temperature and stirred for 22 hours. The mixture is
cooled with ice and the product which crystallises out
is suction filtered, washed with cooled acetone and
dried in vacuo at 70°C.
Yield: 0.37 g (67.20 of theory),
Melting point: 250-252°C
C33H33N3Q5 ( 551. 64 )
Calculated: C 71.85 H 6.03 N 7.62
Found: 71.70 5.99 7.60



~~ _: ~:~: =a
- 85 -
Example 77
4'-[[2-n-Propyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
604 mg (1.0 mMol} of tert.-butyl 4'-[[2-nitro-5-(1-
methylbenzimidazol-2-yl)-N-n-butyryl-anilino]methyl]-
biphenyl-2-carbaxylate are stirred in 50 and of methylene
chloride with the addition of 10 ml of trifluoroacetic
acid at ambient temperature for 3 hours. The solvent is
then distilled off, the residue is dissolved in 25 ml of
glacial acetic acid and hydrogenated at 80°C with the
addition of 500 mg of 10% palladium/charcoal. Tn order
to work up the product, the solvent is distilled off in
vacuo, the residue is dissolved in 30 ml of 2N sodium
hydroxide solution and the solution is washed with 20 ml
of diethyl ether. The crude product precipitated by the
acidification of the aqueous phase is purified by
subsequent column chromatography (80 g silica gel,
eluant: methylene chloride/methanol = 15:1 by volume).
Yield: 90 mg (18% of theory),
Melting point: 224-226°C
C32HZ8N402 ( 5 0 0 . 6 0 )
Calculated: 0 76.78 H 5.64 N 11.19
Found: 76.58 5.49 x.1.30
Example 78
4'-[[2-n-Propyl-6-(2-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
A suspension of 940 mg (2.0 mMol) of tert.-butyl 4°-[(2-
n-propyl-6-carboxy-benzimidazol-1-yl)-methyl]biphenyl-2-
carboxylate and 320 mg (2.0 mMol} of carbonyldiimidazole
in a solution of 1.0 ml of triethylamine in 30 ml of
tetrahydrofuran is stirred for 30 minutes at ambient
temperature, then 250 mg (2.0 mMol} of 2-methylamino-
aniline are added and the mixture is stirred for a



l~ ~~ !~ ~'~ ~a
- 86 -
further 16 hours. Tt is then evaporated to dryness and
the residue is refluxed in 20 ml of phosphorus
oxychloride, with stirring, for 1 hour. The majority of
the phosphorus oxyehloride is then distilled off, the
dark, greasy residue is decomposed with 30 ml of water,
the strongly acidic suspension thus obtained is refluxed
for about 1 hour, adjusted to pH 6 after cooling and
then concentrated by evaporation. The crude product
obtained is purified by column chromatography (120 g of
silica gel, eluant: methylene chloride/methanol = 15:1
by volume).
Yield.: 73 mg (7.3% of theory),
Melting point: 213-215°C
C32H28N4o2 (500.60)
Calculated: C 76.78 H 5.64 N 11.19
Found: 76.61 5.64 10.94
Example 79
4'-[[2-n-Propyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-
ylJ-methyl)-2-{1H-tetrazol-5-yl)-biphenyl
Within 10 minutes, 155 mg (1.0 mMol) of 5-chloro-valeric
acid chloride, dissolved in 5 ml of tetrahydrofuran, are
added dropwise to a solution of 650 mg (l.O mMo1) of 4'-
[(2°n-propyl-6-amino-benzimidazol-1-yl)-methyl]-2-(1H-
triphenylmethyl-tetrazol-5-yl)-biphenyl in 30 ml of
tetrahydrofuran and the mixture is stirred for a further
hour at ambient temperature, then evaporated to dryness.
The residue is stirred into 20 ml of ethanol, then a
solution of 2.0 mMol of sodium ethoxide in 20 ml of
ethanol is added and the resulting mixture is refluxed
for one hour. After cooling, 10 m1 of methanolic
hydrochloric acid are added dropwise, the mixture is
stirred for a further two hours at ambient temperature
and then evaporated down. The residue is mixed with
l0 ml of water and made alkaline with concentrated
ammonia, whereupon the product goes into solution. By
acidifying with'glacial acetic acid the crude product is



