SK394492A3 - Benzimidazoles, process for their preparation and drug containing the same - Google Patents

Abstract

The invention relates to benzimidazoles of the general formuala <IMAGE> in which R1 to R4 are as defined in Claim 1, and their salts, which have useful properties. The novel compounds are, in particular, angiotensin antagonists.

Description

Technical field

The invention relates to benzimidazole compounds, a process for their preparation and medicaments containing them.

BACKGROUND OF THE INVENTION

EP-A-03923117 already describes benzimidazoles which are valuable angiotensin antagonists.

SUMMARY OF THE INVENTION

It has now been found that the benzimidazoles of general formula

in which

R * represents an alkyl group having 1 to 3 carbon atoms, a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom,

ABOUT

R represents in the 2-position a phenyl-substituted oxazol-4-yl- or thiazol-4-yl-group or optionally in the 2-position an alkyl group having 1 to 6 carbon atoms or a phenyl-substituted imidazol-4-yl group, the imidazole- The 4-yl group is substituted in the 1-position by an alkyl group having 1 to 7 carbon atoms which may be substituted in the 1, 2, 3, 4, 5, 6 or 7 position by carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylamino-2-carbonyl-, morpholinocarbonyl-, thiomorpholino-carbonyl- or 1-oxo-thiomorpholinocarbonyl, a (C 2 -C 4) alkyl group which is substituted in the 2, 3 or 4 position with hydroxy, alkoxy, alkoxyalkoxy, dialkylamino- , pyrrolidino-, piperidino-, hexamethylenimino-, morpholino-, thiomorpholino-, 1-oxo-thiomorpholino- or imidazol-1-yl, alkyl substituted with trifluoromethyl, C3-7 cycloalkyl or optionally fluorine and al. or a chlorine, trifluoromethyl, methyl or methoxy group, a mono- or disubstituted phenyl group, an alkyl group substituted by two phenyl groups, and unless otherwise stated, the alkyl and alkoxy moieties each contain 1 to 3 carbon atoms,

Q

R is a (C 2 -C 4) alkyl, alkoxy or (C 2 -C 3) alkylthio group, a cyclopropyl or cyclobutyl group, and is a carboxy-convertible group in vivo, carboxy, cyano, ΙΗ-tetrazolyl-, 1- triphenylmethyltetrazolyl or 2-triphenylmethyl-tetrazolyl group as well as compounds:

(a) 4 '- [(2-n-propyl-4-methyl-6- {1- (2-phenylethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid;

(b) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) benzimidazol-1-yl) methyl] -biphenyl-2-carboxylic acid;

c) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazole-5) yl) biphenyl,

(d) 4 '- [(2-ethoxy-6- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) -biphenyl,

- 3 (e) 4 '- [(2-ethoxy-6- (1-isopropyl-imidazol-4-yl) benzimidazol-1-yl) methyl) biphenyl-2-carboxylic acid,

f) 4 '- [(2-ethoxy-5- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl) -2- (1H-tetrazol-5-yl) -biphenyl,

(g) 4 '- [(2-n-propyl-4-methyl-6- (1-cycloheptyl-imidazol-4-yl) -benzimidazol-1-yl) methyl) -biphenyl-2-carboxylic acid;

h) 4 '- [(2-n-propyl-4-methyl-6- (1-cycloheptyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazole-5- yl) biphenyl,

i) 4 '- [(2-n-propyl-4-methyl-6- (1- (1-n-propyl-n-butyl) -imidazol-4-yl) benzimidazol-1-yl) methyl] - 2- (1H-tetrazol-5-yl) biphenyl,

(j) 4 '- [(2-n-propyl-4-methyl-6- (1,2-dimethyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl) -biphenyl-2-carboxylic acid;

k) 4 '- [(2-n-propyl-4-methyl-6- (1,2-dimethyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazole- 5-yl) biphenyl,

(l) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-thiazol-4-yl) benzimidazol-1-yl) methyl) biphenyl-2-carboxylic acid; and

m) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-thiazol-4-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazole-5) -yl) -biphenyl, and salts thereof, particularly for the pharmaceutical use of their physiologically acceptable salts with inorganic or organic acids or bases, are angiotensin antagonists, in particular angiotensin-II.

For example, a group that is converted to a carboxy group in vivo may include esters of the formula

- 4 -CO-OR '

-CO-O- (HCR) -O-CO-R 'a

-CO-O- (HCR) -O-CO-OR 'in which

R 'denotes a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, benzyl-, 1-phenylethyl-, 2-phenylethyl-,

3-phenylpropyl, methoxymethyl or cinnamyl,

R is hydrogen or methyl; and

R 'represents a straight or branched chain alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a phenyl-, benzyl-, 1-phenylethyl-, 2-phenylethyl- or 3-phenylpropyl group.

The compounds of formula I above exhibit valuable properties. Compounds of formula I in which r 4 is a carboxy- or 1H-tetrazolyl group that can be converted to a carboxy group in vivo have particularly valuable pharmacological properties because they are angiotensin antagonists, in particular angiotensin II antagonists. The other compounds of formula I are valuable intermediates for the preparation of the compounds.

Accordingly, the present invention provides the above-mentioned benzimidazoles, wherein the corresponding alkoxycarbonyl compounds also represent valuable intermediates, their use and their preparation.

The present invention also provides pharmaceutical compositions comprising any of the aforementioned pharmacologically active compounds of formula (I) or a corresponding physiologically acceptable salt thereof, and in particular suitable for the treatment of hypertonia and cardiac insufficiency, further for the treatment of ischemic disorders of blood circulation, myocardial ischemia.

- ⁵ (angina), for the prevention of progression of cardiac insufficiency after myocardial infarction, for the treatment and production of diabetic nephropathy, glaucoma, gastrointestinal diseases and urinary tract.

For the definition of the radicals R ^{@ 1} and R @ ⁴ , for example, the following meanings for

R1, hydrogen, fluorine or chlorine, methyl, ethyl, n-propyl or isopropyl,

ABOUT

R is 2-phenyl-oxazol-4-yl-, 2-phenyl-thiazol-4-yl-, 1-cyclopropylmethyl-imidazol-4-yl-, 1-cyclobutylmethylimidazol-4-yl-, 1-cyclopentylmethylimidazol-4-yl-, 1 -cyclohexylmethylimidazol-4-yl-, 1-cycloheptylmethylimidazol-4-yl-, 1- (2-cyclopropylethyl) imidazol-4-yl-, 1- (2-cyclobutylethyl) imidazol-4-yl-, 1- (2-cyclopentylethyl) 1-Imidazol-4-yl-, 1- (2-cyclohexylethyl) -imidazol-4-yl-, 1- (2-cycloheptylethyl) -imidazol-4-yl-, 1- (3-cyclopropylpropyl) -imidazol-4-yl 1- (3-cyclobutylpropyl) -imidazol-4-yl-, 1- (3-cyclopentylpropyl) imidazol-4-yl-, 1- (3-cyclohexylpropyl) -imidazol-4-yl-, 1- (3-cycloheptylpropyl) 1-Imidazol-4-yl-, 1- (2,2,2-trifluoroethyl) -imidazol-4-yl-, 1- (3,3,3-trifluoropropyl) -imidazol-4-yl-, 1- ( 4-Fluoro-benzyl) -imidazol-4-yl-, 1- (4-chlorobenzyl) -imidazol-4-yl-, 1- (3-chlorobenzyl) imidazol-4-yl-, 1- (4-trifluoromethylbenzyl) -imidazol-4 -yl-, 1- (3-methylbenzyl) -imidazol-4-yl-, 1- (4-methylbenzyl) -imidazol-4-yl-, 1- (3-methoxybenzyl) imidazol-4-yl-, 1- (4-Methoxy-benzyl) -imidazol-4-yl-, 1- (3,4-dimethoxybenzyl) -imidazol-4-y 1-, 1- (3,5-dimethoxybenzyl) imidazol-4-yl-,