_ 87 _
precipitated and then purified by column chromatography
(70 g silica gel, eluant: methylene chloride + 50
ethanol).
Yield: 54 mg (11% of theory),
Melting point: sintering from 117°C
Cz9H29N7o ( 4 91. 6 0 )
Calculated: C 70.85 H 5.95 N 19.95
Found: 70.69 5.94 19.99
The following compounds are obtained analogously:
4'-[[2-n-butyl-6-(2-oxo-piperidin-2-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Yield: 160 of theory,
Melting point: amorphous
C30H31N7~ ( 505 . 63 )
Calculated: C 67.94 H 6.23 N 17.33
Found: 67.81 6.29 17.18
4°-[[2-n-butyl-6-(2-oxo-pyrrolidin-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H--tetrazol-5=yl)-biphenyl
Yield: 90 of theory,
Melting point: 150-151°C
Cz9HzQN'O ( 4 91. 6 0 )
Calculated: C 70.85 H 5.95 N 19.95
Found: 70.61 6.08 19.80
Example 80
4'-[[2-n-Butyl-6-(propanesultam-1-yl)-benzimidazol-1-
yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Within 10 minutes, a solution of 265 mg (1.5 mMo1) of 3-
chloro-propanesulphonic acid chloride in 5 ml of
tetrahydrofuran is added dropwise to a solution of
665 mg (1.0 mMol) of 4'-[(2-n-butyl-6-aminobenzimidazol-
1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-
biphenyl and 1 ml of triethylamine in 30 ml of
tetrahydrofuran 'and the mixture is stirred for 1%, hours



_ $8 _
at ambient temperature. The mixture is then evaporated
to dryness, the residue is taken up in 20 ml of ethanol,
a solution of 3.0 mMo1 of sodium ethoxide in 20 ml of
ethanol is added and the resulting mixture is refluxed
for two hours. After cooling, 10 ml of methanolic
hydrochloric acid are added dropwise, the mixture is
stirred for a further two hours at ambient temperature
and finally concentrated by evaporation. The residue is
mixed with 10 ml of water and brought into solution with
concentrated ammonia. By acidifying with glacial acetic
acid, the crude product is precipitated and then
purified by column chromatography (70 g of silica gel,
eluant: methylene chloride + 5% ethanol).
Yield: 68.5 mg (230 of theory),
Melting point: 202-205°C
C28H29N7~2S ( 5 2 7 . 7 0 )
Calculated: C 63.73 H 5.54 N 18.58
Found: 63.70 5.61 18.35
The following compounds are obtained analogously:
4'-[[2-n-butyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Yield: 10% of theory,
Melting point: 185-187°C
C29H3TN~O2S (541.70)
Calculated: C 64.30 H 5.95 N 18.10
Found: 64.19 5.91 17.92
4'-[[2-n-propyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Yield: 17% of theory,
Melting point: 203-205°C
C28H29IJ702S ( 527 . 63 )
Calculated: C 63.7 3 H 5.54 N 18.58
Found: 63.63 5.54 18.39



- $~
Example 81
4'-[[2-n-Butyl-6-(1-benzyl-imidazolidin-2,4 -dion-3-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
trifluoroacetate
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n=butyl-6-(1-benzyl-imidazolidin-2,4-dion-3-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 58% of theory,
Melting point: amorphous
C35H32N404 X CF3COOH (686.71)
Calculated: C 64.72 H 4.84 N 8.16
Found: 64:48 4.68 8.09
Example 82
4'-[[2-n-Propyl-6-(5,5-pentamethylene-imidazolidin-2,4-
dion-3-yl)-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[2-n-propyl-6-(5,5-pentamethylene-imidazaiidin-2,4-
dion-3-yl)-benzimidazo~ -1-y1]methyl]biphenyl-2-
carboxyiate and trifluoroacetic acid in methylene
chloride.
Yield: 27% of theory,
Melting point: amorphous
C33H34N4~4 ( 5 5 0 . 6 3 )
Calculated: C 71.98 H 6.22 N 10.18
Found: 71.93 6.16 10.09
Rf value: 0.60 (silica gel; eluant: methylene
chloride/ethanol = 9:1 by volume)




Example 83
4'-[[2-Ethyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-
yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-ethyl-6-
(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]methyl]-
biphenyl-2-carboxylic acid nitrile and sodium azide in
dimethylformamide.
Yield: 330 of theory,
Malting point: sintering from 150°C
C28H27~7C (477.58)
Calculated: C ?0.42 H 5.70 N 20.53
Found: 70.48 5.72 19.88
Example 84
4'-[[2-Ethyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-ethyl-6-
(butanesultam-1-yl)-benzimidazol-1-yl]methyl]biphenyl-2-
car~oxyllC aCld nitrile and sodium azide in
dimethylformamide.
Yield: 36% of theory,
Melting point: decomposition from 240°C
C27H27N702S ( 513 . 64 )
Ca3culated: C 63.14 H 5.30 N 19.09
Found: 63.06 5.19 19.08
Example 85
4'-([2-n-Propyl-6-(3-n-hexyl-imidazo[4,5-b]pyridin-2-
yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-propyl-6-(3-n-hexyl-imidazo[4,5-b]pyridin-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and




- 91 -
trifluoroacetic acid in methylene chloride.
Yield: 57% of theory,
Melting point: amorphous
C~6H37NSOZ ( 571. 74 )
Calculated: C 75.63 H 6.52 N 12.25
Found: 75.58 6.48 12.08
Example 86
4'-[[2-n-Propyl-6-(3-methyl-imidazo[4,5-b]pyridin-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-propyl-6-(3-methyl-imidazo[4,5-b]pyridin-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 40% of theory,
Melting point: 208-210°C
C31H27N5~2 { 501. 60 )
Calculated: C 74.23 H 5.43 N 13.96
Found: 74.19 5.32 13.94
Example 87
4'-[[2-n-Propyl-6-(1-methyl-imidazolin-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic said
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-propyl-6-(1-methyl-imidazolin-2-yl)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid in methylene chloride.
Yield: 530 of theory,
Melting point: amorphous
C2sHzaN4Cz ( 4 52 . 57 )
Calculated: C 74.31 H 6.24 N 12.38
Found: 74.31 6.11 12.27




~~'~~~
- 92 -
The .following compounds axe obtained analogously to
Example 87:
~'-[[2 -n-butyl-6-(1-methyl-imidazolin-2-yl)-
benzimidazol-1-yl]methyl)biphenyl-2-carboxylic acid
4'-[[2-n-propyl-6-(1-n-hexyl-imidazolin-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-butyl-6-(1-n-butyl-imidazolin-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-propyl-6-(1-cyclopropyl-imidazolin-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-propyl-6-(~.-cyclohexyl-imidazolin-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-propyl-6-(1-methyl-imidazol-2-yl)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-butyl-6-(1-methyl-imidazol-2-yl)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-propyl-6-(1-n-hexyl-imidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
~'-[[2-n-butyl-6--(1-n-butyl-imidazol-2-yl)-benzimidazol-
2-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-propyl-G-(1-cyclopropyl-imidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-propyl-6-(1-cyclohexyl-imidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid




-° 93 -
Example 88
4'-[[2-n-Propyl-6-(1,5-dimethyl-benzimidazol-2-y1)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-propyl-6-(1,5-dimethyl-benzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 48% of theory,
Melting point: 256-258°C
C33H3oN40z ( 514 . 63 j
Calculated: C 77.02 H 5.88 N 10.89
Found: 76.91 5.83 10.72
Example 89
4'-[[2-n-Propyl-6-(1-methyl-5-trifluoromethyl-
benzimidazol-2-ylj-benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-propyl-6-(1-methyl-5-trifluoromethyl-benzimidazol-
2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate
and trifluoroacetic acid in methylene chloride.
Yield: 560 of theory,
Melting point: 183-186°C
C33Hz7F3N4~z ( 568 . 61 )
Calculated: C 69.71 H 4.79 N 9.85
Found: 69.58 4.72 9.80