1-cyclopropylmethyl-2-methylimidazol-4-yl-, 1-cyclobutylmethyl-2-methyl-imidazol-4-yl-, 1-cyclopentylmethyl-2-methyl-imidazol-4-yl-, 1-cyclohexylmethyl-2-methyl-imidazole-4 -yl-, 1-cycloheptylmethyl-2-methylimidazol-4-yl-, 1- (2-cyclopropylethyl) -2-methyl-imidazol-4-yl-, 1- (2-cyclobutylethyl) -2-methyl-imidazole- 4yl-, 1- (2-cyclopentylethyl) -2-methyl-imidazol-4-yl-, 1- (2-cyclohexylethyl) -2-methylimidazol-4-yl-, 1- (2-cycloheptylethyl) -2-methyl-imidazole -4-yl-, 1- (3-cyclopropylpropyl) -2-methyl-imidazol-4-yl-, 1- (3-cyclobutylpropyl) -2-methyl-imidazol-4-yl-, 1 (3-cyclopentylpropyl) -2-methyl-imidazol-4-yl-, 1- (3-cyclohexylpropyl) -2-methylimidazol-4-yl-, 1- (3-cycloheptylpropyl) -2-methylimidazol-4-yl-, 1- (2,2 1,2-trifluoroethyl) -2-methylimidazol-4-yl-, 1- (3,3,3-trifluoropropyl) -2-methyl-imidazol-4-yl-, 1 (4-fluorobenzyl) -2-methyl-imidazole-4 -yl-, 1- (4-chlorobenzyl) -2-methyl-imidazol-4-yl-, 1- (3-chlorobenzyl) -2-methylsimidazol-4-yl-, 1- (4-trifluoromethylbenzyl) -2-methyl-imidazole -4-yl-, 1- (3-methylbenzyl) -2-methyl-imidazol-4-yl-, 1- (4-methylbenzyl) -2-m ethyl-imidazol-4-yl-, 1- (3-Methoxy-benzyl) -2-methyl-imidazol-4-yl-, 1- (4-methoxy-benzyl) -2-methyl-imidazol-4-yl-, 1 - ( 3,4-dimethoxybenzyl) -2-methyl-imidazol-4-yl-, 1- (3,5-dimethoxy-benzyl) 2-methyl-imidazol-4-yl-, 1-carboxymethyl-imidazol-4-yl- 1- (2-carboxyethyl) -imidazol-4-yl-, 1- (3-carboxypropyl) -imidazol-4-yl-, 1- (4-carboxybutyl) -imidazol-4-yl-, 1- (5-carboxypentyl) imidazole -4-yl-, 1- (6-carboxyhexyl) -imidazol-4-yl-, 1- (7-carboxyheptyl) -imidazol-4-yl-, 1-methoxycarbonylmethyl-imidazol-4-yl-, 1- (2- methoxycarbonylethyl) -imidazol-4-yl-, 1- (3-methoxycarbonylpropyl) -imidazol-4-yl-, 1- (4-methoxycarbonylbutyl) imidazol-4-yl-, 1- (5-methoxycarbonylpentyl) -imidazole-4 -yl-, 1- (6-methoxycarbonylhexyl) -imidazol-4-yl-, 1- (7-methoxycarbonylheptyl) -imidazol-4-yl-, 1-ethoxycarbonylmethyl-imidazol-4-yl-, 1- (2-ethoxycarbonylethyl) imidazol-4-yl-, 1- (3-ethoxycarbonylpropyl) -imidazol-4-yl-, 1- (4-ethoxycarbonylbutyl) imidazol-4-yl-, 1- (5-ethoxycarbonylpentyl) imidazol-4-yl-, l- - (6-ethoxycarbonylhexyl) -imidazol-4-yl-, 1- (7-ethoxycarbonylheptyl) -imid Azol-4-yl-, 1'-propoxycarbonylmethyl-imidazol-4-yl-, 1- (2'-propoxycarbonylethyl) -imidazol-4-yl-, 1- (3-n-propoxycarbonylpropyl) -imidazol-4-yl-, 1- (4-n-propoxycarbonylbutyl) -imidazol-4-yl-, 1- (5-n-propoxycarbonylpentyl) imidazol-4-yl-, 1- (6-n-propoxycarbonylhexyl) imidazol-4-yl-, 1- (7-n-Propoxycarbonylheptyl) -imidazol-4-yl-, 1-isopropoxycarbonylmethylimidazol-4-yl-, 1- (2-isopropoxycarbonylethyl) imidazol-4-yl-, 1- (3-isopropoxycarbonylpropyl) imidazol-4-yl-, 1- (4-isopropoxycarbonylbutyl) -imidazol-4-yl-, 1- (5-isopropoxycarbonylpentyl) imidazol-4-yl-, 1- (6-isopropoxycarbonylhexyl) imidazol-4-yl-, 1- (7-isopropoxycarbonylheptyl) -imidazol-4-yl-, 1-aminocarbonylmethyl-imidazol-4-yl-, 1- (2-aminocarbonylethyl) -imidazol-4-yl-, 1- (3-aminocarbonylpropyl) imidazol-4-yl-, 1- (4 -aminocarbonylbutyl) imidazol-4-yl-, 1- (5-aminocarbonylpentyl) -imidazol-4-yl-, 1- (6-aminocarbonylhexyl) imidazol-4-yl-, 1- (7-aminocarbonylheptyl) -imidazole-4 -yl-, 1-methylaminocarbonylmethylimidazol-4-yl-, 1- (2-methylaminocarbonylethyl) imidazol-4-yl 1- (3-methylaminocarbonylpropyl) imidazol-4-yl-, 1- (4-methylaminocarbonylbutyl) imidazol-4-yl-, 1- (5-methylaminocarbonylpentyl) imidazol-4-yl-, 1- (6) -methylaminocarbonylhexyl) -imidazol-4-yl-, 1- (7-methylaminocarbonylheptyl) imidazol-4-yl-, 1-ethylaminocarbonylmethyl-imidazol-4-yl-, 1- (2-ethylaminocarbonylethyl) -imidazol-4-yl-, 1 - (3-ethylaminocarbonylpropyl) imidazol-4-yl-, 1- (4-ethylaminocarbonylbutyl) imidazol-4-yl-, 1- (5-ethylaminocarbonylpentyl) imidazol-4-yl-, 1- (6-ethylaminocarbonylhexyl) imidazol-4- yl-, 1- (7-ethylaminocarbonylheptyl) -imidazol-4-yl-, 1'-propylaminocarbonylmethyl-imidazol-4-yl-, 1,1- (2-n-propylaminocarbonylethyl) imidazol-4-yl-, 1- (3- n-Propylaminocarbonylpropyl) -imidazol-4-yl-, 1- (4-n-propylaminocarbonylbutyl) -imidazol-4-yl-, 1- (5-n-propylaminocarbonylpentyl) imidazol-4-yl-, 1- (6 n-propylaminokarbonylhexyl) -imidazo _of l_4_yl_, i- (7-n-propylaminokarbonylheptyl) imidazol-4-yl, l-izopropylaminokarbonylmetylimidazol-4-yl, 1- (2-izopropylaminokarbonyletyl) imidazole-4-yl- 1- (3-isopropyl) minocarbonylpropyl) imidazol-4-yl-, 1- (4-isopropylaminocarbonylbutyl) imidazol-4-yl-, 1- (5-isopropylaminocarbonylpentyl) imidazol-4-yl-, 1- (6-isopropylaminocarbonylhexyl) imidazol-4-yl- 1- (7-Isopropylaminocarbonylheptyl) -imidazol-4-yl-, 1-dimethylaminocarbonylmethylimidazol-4-yl-, 1- (2-dimethylaminocarbonylethyl) imidazol-4-yl-, 1- (3-dimethylaminocarbonylpropyl) imidazole-4- yl-, 1- (4-dimethylaminocarbonylbutyl) imidazol-4-yl-, 1- (5-dimethylaminocarbonylpentyl) imidazol-4-yl-, 1- (6-dimethylaminocarbonylhexyl) imidazol-4-yl-, 1- (7) -dimethylaminocarbonylheptyl) -imidazol-4-yl-, 1-diethylaminocarbonylmethyl-imidazol-4-yl-, 1- (2-diethylaminocarbonylethyl) -imidazol-4-yl-, 1,1 (3-diethylaminocarbonylpropyl) imidazol-4-yl-, 1- (4-diethylaminocarbonylbutyl) imidazol-4-yl-, 1- (5-diethylaminocarbonylpentyl) imidazol-4-yl-, 1- (6-diethylaminocarbonylhexyl) imidazol-4-yl-, 1- (7-diethylaminocarbonylheptyl) imidazole -4-yl-, 1-diol

- 8-n-propylaminocarbonylmethyl-imidazol-4-yl-, 1- (2-di-n-propylaminocarbonylethyl) imidazol-4-yl-, 1- (3-di-n-propylaminocarbonylpropyl) imidazol-4-yl-, 1- (4-Di-n-propylaminocarbonylbutyl) imidazol-4-yl-, 1- (S-di-n-propylaminocarbonylpentyl) imidazol-4-yl-, 1- (6-di-n-propylaminocarbonylhexyl) imidazole- 4yl-, 1- (7-di-n-propylaminocarbonylheptyl) -imidazol-4-yl-, 1di-isopropylaminocarbonylmethyl-imidazol-4-yl-, 1- (2-di-isopropylaminocarbonylethyl) imidazol-4-yl-, 1 - (3-diisopropylaminocarbonylpropyl) imidazol-4-yl-, 1- (4-diisopropylaminocarbonylbutyl) imidazol-4-yl-, 1- (5-diisopropylaminocarbonylpentyl) imidazol-4-yl, 1- (6-diisopropylaminocarbonylhexyl) - imidazol-4-yl-, 1- (7-diisopropylaminocarbonylheptyl) imidazol-4yl-, 1-morpholinocarbonylmethylimidazol-4-yl-, 1- (2-morpholinocarbonylethyl) imidazol-4-yl-, 1- (3-morpholinocarbonylpropyl) imidazol-4-yl-, 1- (4-morpholinocarbonylbutyl) -imidazol-4-yl-, 1- (5-morpholinocarbonylperrtyl) -imidazol-4-yl-, 1- (6-morpholinocarbonylhexyl) -imidazol-4-yl -, 1- (7-morpholinoc arbonylheptyl) -imidazol-4-yl-, 1-thiomorpholinocarbonylmethyl-imidazol-4-yl-, 1- (2-thiomorpholinocarbonylethyl) -imidazol-4-yl-, 1- (3-thiomorpholinocarbonylpropyl) -imidazol-4-yl-, 1 - (4-thiomorpholinocarbonylbutyl) -imidazol-4-yl-, 1- (5-thiomorpholinocarbonylpentyl) imidazol-4-yl-, 1- (6-thiomorpholinocarbonylhexyl) imidazol-4-yl-, 1- (7-thiomorpholinocarbonylheptyl) - imidazol-4-yl-, 1-oxothiomorpholinocarbonylmethylimidazol-4-yl-, 1- (2-oxothiomorpholinocarbonylethyl) -imidazol-4-yl-, 1- (3-oxothiomorpholinocarbonylpropyl) -imidazol-4-yl-, 1- (4-oxothiomorpholinocarbonylbutyl) imidazol-4-yl-, 1- (5-oxothiomorpholinocarbonylpentyl) imidazol-4-yl-, 1- (6-oxothiomorpholinocarbonylhexyl) -imidazol-4-yl-, 1- (7-oxothiomorpholinocarbonylheptyl) -imidazol-4-yl- 1-carboxymethyl-2-methyl-imidazol-4-yl-, 1- (2-carboxyethyl) -2-methyl-imidazol-4-yl-, 1- (3-carboxypropyl) -2-methyl-imidazol-4-yl-, 1- (4-carboxybutyl) -2-methylimidazol-4-yl-, 1- (5-carboxypentyl) -2-methylimidazol-4-yl-, 1- (6-carboxyhexyl) -2-methylimidazol-4- yl-, 1- (7-carboxyheptyl) -2-methyl 1-imidazol-4-yl-, 1-methoxycarbonylmethyl-2-methylimidazol-4-yl-, 1- (2-methoxycarbonylethyl) -2-methyl-imidazol-4-yl-, 1- (3-methoxycarbonylpropyl) -2 -methyl-imidazol-4-yl-, 1- (4-methoxycarbonylbutyl) -2-methyl

- 9-xyl-imidazol-4-yl-, 1- (5-mexoxycarbonylpentyl) -2-mexyl-imidazol-4-yl-, 1- (6-methoxycarbonylhexyl) -2-methoxy-imidazol-4-yl-, 1- ( 7-Methoxycarbonylheptyl) -2-methyl-imidazol-4-yl-, 1-methoxycarbonylmethyl-2-methyl-imidazol-4-yl-, 1- (2-exoxycarbonylexyl) -2-methyl-imidazol-4-yl-, 1- (3-methoxycarbonylpropyl) 2-mexyl-imidazol-4-yl-, 1- (4-exoxycarbonylbenzyl) -2-mexylimidazol-4-yl-, 1- (5-exoxycarbonylpenxyl) -2-mexyl-imidazol-4-yl 1- (6-methoxycarbonylhexyl) -2-methoxy-imidazol-4-yl-, 1- (7-methoxycarbonylhepXyl) -2-mexyl-imidazol-4-yl-, 1-n-propoxycarbonylmexyl-2-mexyl-imidazole- 4-yl-, 1- (2-n-propoxycarbonylexyl) -2-methoxy-imidazol-4-yl-, 1- (3-n-propoxycarbonylpropyl) -2-mexylimidazol-4-yl-, 1- (4-n) -propoxycarbonylbenzyl) -2-methoxyimidazol-4-yl-, 1- (5-n-propoxycarbonylperoxy) -2-methoxyimidazol-4-yl-, 1- (6-n-propoxycarbonylhexyl) -2-methoxyimidazol-4-yl- , 1- (7-n-Propoxycarbonylhepxyl) -2-methoxy-imidazol-4-yl-,

1-isopropoxycarbonylmethyl-2-mexyl-imidazol-4-yl-, 1- (2-isopropoxycarbonyloxy) -2-methoxy-imidazol-4-yl-, 1- (3-isopropoxycarbonylpropyl) -2-methoxyimidazol-4-yl- 1- (4-isopropoxycarbonylbuxyl) -2-methoxy-imidazol-4-yl-, 1- (5-isopropoxycarbonylpenxyl) -2-mexyl-imidazol-4-yl-, 1- (6-isopropoxycarbonylhexyl) -2-mexyl -imidazol-4-yl-, 1- (7-isopropoxycarbonylhepxyl) -2-methyl-imidazol-4-yl-, 1-aminocarbonylmethyl-2-methoxy-imidazol-4-yl-, 1- (2-aminocarbonylexyl) -2 -exyl-imidazol-4-yl-, 1- (3-aminocarbonylpropyl) -2-methoxyimidazol-4-yl-, 1- (4-aminocarbonylbuxyl) -2-methoxyimidazol-4-yl-, 1- (5-aminocarbonylpentyl) ) -2-Mexyl-imidazol-4-yl-, 1- (6-aminocarbonylhexyl) -2-methoxy-imidazol-4-yl-, 1- (7-aminocarbonylhepoxy) -2-methoxy-imidazol-4-yl- , 1-mexylaminocarbonylmexyl-2-methoxy-imidazol-4-yl-, 1- (2-mexylaminocarbonyloxy) -2-methoxyimidazol-4-yl-, 1- (3-methoxylaminocarbonylpropyl) -2-methoxy-imidazol-4-yl 1- (4-Methylaminocarbonylbuxyl) -2-methoxy-imidazol-4-yl-, 1- (5-methoxylaminocarbonylpenxyl) -2-methoxy-imidazol-4-yl-, 1- (6-mexylamino) arbonylhexyl) -2-methoxy-imidazol-4-yl-, 1- (7-methylaminocarbonylhepxyl) -2-methoxy-imidazol-4-yl-, 1-methylaminocarbonylmexyl-2-methyl-imidazol-4-yl-, 1- (2 -exylaminocarbonylexyl) -2-methoxyimidazol-4-yl-, 1- (3-exylaminocarbonylpropyl) -2-mexyl-imidazol-4-yl-, 1- (4-ethylaminocarbonylbutyl) -2-mexyl-imidazol-4-ylmethyl 1- (5-ethylaminocarbonylpentyl) -2-methylimidazol-4-yl-, 1- (6-ethylaminocarbonylhexyl) -2-methylimidazol-4-yl-, 1- (7-ethylaminocarbonylheptyl) -2-methylimidazol-4-yl -, 1-n-propylaminocarbonylmethyl-2-methyl-imidazol-4-yl-, 1- (2-n-propylaminocarbonylethyl) -2-methyl-imidazol-4-yl-, 1- (3-n-propylaminocarbonylpropyl) - 2-methyl-imidazol-4-yl-, 1- (4-n-propylaminocarbonylbutyl) -2-methylimidazol-4-yl-, 1- (5-n-propylaminocarbonylpentyl) -2-methylimidazol-4-yl- 1- (6-n-propylaminocarbonylhexyl) -2-methylimidazol-4-yl-, 1- (7-n-propylaminocarbonylheptyl) -2-methylimidazol-4-yl-, 1-isopropylaminocarbonylmethyl-12-methylimidazol-4 -yl-, 1- (2-isopropylaminocarbonylethyl) -2-methyl-imidazol-4-yl-, 1- (3-isopropylaminocarbonylpropyl) 2-methylimidazol-4-yl-, 1- (4-isopropylaminocarbonylbutyl) -2-methyl-imidazol-4-yl-, 1- (5-isopropylaminocarbonylpentyl) -2-methyl-imidazol-4-yl-, 1- (6 -isopropylaminocarbonylhexyl) -2-methyl-imidazol-4-yl-, 1- (7-isopropylaminocarbonylheptyl) -2-methyl-imidazol-4-yl-, 1-dimethylaminocarbonylmethyl-2-methylimidazol-4-yl-, 1- ( 2-dimethylaminocarbonylethyl) -2-methylimidazol-4-yl-, 1- (3-dimethylaminocarbonylpropyl) -2-methylimidazol-4-yl-,