Example 90
4'-[[2-n-Propyl-6-(5-methyl-imidazolidin-2,4-dion-3-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4°-
[[2-n-propyl-6-(5-methyl-imidazolidin-2,4-dion-3-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 29~ of theory,
Melting point: amorphous
C28H2bN4~4 ( 4 8 2 . 5 5 )
Calculated: C 69.69 H 5.43 N 11.61
Found: 69.67 5.40 11.55
Example 91
4°-[(2-n-Propyl-6-(1-methyl-imidazolidin-2,4-dion-3-yl)-
benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[(2-n-propyl-6-(1-methyl-imidazolidin-2,4-dion-3-yl}-
benzimidazol-1-yl}-methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 320 of theory,
Melting point: amorphous
C2sN26N4C4 ( 4 8 2 . 55 }
Calculated: C 69.69 H 5.43 N 11.61
Found: 69.61 5.38 11.49
Exam~l a 9 2
4'-[(2-n-Propyl-6-(1-butyl-benzimidazol-2-yl}-
benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[(2-n-propyl-6-(1-butyl-benzimidazol-2-yl)-benzimidazol-
1-yl}-methyl]biphenyl-2-carboxylate and trifluoroacetic




~~~'~~~~Q
- 95 -
acid in methylene chloride.
Yield: 59% of theory,
Melting point: sintering from 149°C
~35H34N4~2 ( 542 . 69 )
Calculated: C 77.46 H 6.32 N 10.32
Found: 77.37 6.31 10.35
Example 93
4'-((2-n-Butyl-6-(1H-benzimidazol-2-yl}-benzimidazol-1-
yl)methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[(2-n-butyl-6-(1H-benzimidazol-2-yl)-benzimidazol-1-yl)-
methyl]biphenyl-2-carboxylate and trifluoroacetic acid
in methylene chloride.
Yield: 62% of theory,
Melting point: 200-202°C
C3zHzaN4~z ( 5 0 0 . 61 }
Calculated: C 76.78 H 5.64 N 11.19
Found: 76.54 5.60 11.16
Example 94
4'-[(2-n-Butyl-6-hexahydrohomophthalimino-benzimidazol-
1-yl)methyl]biphenyl-2-carboxylic acid
0.4 g (0.64 mMol) of tart.-butyl 4'-((2-n-butyl-6-(2-
carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-1-
yl)-methyl]biphenyl-2-carboxylate are refluxed for 1=
hours with stirring in 5 ml of phosphorus oxychloride.
After cooling, the mixture is poured onto ice water and
the crude product precipitated is removed by suction
filtering. This is dissolved in ethanol/wa~ter, made
alkaline with ammonia and concentrated in vacuo until it
crystallises out. It is then suction filtered, washed
with water arid dried in vacuo at 120°C.
Yield: 0.15 g (42.80 of theory},



~~~."'~t~~
- 96 -
Melting point: 241-243°C.
C34H35N~ 04 ( 5 4 9 . 6 6 )
Calculated: C 74.29 H 6.49 N 7.64
Found: 74.14 6.64 7.81
Example 95
4°-[(2-n-Butyl-6-(7-vitro-benzofurazan-4-yl-amino)-
benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid
Prepared from 4'-[(6-amino-2-n-butyl-benzimidazol-1-
yl)methyl]biphenyl-2-carboxylic acid and 4-chloro-7-
nitro-benzofurazan in pyridine at ambient temperature.
Yield: 13.1% of theory,
Rf value: 0.75 (silica gel, methylene chloride/ethanol =
9:1)
C31H26N6~5 (562.58)
Calculated: C 66.18 I~I 4.66 N 14.93
Found: 66.35 4.76 25.13
Example 96
4°-[[2-Ethyl-6-(pyrrolidinocarbonylamino)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylic acid-trifluoroacetate-
semihydrate
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-ethyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-
yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic
acid in methylene chloride.
Yield: 80. 9 0 of theory,
Melting point: 178-179°C
C2aH28N403 x CF3COOH x 0 . 5 H20 ( 591. 59 ) .
Calculated: C 60.90 H 5.11 N 9.47
Found: 61.10 5.22 9.26
Rf value: 0.48 (silica gel: ethyl acetate/ethanol/ammonia
- 50:45:5 by volume)



s~
_ 97 -
Example 97
4'-[[2-Methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylic acid-trifluoroacetate
Prepared analogously to Example 1 .from tart.-butyl 4°-
[[2-methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-
yl]-methyl]biphenyl-2-carboxylate and trifluoraacetic
acid in methylene chloride.
Yield: 82.1% of theory,
Melting point: 181-282°C
C27H26N603 x CF3COOH (568.55)
Calculated: C 61.26 H 4.79 N 9.85
Found: ~ 60.99 5.09 9.89
Rf value: 0.38 (silica gel; ethyl acetatefethanol/ammonia
- 50:45:5 by volume)
Example 98
4°-[[2-n-Prapyl-6-(pyrrolidinocarbonylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid-
trifluoroacetate
Prepared analogously to Example 1 from tart.-butyl 4°-
[[2-n-propyl-6-(pyrrolidinocarbonylamino)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid in methylene chloride.
Yield: 79.7% of theory,
Melting point: 207-208°C
C29H~oN403 X CF3COOH ( 59 6 . 61 )
Calculated: C 62.41 H 5.24 N 9.39
Found: 62.38 5.36 9.42
Rf value: 0.55 (silica gel; ethyl acetate/ethanoljammonia
- 50:45:5 by volume)



- 98 -
Example 99
4'-[[2-Methylmercapto-6-(pyrrolidinocarbonylamino)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid-
trifluoroacetate
Prepared analogously to Example 1 from tert.-butyl 4'-
([2-methylmercapto-6-(pyrrolidinocarbonylamino)-
benzimidazol-1-yl)methyl)biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 96.1% of theory,
Melting point: 177-178°C
C27Hz6N4D3s x CF3COOH (600.61)
Calculated: C 57.99 H 4.53 N 9.33
Found: 57.68 4.75 9.30
Rf value: 0.52 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5 by volume)
Example 100
4'-[[6-(2,3-Dimethylmaleic acid imido)-2-methylmercapto-
benzimidazol-1-yl)methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example l from tert.-butyl 4'-
[[6-(2,3-dimethylmaleic acid imido)-2-methylmercapto-
benzimidazol-1-yl]methyl)biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 91.7% of theory,
Malting point: 276-277°C
CzsHz3N3D4s ( 4 97 . 5? )
Calculated: C 67.59 H 4.66 N 8.45 S 6.44
Found: 67.57 4.94 8.40 6.37
Rf value: 0.47 (silica gel: ethyl acetate/ethanol/ammonia
- 50:45:5 by volume)




- 99 -
Example 101
4'-jj2-n-Butyl-6-[3-(7 -nitrobenzofurazan-4-yl-amino)-
propionylamino]benzimidazol-1-yl]methyl]-2-(1H-tetrazol-
5-yl)-biphenyl-hydrate
Prepared analogously to Example 55 from 4'-[[2-n-butyl-
6-[3-(7-nitrobenzofurazan-4-yl-amino)-propionylamino]-
benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-
5-yl)-biphenyl and 2 N hydrochloric acid in ethanol.
Yield: 33.3% of theory,
Melting point: 179-181°C
C34H31 N1104 x H20 ( 6 7 5 . 7 0 )
Calculated: C 60.43 H 4.92 N 22.80
Found: 60.24 5.09 22.69
Example 102
4'-j[2-n-Butyl-6-[3-(?-nitrobenzofurazan-4-y1-amino)-
propionylamino]benzimidazol-1-yl]methyl]biphenyl-2-
carboxylic acid-trifluoroacetate-hydrate
Prepared analogously to Example l from tert.-butyl 4'- .
[[2-n-butyl-6-[3-(7--nitrobenzofurazan-4-yl-amino)-
propionylamino]benzimidazol-1-yl]methyl]biphenyl-2-
carboxylate and trifluoroacetic acid in methylene
chloride.
Yield: 87.50 of theory,
Melting point: 12?°C (decomp.)
C34H31N706 x CF3COOH x HZO ( 7 65 . 69 )
Calculated: C 56.47 H 4.47 N 12.80
Found: 56.68 4.27 12.67