1- (4-dimethylaminocarbonylbutyl) -2-methyl-imidazol-4-yl-, 1- (5-dimethylaminocarbonylpentyl) -2-methyl-imidazol-4-yl-, 1- (6-dimethylaminocarbonylhexyl) -2-methyl- imidazol-4-yl-, 1- (7-dimethylaminocarbonylheptyl) -2-methyl-imidazol-4-yl-, 1-diethylaminocarbonylmethyl-2-methyl-imidazol-4-yl-, 1- (2-diethylaminocarbonylethyl) -2 -methyl-imidazol-4-yl-, 1- (3-diethylaminocarbonylpropyl) -2-methyl-imidazol-4-yl-, 1- (4-diethylaminocarbonylbutyl) -2-methylimidazol-4-yl-, 1- (5 -diethylaminocarbonylpentyl) 2-methyl-imidazol-4-yl-, 1- (6-diethylaminocarbonylhexyl) -2-, methylimidazol-4-yl-, 1- (7-diethylaminocarbonylheptyl) -2-methylimidazol-4-yl-; 1-di-n-propylaminocarbonylmethyl-2-methyl-imidazol-4-yl-, 1- (2-di-n-propylaminocarbonylethyl) -2-methyl-imidazol-4-yl-, 1- (3-di-1-ene) -propylaminocarbonylpropyl) -2-methylimidazol-4-yl-, 1- (4-di-n-propylaminocarbonylbutyl) -2-methylimidazol-4-yl-, 1- (5-di-n-propylaminocarbonylpentyl) -2-methyl- imidazol-4-yl-, 1- (6-di-n-propylaminocarbonylhexyl) -2-methyl-imidazol-4-yl-, 1- (7-di-n-propylaminocarbonylheptyl) 2-methylimidazol-4-yl-, 1- diisopropylaminocarbonylmethyl-2-methyl-imidazol-4-yl-, 1- (2-diisopropylaminocarbonylethyl) -2-methyl-imidazol-4-yl-, 1- (3-diisopropylaminocarbonylpropyl) -2-methyl-imidazol-4-yl 1- (4-diisopropylaminocarbonylbutyl) -2-methyl-imidazol-4-yl-, 1- (5-disopropylaminocarbonylpentyl) -2-methyl-imidazol-4-yl-, 1- (6-diisopropylaminocarbonylhexyl) -2-methylimidazol-4-yl- 1- (7-diisopropylaminocarbonylheptyl) -2-methyl-imidazol-4-yl-, 1-morpholinocarbonylmethyl-2-methylimidazol-4-yl-, 1- (2-morpholinocarbonylethyl) -2-methyl-imidazol-4-yl-, 1- (3-morfolinokarbonylpropyl) -2-methyl-imidazol-4-yl,

1- (4-morpholinocarbonylbutyl) -2-methyl-imidazol-4-yl-, 1- (5-morpholinocarbonylpentyl) -2-methyl-imidazol-4-yl-, 1- (6-morpholinocarbonylhexyl) -2-methylimidazole-4- yl-, 1- (7-morpholinocarbonylhepxyl) -2-methoxy-imidazol-4-yl-, 1-xiomorpholinocarbonylmethyl-2-methylimidazol-4-yl-, 1- (2-thiomorpholinocarbonylethyl) 2-methyl-imidazole-4- yl-, 1- (3-thiomorpholinocarbonylpropyl) -2-methylimidazol-4-yl-, 1- (4-thiomorpholinocarbonylbutyl) -2-methylimidazol-4-yl-, 1- (5-thiomorpholinocarbonylpentyl) -2-methylimidazole-4 -yl-, 1- (6-thiomorpholinocarbonylhexyl) -2-methyl-imidazol-4-yl-, 1- (7-thiomorpholinocarbonylheptyl) -2-methyl-imidazol-4-yl-, 1-oxothiomorpholinocarbonylmethyl-2-methyl- imidazol-4-yl-, 1- (2-oxothiomorpholinocarbonylethyl) -2-methyl-imidazol-4-yl-, 1- (3-oxothiomorpholinocarbonylpropyl) -2-methyl-imidazol-4-yl-, 1- (4-oxothiomorpholinocarbonylbutyl) -2-methyl -imidazol-4-yl-, 1- (5-oxothiomorpholinocarbonylpentyl) -2-methyl-imidazol-4-yl-, 1- (6-oxothiomorpholinocarbonylhexyl) -2-methyl-imidazol-4-yl-, 1- (7-oxothiomorpholinocarbonylheptyl) -2- methyl-imidazol-4-yl 1-, 1- (2-hydroxyethyl) -imidazol-4-yl-, 1- (3-hydroxypropyl) imidazol-4-yl-, 1- (4-hydroxybutyl) imidazol-4-yl-; 1- (2-methoxyethyl) imidazol-4-yl-, 1- (3-methoxypropyl) imidazol-4-yl-, 1- (4-methoxybutyl) imidazol-4-yl-, 1- (2-ethoxyethyl) 1-Imidazol-4-yl-, 1- (3-ethoxypropyl) -imidazol-4-yl-, 1- (4-ethoxybutyl) -imidazol-4-yl-, 1- (2-n-propoxyethyl) imidazole-4 -yl-, 1- (3-n-propoxypropyl) -imidazol-4-yl-, 1- (4-n-propoxybutyl) -imidazol-4-yl-, 1- (2-isopropoxyethyl) imidazol-4-yl-, 1- (3-Isopropoxypropyl) -imidazol-4-yl-, 1- (4-Isopropoxybutyl) -imidazol-4-yl-, 1- (2-Imidazol-1-yl-ethyl) -imidazol-4-yl- 1- (3-Imidazol-1-yl-propyl) -imidazol-4-yl-, 1- (4-imidazol-1-yl-butyl) -imidazol-4I