l1 i3
f~ ~ .: ~ e~: zt
- 100 -
Example 103
4'-[[6-(2,3-Dimethylmaleic acid imido)-2-methyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'--
[[6-(2,3-dimethylmaleic acid imido)-2-methyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 94.4% of theory,
Melting point: 327-328°C
C28H23N304 ( 4 6 5 . 5 2 )
Calculated: C 72.25 H 4.98 N 9.03
Found: 72.00 5.08 9.06
Rf value: 0.33 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5 by volume)
Example 104
4'-[[6-(2,3-Dimethylmaleic acid imido)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylic acid-semihydrate
Prepared analogously to Example 1 from tert.-butyl 4'-
[[6-(2,3-dimethylmaleic acid imido)-benzimidazol-1-yl]-
methyl]biphenyl-2-carboxylate and trifluoroacetic acid
in methylene chloride.
Yield: 95.5% of theory,
Melting point: 223-224°C
C27H2tN3Q4 x 0.5 H20 (460.49)
Calculated: C 70.42 H 4.82 N 9.13
Found: 70.30 4.88 8.81
Rf value: 0.34 (silica gel; ethyl acetatefethanol/ammonia
- 50:45:5 by volume)



~~~~ brr
- 101 -
Example 105
4'-[[6-(2,3-Dimethylmaleic acid imido}-2-n-propyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid-
monohydrate
Prepared analogously to Example 1 from tart.-butyl 4'-
[[6-(2,3-dimethylmaleic acid imido)-2-n-prapyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 92.5% of theory,
Melting point: 309-310°C
C3oH2~N304 x H20 ( 511. 58 )
Calculated: C 70.44 H 5.71 N 8.21
Found: ?0.44 5.64 8.19
Rf value: 0.47 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5 by volume)
Example 106
4'-[[6-(2,3-Dimethylmaleic acid imido)-2-ethyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tart.-butyl 4'-
[[6-(2,3-dimethylmaleic acid imido}-2-ethyl-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 87.5% of theory,
Melting point: 307-308°C
C29H25N3~4 (479.53)
Calculated: C 72.64 H 5.25 N 8.76
Found: 72.41 5.37 8.94
Rf value: 0.40 (silica Belt ethyl acetate/ethanol/ammonia
- 50:45:5 by volume)



~~~~_~~t,3.~z
-- 102 -
Example 107
4'-[[2-Ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-ethyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
acid in methylene chloride.
Yield: 31% of theory,
Melting point: 183--185°C
C31Hz6N4C2 (486.60)
Calculated: C 76.52 H 5.39 N 11.52
Found: 76.73 5.49 11.70
Examt~le 108
4'-[[2-Methyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl)methyl;]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-methyl-6-
(butanesultam-1-yl)-benzimidazol-1-yl]methyl]-2-cyano-
biphenyl and sodium azide in dimethylformamide.
Yield: 27% of theory,
Melting point: 173-175°C
c26H2sN7~zS ( 4 g 9 . 6 0 )
Calculated: C 62.51 H 5.04 N 19.63 S 6.42
Found: 62.39 5.05 19.44 6.33
Mass spectrum: m/e = 499
Example 109
4'-[[2-Methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methy:l]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-methyl-6-
(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-
cyano-biphenyl and sodium azide in dimethylformamide.



~~~~ d ~v
- 103 -
Yield: 26.5% of theory,
Melting point: 214-217°C
C3oH24Ns ( 4 9 6 . 8 0 )
Calculated: C 72.56 H 4.87 N 22.56
Found: 72.32 5.01 22.23
Example 110
4'-[[6-(Butanesultam-1-yl)-benzimidazol-1-yl]methyl]-2-
(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-((6-
(butanesultam-1-yl)-benzimidazol-1-yl]methyl]-2-cyano-
biphenyl and sodium azide in dimethylformamide.
Yield: 60.0% of theory,
Melting point: 246°249°C
C25H23N702S ( 4 8 5 . 6 0 )
Calculated: C 61.84 H 4.77 N 20.19
Found: 61.75 4.92 20.28
Example 111
4'-[[2-Ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-
1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[(2-ethyl-6-
(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]-
2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 41.0% of theory,
Melting point: from 178°C (sintering)
C3~H26N8 (510.60)
Calculated: C 72.92 H 5.13 N 21.95
Found: 72.94 5.25 21.71
Mass spectrum: m/e = 510




~~ l.''~~c~
- 104 -
Example 212
4°-[[2-Ethyl-6-(N-benzenesulphonyl-methylamino)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4°-[[2-ethyl-6-
(N-benzenesulphonyl-methylamino)-benzimidazol-1-yL]-
methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 66.0% of theory,
Melting point: 226-228°C
G30H27N7~2S ( 5 4 9 . 7 0 )
Calculated: C 65.55 FI 4.95 N 17.84 S 5,83
Found: 65.38 4.95 17.59 5.79
Example 113
4'-[[2-n-Propyl-6-(N-benzenesulphonyl-methylamino)-
benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 41 from 4'-[[2-n-propyl-
6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]-
methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 83.4% of theory,
Melting point: 177-179°C .
C3~H29N702S (563.70)
Calculated: C 66.05 H 5.18 N 17.40 S 5.69
Found: 65.89 5.14 17.21 5.73
Example 114
4'-[(2-n-Butyl-6-benzenesulphonyloxy-benzimidazol-1-yl)-
methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[(2-n-butyl-6-benzenesulphonyloxy-benzimidazol-1-yl)-
methyl]biphenyl-2-carboxylate and trifluoroacetic acid '
in methylene chloride.




- 105 -
Yield: 8.2% of theory,
Melting point: 193-195°C
C31H28N2~5s (540.60)
Calculated: C 68.92 H 5.22 N 5.18
Found: 68.94 5.08 5.08
Example 115
4'-[[2-n-Butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinon-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-
tetrazol-5-yl)-biphenyl
Prepared analogously to Example 55 from 4°-[[2-n-butyl-
6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-
benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-
5-yl)-biphenyl arid methanol in methanolio hydrochloric
acid.
Yield: 28.0% of theory,
Melting point: from 125°C (decomp.}
C36H36NsC ( 5 q 6 . 8 0 )
Calculated: C '72.46 H 6.08 N 18.78
Found: 72.26 5.94 18.85
Example 116
4'-[[2-n-Butyl-5-(3-benzyl-3,4,5,6--tetrahydro-2(1H)-
pyrimidinon-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-
tetrazol-5-yl)-biphenyl
Prepared analogously to Example 55 from 4°-[[2-n-butyl-
5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-
benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-
5-yl}-biphenyl and methanol in methanolic hydrochloric
acid.
Yield: 31.0% of theory,
Melting point: from 125°C (decomp.)
C36H36N80 ( 59 5 . 8 0 )
Calculated: C 72.46 H 6.08 N 18.78




f''
- 106 -
Found: 72.27 6.03 18.61
Example 117
4'-[[2-n-Propyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinon-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-
tetrazol-5-yl)-biphenyl
Prepared analogously to Example 55 from 4°-[[2-n- propyl-
6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-
benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-
5-yl)-biphenyl and methanol in methanolic hydrochloric
acid.
Yield: 35.00 of theory,
Melting point: from 132°C (decamp.)
C35H3~Ns0 ( 582 . 71 )
Calculated: C 72.14 H 5.88 N 19.23
Found: 71.98 6.02 19.11
Exam~l a 118
4'-[(2-Ethyl-6--(3-benzyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinon-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-
tetrazol-5-yl)-biphenyl
Prepared analogously to Example 55 from 4'-[[2-ethyl-6-
(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-