- 12-yl-, 1- (2,2-diphenyl-ethyl) -imidazol-4-yl-, 1- (3,3-diphenyl-propyl) -imidazol-4-yl-, 1- (4,4-diphenyl-butyl) 1-Imidazol-4-yl-, 1- (2-hydroxyethyl) -2-methyl-imidazol-4-yl-, 1- (3-hydroxypropyl) -2-methyl-imidazol-4-yl-, 1- (4- hydroxybutyl) -2-methyl-imidazol-4-yl-, 1- (2-methoxyethyl) -2-methyl-imidazol-4-yl-, 1- (3-methoxypropyl) -2-methylimidazol-4-yl-, 1- (4-Methoxybutyl) -2-methylimidazol-4-yl-, 1- (2-ethoxyethyl) -2-methylimidazol-4-yl-, 1- (3-ethoxypropyl) -2-methylimidazol-4-yl- 1- (4-ethoxybutyl) -2-methyl-imidazol-4-yl-, 1- (2-n-propoxyethyl) -2-methyl-imidazol-4-yl-, 1- (3-n-propoxypropyl) -2 -methyl-imidazol-4-yl-, 1- (4-n-propoxybutyl) -2-methyl-imidazol-4-yl-, 1- (2-isopropoxyethyl) -2-methyl-imidazol-4-yl-, 1- ( 3-isopropoxypropyl) -2-methylimidazol-4-yl-, 1- (4-isopropoxybutyl) -2-methylimidazol-4-yl-, 1 (2-imidazol-1-yl-ethyl) -2-methylimidazole- 4-yl-, 1- (3-imidazol-1-yl-propyl) -2-methyl-imidazol-4-yl-, 1- (4-imidazol-1-yl-butyl) -2-methyl-imidazol-4- yl-, 1- (2,2-diphenyl-ethyl) -2-methylimidazol-4-yl-, 1- (3,3-diphenylpropyl) -2-methylimidazol-4-yl-, 1- (4,4-Diphenyl-butyl) -2-methylimidazol-4-yl-, 1- (2- (2-methoxyethoxy) ethyl) imidazol-4-yl-, 1- [3- (2-methoxyethoxy) 1-Propyl] imidazol-4-yl-, 1- [4- (2-methoxyethoxy) butyl] -imidazol-4-yl-, 1- [2- (2-ethoxyethoxy) ethyl] -imidazol-4-yl 1- [3- (2-ethoxyethoxy) propyl] -imidazol-4-yl-, 1- [4- (2-ethoxyethoxy) butyl] -imidazol-4-yl-, 1- [2- (2-n-propyl) -propoxyethoxy) ethyl] -imidazol-4-yl-, 1- [3- (2-n-propoxyethoxy) propyl] imidazol-4-yl-, 1- [4- (2-n-propoxyethoxy) butyl] -imidazol-4-yl-, 1- [2- (2-isopropoxyethoxy) ethyl] imidazol-4-yl-, 1- [3- (2-isopropoxyethoxy) -propyl] -imidazol-4-yl-, 1- [4 - (2-Isopropoxyethoxy) butyl] -imidazol-4-yl-, 1- (2-dimethylaminoethyl) -imidazol-4-yl-, 1- (2-diethylaminoethyl) -imidazol-4-yl-, 1- (2- di-n-propylamino-ethyl) -imidazol-4-yl-, 1- (2-diisopropylamino-ethyl) -imidazol-4-yl-, 1- (3-dimethylaminopropyl) -imidazol-4-yl-, 1- ( 3-diethylamino-propyl) -imidazol-4-yl-, 1- (3-di-n-propylamino-propyl) -imidazol-4-yl-, 1- (3-diisopropylamino-propyl) -imidazol-4-yl-, 1- (4-dimethylamino-butyl) -imidazol-4-yl-, 1- (4-diethylaminobutyl) -imidazol-4-yl-, 1- (4-di-n-propylamino-butyl) -imidazol-4-yl-, 1- (4-diisopropylamino-butyl) imidazol-4-yl-, 1- (2-morpholinoethyl) imidazol-4-yl- 1- (3-morpholino-propyl) imidazol-4-yl-, 1- (4-morpholino-13-butyl) -imidazol-4-yl-, 1- (2-pyrrolidino-ethyl) -imidazol-4-yl 1- (3-pyrrolidino-propyl) -imidazol-4-yl-, 1- (4-pyrrolidino-butyl) -imidazol-4-yl-, 1- (2-piperidinoethyl) -imidazol-4-yl- 1- (3-piperidino-propyl) -imidazol-4-yl-, 1- (4-piperidinobutyl) imidazol-4-yl-, 1- (2-hexamethylenimino-ethyl) -imidazol-4-yl-,

1- (3-Hexamethylenimino-propyl) -imidazol-4-yl-, 1- (4-Hexamethylenimino-butyl) -imidazol-4-yl-, 1- (2-thiomorpholino-ethyl) -imidazol-4-yl- 1- (3-Thiomorpholino-propyl) -imidazol-4-yl-, 1- (4-thiomorpholino-butyl) -imidazol-4-yl-, 1- [2- (1-oxothiomorpholino) -ethyl] -imidazol-4-yl- 1- [3- (1-oxo-thiomorpholino) -propyl] imidazol-4-yl- or 1- [4- (1-oxo-thiomorpholino) -butyl] -imidazol-4-yl group.

R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, ethoxy, n-propoxy, isopropoxy, ethylthio, n-propylthio or isopropylthio and

R ⁴ denotes hydroxycarbonyl-, methoxycarbonyl-, ethoxycarbonyl-, n-propyloxycarbonyl-, isopropyloxycarbonyl-, n-butyloxycarbonyl-, isobutyloxycarbonyl-, tert-butyloxycarbonyl-, n-pentyloxycarbonyl-, isoxyloxycarbonyloxy-, n-propyloxy- benzyloxycarbonyl-, 1-phenylethyloxycarbonyl-, 2-phenylethyloxycarbonyl-, 3-phenylpropyloxycarbonyl-, methoxymethoxycarbonyl-, cinnamyloxycarbonyl-, acetoxymethoxycarbonyl-, propionyloxymethoxycarbonyl-, n-butyryloxymethoxycarbonyl-, n-butyryloxymethoxycarbonyl- , n-hexanoyloxymethoxycarbonyl-, cyclopentanoyloxymethoxycarbonyl-, cyclohexanoyloxymethoxycarbonyl, phenylacetoxymethoxycarbonyl-,

2-phenylpropionyloxymethoxycarbonyl-, 3-phenylpropionyloxymethoxycarbonyl-, 4-phenylbutyryloxymethoxycarbonyl-, benzoyloxymethoxycarbonyl-, 1-acetoxyethoxycarbonyl-, 1-propionyloxyethoxycarbonyl-, 1-n-butyryloxyethoxycarbonyl-, 1-isobenzyloxyethoxycarbonyl-, 1-isobutyl 1-pivaloyloxyethoxycarbonyl-, 1-n-hexanoyloxyethoxycarbonyl-, 1-cyclopentanoyloxyethoxycarbonyl-, 1-cyclohexanoyloxyethoxycarbonyl-, 1-phenylacetoxyethoxycarbonyl-, 1,4- (1-phenylpropionyloxy) ethoxycarbonylpropionyl, 1- (2-phenylcarbonyloxy) carbonyl -, 1- (3-phenylbutyryloxy) -ethoxycarbonyl-,

1-benzoyloxyetoxykarbonyl-, metoxykarbonyloxymetoxykarbonyl-, etoxykarbonyloxymetoxykarbonyl-, n propyloxykarbonyloxymetoxykarbonyl-, ízopropyloxykarbonyloxymetoxykarbonyl-, n butyloxykarbonyloxymetoxykarbonyl-, izobutyloxykarbonyloxymetoxykarbonyl-, terc.butyloxykarbonyloxymetoxykarbonyl-, n pentyloxykarbonyloxymetoxykarbonyl-, izoamyloxykarbonyloxymetoxykarbonyl-, n hexyloxykarbonyloxymetoxykarbonyl-, cyklopentyloxykarbonyloxymetoxykarbonyl-, cyklohexyloxykarbonyloxymetoxykarbonyl- , benzyloxycarbonyloxymethoxycarbonyl-, 1-phenylethoxycarbonyloxymethoxycarbonyl-, 2-phenylethoxycarbonyloxymethoxycarbonyl-, 3-phenylpropyloxycarbonyloxymethoxycarbonyl-, cinnamyloxycarbonyloxycarbonyloxycarbonyloxy- (ethoxycarbonyloxy) ethoxy (ethoxycarbonyloxy) ethoxycarbonyloxy) 1- (isopropyloxycarbonyloxy) -ethoxycarbonyl-, 1- (n-butyloxycarbonyloxy) -ethoxycarbonyl-, 1- (isobutyloxycarbonyloxy) -ethoxycarbonyl-, 1- (tert-butyloxycarbonyloxy) -ethoxycarbonyl-, 1- (n-pentyloxy) carbonyloxy) ethoxycarbonyl-, 1- (isoamyloxycarbonyloxy) ethoxycarbonyl-, 1- (n-hexyloxycarbonyloxy) ethoxycarbonyl-, 1 (cyclopentyloxycarbonyloxy) ethoxycarbonyl-, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl-, cyclopentylcarbonyloxy-, cyclopentylcarbonyloxy- 1- (1-phenylethoxycarbonyloxy) -ethoxycarbonyl-, 1- (2-phenylethoxycarbonyloxy) -ethoxycarbonyl-, 1- (3-phenylpropyloxycarbonyloxy) ethoxycarbonyl-, 1- (cinnamyloxycarbonyloxy) ethoxycarbonyl-, cyano-, 1H-tetrazolyl-, 1-tetrazolyl-, 1-tetrazolyl-, 1-tetrazolyl- -triphenylmethyltetrazolyl- or 2-triphenylmethyl-tetrazolyl.

Preferred compounds of the above formula are those wherein up to R 1 are as defined above and R 1 is in the 6-position of the benzimidazole ring, especially those compounds of formula I wherein R 1 is hydrogen or chlorine or methyl { , i

and

I »···»

- 15 R represents in the 6-position attached at the 2-position a phenyl-substituted oxazol-4-yl- or thiazol-4-yl-group or, optionally at the 2-position, a methyl-substituted imidazol-4-yl-group which can be substituted at the 1-position C 1 -C 7 alkyl which may be substituted in the 1, 2, 3, 4, 5, 6 or 7 position by carboxy-, methoxycarbonyl-, aminocarbonyl-, methylaminocarbonyl-, ethylaminocarbonyl-, n-propylaminocarbonyl-, dimethylaminocarbonyl- , morpholinocarbonyl-, thiomorpholinocarbonyl- or 1-oxothiomorpholinocarbonyl, a (C 2 -C 4) alkyl group substituted in the 2, 3 or 4 position with hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino piperidino, morpholino or imidazol-1-yl, or substituted with 2,2,2-trifluoroethyl-, 3,3,3-trifluoropropyl-, cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, 2 -phenylethyl-, 4-fluorobenzyl-, 3-chlorobenzyl-, 4-methyl 1-benzyl-, 4-trifluoromethylbenzyl-, 3,5-dimethoxybenzyl- or 2,2-diphenylethyl means an alkyl group having 2 to 4 carbon atoms, an alkoxy or alkylthio group having 2 or 3 carbon atoms in each alkyl moiety, cyclopropyl or cyclobutyl and

R ⁴ represents a group convertible in vivo into a carboxy, carboxy- or 1H-tetrazolyl group, and salts thereof, in particular for pharmaceutical use, their physiologically acceptable salts with inorganic or organic acids or bases.

Particularly preferred of the above compounds of formula I are those in which:

R ¹ represents a hydrogen atom or a methyl group,

R represents at the 6-position attached at the 2-position a phenyl-substituted oxazol-4-yl- or thiazol-4-yl-group or an optionally at the 2-position a methyl-substituted imidazol-4-yl-group which may be substituted by an alkyl group C1-C7 which may be substituted in the 1, 2, 3, 4, 5, 6 or 7 position by carboxy-, methoxycarbonyl-, dimethylaminocarbonyl- or morpholinocarbonyl-; 2, 3 or 4 is substituted with hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-1-yl, or is substituted with 2,2,2- trifluoroethyl-, 3,3,3-trifluoropropyl-, cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, or 4-fluorobenzyl,

R ³ is C 2 -C 4 alkyl, ethoxy, ethylthio, cyclopropyl, or cyclobutyl; and

R ⁴ represents a carboxy- or tet-tetrazolyl group, in particular those of the compounds of formula I above, in which R ¹ to R ⁴ are as defined above and R ² is in the 6-position, and salts thereof, particularly for pharmaceutical use, their physiologically acceptable salts with inorganic or organic acids or bases.

Particularly preferred compounds of formula I above are:

(i) 4 '- [(2-n-propyl-4-methyl-6- (1- (2-N-morpholinoethyl) -imidazol-4-yl) -benzimidazol-1-yl) -methyl] biphenyl- 2-carboxylic acid, (ii) 4 '- [(2-n-propyl-4-methyl-6- (1- (2-methoxyethoxy-2-ethyl) -imidazol-4-yl) -benzimidazol-1-yl) - methyl] -biphenyl-2-carboxylic acid.

(iii) 4 '- ((2-ethyl-4-methyl-6- (1- (2-diethylaminoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl) -2- (1H-tetrazole-5- yl) biphenyl, (iv) 4 '- [(2-ethyl-4-methyl-6- (1- (3-N-piperidinopropyl) imidazol-4-yl) benzimidazol-1-yl) methyl] -2 - (1H-tetrazol-5-yl) biphenyl, (v) 4 '- [(2-n-propyl-4-methyl-6- (1- (3-dimethylaminopropyl) imidazol-4-yl) benzimidazole) (1-yl) -methyl] -biphenyl-2-carboxylic acid, (vi) 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-morpholinoethyl) imidazol-4-yl) -benzimidazole) (1-yl) -methyl] -biphenyl-2-carboxylic acid, (vii) 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-morpholinoethyl) -imidazol-4-yl) -benzimidazole) (1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl; (viii) 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-pyrrolidinoethyl) acid)) (imidazol-4-yl) -benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid, (ix) 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-)) pyrrolidinoethyl) imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl, (x) 4 '- [(2-ethyl-4-methyl-6- ( 1- (2-diethylamino-ethyl) -imidazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-ka and (xi) 4 '- [(2-ethyl-4-methyl-6- (1- (3-N-piperidinopropyl) imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl- 2-carboxylic acids as well as their salts, in particular for pharmaceutical use their physiologically acceptable salts with inorganic or organic acids or bases.

According to the invention, it is possible in the following ways:

to prepare said compounds

a) cyclizing, optionally in the reaction compound of formula II, the mixture prepared

(II) in which Ί 9

R ^{@ 1} and R @ 2 are as defined above, one of the radicals X ^{@ 1} or Y ^{@ 1} represents a group of the formula

a group of the general formula

Z ¹ Z ² \ '3

- NH - C - R ^J where

R1 and R4 are as defined above, e and a

R ^ represents a hydrogen atom or R R a CO group, wherein R má is as defined above,

Z ¹ and Z ² , which may be the same or different, represent optionally substituted amino or optionally C 1 -C 6 -alkyl substituted hydroxy or mercapto groups, or

Z ¹ and Z ² together with an oxygen or sulfur atom or an alkyl group having 1 to 3 carbon atoms each have a substituted amino, alkylenedioxy or alkylenedithio group having 2 or 3 carbon atoms in each case.

The cyclization is preferably carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin corresponding to the reagents used to produce e.g. , ester or amide, or in excess of the acylating compounds of formula II, nitrile, anhydride, halide, for example at temperatures up to 250 ° C, preferably at the boiling point of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, acid sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally in the presence of a base such as potassium ethylate or potassium tert-butylate. However, the cyclization can also be carried out without a solvent and / or a condensing agent.

However, the reaction is particularly preferably carried out by preparing a compound of the formula II in the reaction mixture by reducing the corresponding o-nitroamino compound optionally

Q in the presence of a carboxylic acid of the formula RCOOH or by acylation of the corresponding o-diamino compound. When the reduction of the nitro group in the hydroxylamine step is interrupted, the N-oxide of the compound of the formula I is obtained after subsequent cyclization. The N-oxide thus obtained is then converted by reduction to the corresponding compound of the formula I.

The subsequent reduction of the obtained N-oxide of formula I 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 on activated carbon. metals such as iron, tin or zinc in the presence of an acid such as acetic acid, hydrochloric acid or sulfuric acid, salts such as ferrous sulfate, stannous chloride or sodium dithionite, or hydrazine in the presence of Raney-nickel at temperatures between 0 ° C and 50 ° C, preferably at room temperature, (III)

b) reacting the benzimidazole of formula III

H in which

-i _v and _t vw.

R @ 1 to R @ 2 are as defined above, with a biphenyl compound of formula IV

(IV) atom and which

R ⁴ is as defined above and

7? means a nucleophilic leaving group such as a logene, for example a chlorine, bromine or iodine atom or a substituted sulfonyloxy group, for example a methanesulfonyloxy-, phenylsulfonyloxy- or p-toluenesulfonyloxy group.

The reaction is preferably carried out in a solvent or solvent mixture such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butylate, sodium hydride, triethylamine or pyridine, the latter two can also be used as solvents at the same time, preferably at temperatures between 0 and 100 ° C, for example at temperatures between room temperature and 50 ° C.

The reaction preferably yields a mixture of 1- and 3-isomers, from which the corresponding 1-isomer is separated by crystallization or chromatography using a carrier such as silica gel or alumina,

c) converting a compound of formula V to produce a compound of formula I wherein R R is carboxy

in which lv3

R to R are as defined above and

R ⁴ is a group convertible by hydrolysis, thermolysis or hydrogenolysis into a carboxy group.