benzimidazol-1-yl]methyl}-2-(1-triphenylmethyl-tetrazol-
5-yl)-biphenyl and methanol in methanolic hydrochloric
acid.
Yield: 22.0% of theory,
Melting point: from 106°C (decamp.)
C34H32Ns0 ( 5 6 8 . 6 8 )
Calculated: C 71.81 H 5.67 N 19.70
Found: 71.73 5.54 19.92




- 107 -
Example 119
4'-[[2-n-Butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-y1)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 64 from methyl 4'-[[2-n-
butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-
benzimidazol-1-yl]methyl] biphenyl-2-carboxylate and
sodium hydroxide solution in ethanol.
Yield: 80.0°s of theory,
Melting point: 276-283°C
C29H28N4~3 ( 4 8 0 : 6 0 )
Calculated: C 72.48 H 5.87 N 11.66
Found: 72.20 6.13 11.53
Mass spectrum: m/e = 480
The following compounds are obtained analogously to
Example 119:
4'-[[2-ethyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n~propyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-butyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-
1-yl]methyl]biphenyl-2-carboxylic acid
4'-[[2-n-propyl-6-(2-methyl-4,5-dihydro-pyridazin-3-on-
6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic
acid
4'-[[2-n-propyl-6-(2-benzyl-4,5-dihydro-pyridazin-3-on-
6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic
acid




t~~ ~t z .~
J.
- 108 -
ExamQle 120
4'-[[2-n-Propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 64 from methyl 4'-[[2-n-
propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-
benzimidazol-1-yl]methyl] biphenyl-2-carboxylate and
sodium hydroxide solution in ethanol.
Yield: 66.0% of theary,
Malting point: 236-241°C
C2aH26N4o3 ( 4 6 6 . 5 4 }
Calculated: C 72.09 H 5.62 N 12.01
Found: 71.88 5.61 11.95
Example 121
4'-[[2-Ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 64 from methyl 4'-[[2-
ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl}-
benzimidazol-1-yl]methyl] biphenyl-2-carboxylate and
sodium hydroxide solution~in ethanol.
Yield: 71.0% of theory,
Melting point: 255-257°C
~27H24N4~3 ( 4 5 2 . 51 }
Calculated: C 71.67 H 5.35 N 12.38
Found: 71.41 5.51 12.12
Example 122
4'-[[2-n-Butyl-6-(3-cyclohexyl-propylamino)-
benzimidazol -1-yl]methyl]biphenyl-2-carboxylic acid
Prepared analogously to Example 1 from tert.-butyl 4'-
[[2-n-butyl-6-(3-cyclohexyl-propylamino)-benzimidazol-1-
yl]methyl]biphenyl-2-carboxylate and trifluoroacetic
r




9 - ~ :~ i~, ~~ I
acid in methylene chloride.
Yield: 85.70 of theory,
Melting point: 152-153°C
C34H'~N302 X 0.75 CF3COOH (609.24)
Calculated: C 69.99 H 6.91 N 5.90
Found: 70.02 6.93 6.84
12f value: 0.24 (eilica gel; ethyl acetate/ethanal/ammonia
- 80:40:2 by volume)




110 -
In the Examples of Pharmaceutical Formulations which
follow, any suitable compound of formula I, particularly
compounds A to L of the pharmacological test report, may
be used as the active substance:
Example I
Ampoules containing 50 mg of active substance per 5 ml
Active substance 50 mg
I~I2P04 2 mg
NaZHP04 x 2Hz0 50 mg
NaCl 12 mg
Water far injections ad 5 ml
Preparation:
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.
Example II
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 ad 5 ml
Preparation:
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.
Example III
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 mg
200.0 mg
Preparation;
The active substance, CaHPO~, lactose and porn starch are
uniformly moistened with an agueous 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.
Example IV
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 mg


Gelatin 10.0 mg


Magnesium stearate 1.0 ma


180.0 mg




- 112 -
Preparation:
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.
Example V
Coated tablets containing 100 mg of active substance
Active substance 100.0 mg


Lysine 50.0 mg


Lactose 8f.0 mg '


Corn starch 50.0 mg


Polyvinylpyrrolidone 2.8 mg


Microcrystalline cellulose 60.o mg


Magnesium stearate 1.2 ma


350.0 mg


Preparation:
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 then 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.




a
- 113 -
Example VI
Capsules containing 250 mg of active substance
Active substance 250.0 mg
Corn starch 68.5 mg
Magnesium stearate 1.5 mg
320.0 mg
Preparation:
The active substance and corn starch are mixed together
and moistened with water. The moist mass is screened
and dried. The dry granules axe screened and mixed with
magnesium stearate. The final mixture is packed into
size 2 hard gelatine capsules.
Example VII
Gral 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 ad 5.0 ml


Preparation:
Distilled water is heated to 70°C. Hydroxyethyl-
cellulose is dissolved therein with stirring. Hy the
addition of sorbitol solution and glycerol the mixture
is cooled to ambient temperature. At ambient

°


114 °
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.
Example VIII
Suppositories containing 100 mg of active substance
Active substance 100.0 mg
Solid fat 1600.0 ma
1700.0 mg
Preparation:
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.

Representative Drawing