Functional derivatives of the carboxy group such as its unsubstituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides, nitrile or teterazolyl groups can be converted to the carboxy group by hydrolysis, ester with tertiary alcohols, for example tert-butyl ester, by thermolysis a carboxy group and an ester with aralkanols, for example the benzyl ester, can be converted to a carboxy group by hydrogenolysis.

The hydrolysis is preferably carried out either in the presence of an acid such as hydrochloric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / ethanol, water / isopropanol, water / dioxane, methylene chloride or chloroform at temperatures between -10 ° C to 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture. When hydrolyzed in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, the optionally present alcoholic hydroxy groups can be simultaneously converted to the corresponding acyloxy group such as trifluoroacetoxy.

When R in the compound of formula (V) is cyano or amino, these groups can also be converted to a carboxyl group by a nitrite, for example sodium nitrite, in the presence of an acid such as sulfuric acid, preferably simultaneously used as a solvent at temperatures between 0 to 50 ° C.

When R in the compound of formula (V) is, for example, tert-butyloxycarbonyl, the tert-butyl may also be cleaved thermally 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 acid such as p- toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid at the boiling point of the solvent used, for example at temperatures between 40 ° C and 100 ° C.

When R is, for example, benzyloxycarbonyl in the compound of formula (V), the benzyl group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium on carbon 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, for example at room temperature and a hydrogen pressure of 1 to 5 bar. In hydrogenolysis, at the same time other residues, for example nitro to amino, benzyloxy to hydroxy, vinylidene to the corresponding alkylidene or cinnamic acid to the corresponding phenylpropionic acid group, can be reduced or replaced by a hydrogen atom, for example a halogen atom by a hydrogen atom.

d) For the preparation of a compound of the formula I in which R 1 is ΙΗ-tetrazolyl, the protective group of the compound of the formula VI is cleaved off.

(VI) in which f 2 3

R, R and R are as defined above and

R represents a ΙΗ-tetrazolyl group protected at the 1 or 3 position by a protecting group.

Suitable protecting groups are triphenylmethyl, tributyltin or triphenyltin.

The cleavage of the protecting group used is preferably carried out in the presence of hydrogen halide, preferably in the presence of hydrogen chloride, in the presence of a base such as sodium hydroxide or alcoholic ammonia in a suitable solvent such as methylene chloride, methanol, methanol / ammonia, ethanol or isopropanol at temperatures but preferably at room temperature or even if the reaction was carried out in alcoholic ammonia, at elevated temperatures, for example at temperatures between 100 and 150 ° C, preferably at temperatures between 120 and 140 ° C.

e) To produce a compound of formula I wherein R ⁴ is 4-tetrazolyl, a reaction of a compound of formula VII is carried out

wherein R ¹ to R 6 are as previously defined, with hydrochloric acid or its salts.

The reaction is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 to 150 ° C, preferably at 125 ° C. Advantageously in that respect either the hydrazoic acid is released during the reaction of the alkali metal azide such as sodium azide, in the presence of a weak acid such as ammonium chloride or a salt of the tetrazolidová získa- 24 for the reaction mixture in the reaction of hydrazoic acid salt ^of S, preferably aluminum azide or tributyltin azide, which can conveniently be prepared in the reaction mixture by reacting aluminum chloride or tributyltin chloride with an alkali metal azide such as sodium azide, then liberating by diluting with a dilute acid such as 2N hydrochloric acid or 2N sulfuric acid.

When a compound of the formula I is obtained by the process of the invention, where R @ 1 is carboxy, it can be converted by the transesterification to the corresponding compound of the formula I, wherein R @ 1 is a carboxyl group convertible in vivo. of formula I, wherein R is an imidazol-4-yl group which is substituted in the 1-position by a (C 2 -C 4) alkyl group wherein the alkyl group at the 2, 3 or 4 position is substituted by an alkoxy or alkoxyalkoxy group, can be converted by ether cleavage to the corresponding compound of formula I wherein R is imidazol-4-yl substituted in the 1-position with C 2 -C 4 alkyl, wherein the alkyl group is substituted in the 2, 3 or 4 position with hydroxy.

Conversion of the carboxyl group to a group which is metabolically converted to a carboxy group is conveniently effected by esterification with the corresponding alcohol or a corresponding reaction capable of an acyl derivative, preferably in a solvent or solvent mixture such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide. an acylating agent as solvent, optionally in the presence of an acid activating or water-withdrawable agent such as thionyl chloride, with anhydrides, esters or halides optionally in the presence of an inorganic or tertiary organic base such as sodium hydroxide, potassium carbonate, triethylamine or pyridine; serve as a solvent, at temperatures between -25 to 100 ° C, but preferably at temperatures between -25 ° C and 100 ° C

-10 to 80 ’C.

The subsequent ether cleavage is carried out hydrolytically in an aqueous solvent, for example water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydroiodic or hydrobromic acid, preferably under the influence of Lewis acid such as boron trifluoride, boron tribromide. , dimethylboron bromide or aluminum chloride in a suitable solvent such as dichloromethane or chloroform, or with bromotrimethylsilane, iodotrimethylsilane or chlorotrimethylsilane in a suitable solvent such as acetonitrile, dichloromethane or chloroform at temperatures between 0 to 100 C, preferably at 20 ° C, and then treated with water .

In the reactions described above, reaction groups such as hydroxy, amino or alkylamino groups optionally present during the reaction may be protected with the usual protecting groups which may be cleaved again after the reaction.

Examples of the protecting group for the hydroxy group are, for example, trimethylsilyl-, acetyl-, benzoyl-, methyl-, ethyl-, tert-butyl-, benzyl- or tetrahydropyranyl- and, for the amino-, alkylamino- or imino-, acetyl-, benzoyl-protecting groups. -, ethoxycarbonyl or benzyl.

Optionally, the subsequent cleavage of the protecting group used is preferably carried out hydrolytically in an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or dioxane / water in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 ° C and 100 ° C, preferably at the boiling point of the reaction mixture. However, the cleavage of the benzyl residue is preferably carried out hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium on carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with an acid such as hydrochloric acid at temperatures between 0 to 50 ° C. but preferably at room temperature and at a pressure of about 0.1 to 0.7 MPa, preferably about 0.3 to 0.5 MPa.

The 1-isomer is preferably separated from the mixture of the 1-, 3-isomers of the compounds of formula (I) thus obtained by chromatography such as silica gel or alumina.

Furthermore, the compounds of the formula I obtained can be converted into their acid addition salts, in particular for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Suitable acids here are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the compounds of formula I thus obtained, if they contain a carboxy- or 1H-tetrazolyl group, optionally converted into their salts with inorganic or organic bases, for pharmaceutical use, can be converted into their physiologically acceptable salts. Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, cyclohexane, ethanolamine, diethanolamine and triethanolamine.

As starting materials, the compounds of the formulas I, II used are partly known from the literature or can be obtained by methods known from the literature.

The compound of formula II is thus obtained, for example, by alkylation of the corresponding o-aminoacylamino compound of formula IV. The o-aminoacylamino compound required for this reaction is obtained by reducing the corresponding o-nitro-acylamino compound, which is obtained by nitrating the corresponding acylaminoacetophenone, then converting the obtained o-nitro-acylaminoacetophenone to the corresponding -bromoacetophenone, followed by cyclization of -bromoacetophenone with the appropriate amide. by subsequent reduction of the nitro group. Prior to reduction of the nitro group, the oxazol-4-yl compound thus obtained can be converted to the corresponding imidazol-4-yl compound under pressure with the corresponding amine, preferably ammonia, or the unsubstituted imidazol-4-yl compound thus obtained can be converted to the 1-position. corresponding to the 1-position of the alkylated imidazol-4-yl compound.

The starting compound of formula III is obtained by reduction or cyclization of the above-described o-nitro-acylamino compound.

The starting compound of formula (V), (VI) and (VII) is obtained by reacting a compound of formula (III) with the corresponding compound of formula (IV).

The compounds of the formula I and their physiologically acceptable salts have valuable pharmacological properties. They are angiotensin antagonists, in particular angiotensin II antagonists.

Examples are compounds:

A = 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid (nicht erfindungsgemä),

B = 4 '- [(2-n-propyl-4-methyl-6- (1-isopropyl-imidazol-4-yl) benzimidazol-1-yl) methyl) -2- (1H-tetrazol-5-yl) ) -biphenyl (nicht erfindungsgemä)

C = 4 '- [{2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid,

D = 4 '- [(2-ethoxy-6- (1-isopropyl-imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid,

E = 4 '- ((2-n-propyl-4-methyl-6- (1-cycloheptylimidazol-4-yl) -benzimidazol-1-yl) methyl) -biphenyl-2-carboxylic acid,

F = 4 '- [(2-n-propyl-4-methyl-6- (1-aminocarbonylmethyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid and

G = 4 '- [(2-n-propyl-4-methyl-6- (1- (3-dimethylaminopropyl) -imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2 dihydrochloride pentahydrate -carboxylic acid was tested for their biological activity.

Angiotensin II receptor binding method

The tissue (rat lung) is homogenized in tris buffer (50 mmol Tris, 150 mmol NaCl, 5 mmol EDTA, pH 7.4) and centrifuged twice for 20 minutes at 20000xg. The obtained pellet is resuspended in incubation buffer (50 mmol Tris, 5 mmol MgCl ₂ , 0.2% BSA, pH 7.4) 1:75, based on tissue moisture. 0.1 ml of homogenate is incubated for 60 minutes at 37 ° C with 50 µM [125 *] - angiotensin II (NEN, Dreieich, Germany) and at increasing concentrations of the test substance in a total volume of 0.25 ml. Incubation is terminated by rapid filtration through a glass fiber filter. The filters were washed with 4 ml of ice-cold buffer (25 mmol Tris, 2.5 mmol MgCl ₂ , 0.1% BSA, pH 7.4) each. Bound radioactivity is calculated by a gamma counter. The corresponding IC 50 value is calculated from the dose-effectiveness curve.

substance IC ₅₀ [nM] A 1.2 B 1.5 C 40 D 10 E 15 F 3.4 G 1.3

Because of their pharmacological properties, in particular blood pressure lowering with a diuretic / saluretic component, these compounds and their physiologically acceptable salts are suitable for the treatment of hypertonia and cardiac insufficiency, for the treatment of chronic renal insufficiency, for the treatment of ischemic peripheral (e.g. Raynaud's syndrome) cerebrovascular disorders of blood flow, myocardial ischemia (angina), for preventing the progression of cardiac insufficiency after myocardial infarction, for the treatment of diabetic nephro- and retinopathy, glaucoma, gastrointestinal diseases and urinary tract diseases.

Further, the compounds and their physiologically acceptable salts are suitable for the treatment of pulmonary diseases such as pulmonary edema and chronic bronchitis, for the prevention of arterial restenosis after angioplasty, for strengthening the vessel wall after vascular surgery, arteriosclerosis, diabetic angiopathy, hyperuricemia and gout. By influencing the release of acetylcholine and dopamine by angiotensin in the brain, novel angiotensin antagonists are also useful for the treatment of central nervous system disorders such as depression, Alzheimer's disease, Parkinson's syndrome as well as cognitive impairment.

The dose required to achieve a corresponding effect in adults is generally 0.5 to 100 mg, preferably 1 to 70 mg intravenously, and 0.1 to 200 mg, preferably 1 to 100 mg, orally 1 to 3 times daily for oral administration. Accordingly, the compounds of formula (I) may be prepared by the process of the invention, optionally in combination with other active substances such as blood pressure lowering agents, ACE suppressants, diuretics and / or calcium antagonists, together with one or more inert conventional carriers and / or diluents, e.g. corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol water / glycerin, water / sorbitol, water / polyethylene glycol, fatty acid, propylene glycol, cetyl ether glycol, , such as hardened fat or suitable mixtures thereof, may be formulated into conventional galenic formulations such as tablets, dragees, capsules, powders, suspensions or suppositories.

Suitable combinations for the above combinations include, for example, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzthiazide, cyclotiazide, ethacrinic acid, furosemide, metoprolol, prazosin, atenolol, propranolol, (di) hydralazin-hydro, diiphoride, hydro-azine, hydro-azine. nicardipine, nifedipine, nisoldipine, nitrendipine, captopril, enalapril, quinapril, fosinopril and ramiril.

The dose for these active ingredients is preferably 1/5 of the usually recommended lowest dose up to 1/1 of the commonly recommended dose, for example 15 to 200 mg hydrochlorothiazide, 125 to 2000 mg chlorothiazide, 15 to 200 mg etacrinic acid, 5 to 80 mg furosemide, 20 to 480 mg propranolol, 5 to 60 mg felopidine, 5 to 60 mg nifedipine or 5 to 60 mg nitrendipine.

The following examples illustrate the invention in more detail.

DETAILED DESCRIPTION OF THE INVENTION

Example A

4 '- [(2-n-Propyl-4-methyl) -6- (1-methyl-imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

(a) 3-methyl-4-butyrylamino-5-nitro-acetophenone

32.6 g (148 mmol) of 3-methyl-4-butyrylamino-acetophenone are introduced portionwise at -15 ° C with stirring in 300 ml of fuming nitric acid and stirred at -15 ° C for a further 30 minutes. The reaction mixture is poured on ice with stirring, the precipitated crude product is filtered off with suction, washed with 400 ml of water, dried and purified by recrystallization from a mixture of ethanol (diethyl ether (1: 1). Yield: 23.8 g (61.0% of theory). .

Rf value: 0.32 (silica gel, methylene chloride)

Rf value: 0.48 (silica gel, methylene chloride / methanol = 50: 1)

b) 3-methyl-4-butyrylamino-5-nitro-bromoacetophenone

To a solution of 23.8 g (90 mmol) of 3-methyl-4-butyrylamino-5-nitroacetophenone in 900 ml of dichloromethane at room temperature with stirring is added dropwise a solution of 16.0 g (200 mmol) of bromine in 140 ml of dioxane. The reaction mixture was completely decolorized. After stirring for a further two hours, the reaction mixture is suctioned to dryness under vacuum, the residue thus obtained is triturated with about 20 ml of a dichloromethane / diethyl ether (1: 1) mixture, filtered off with suction and then dried. 23 g (74% of theory) of 3-methyl-4-butyrylamino-5-nitro-bromoacetophenone are obtained, in which about 10% of the starting material is still present. the product was used in the next reaction without further purification.

Rf value: 0.69 (silica gel, methylene chloride / methanol = 50: 1) Rf value: 0.84 (silica gel, methylene chloride / methanol = 9: 1)

c) 2-butyrylamino-3-nitro-5- (imidazol-4-yl) toluene

A solution of 6.8 g (20 mmol) of 3-methyl-4-butyrylamino-5-nitrobromoacetophenone in 20 ml of formamide was heated at room temperature for 2 hours.

140 ’C. The cooled solution is then poured into about 50 ml of 1N ammonia and stirred for about 15 minutes. The precipitated crude product is filtered off with suction, washed with about 50 ml of water and dried. 4.4 g (75% of theory) of the product are obtained, which product is used without further purification.

Rf value: 0.29 (silica gel, methylene chloride / methanol = 9: 1)

d) 2-butyrylamino-3-nitro-5- (1-methyl-imidazol-4-yl) toluene

To a solution of 2.5 g (8.7 mmol) of 2-butyrylamino-3-nitro-5- (imidazol-4-yl) -toluene and 5.2 g (30 mmol of potassium carbonate dihydrate in 30 ml of dimethyl sulfoxide) was added dropwise at room temperature. Methyl iodide (1.3 g, 9.5 mmol) was added and the reaction mixture was stirred into 150 ml of water, extracted four times with 25 ml of acetate each time, and the organic extracts were washed with about 30 ml of water and dried. The crude product obtained is purified by column chromatography (300 g silica gel, eluent: methylene chloride / methanol = 30: 1).

Yield: 640 mg (24% of theory)

Rf value: 0.54 (silica gel, methylene chloride / methanol = 9: 1)

e) 2-Butyrylamino-3-amino-5- (1-methyl-imidazol-4-yl) -toluenol

640 mg (2.1 mmol) of 2-butyrylamino-3-nitro-5- (1-methylimidazol-4-yl) toluene are hydrogenated in 30 ml of methanol after addition of about 200 mg of palladium on carbon (20%) at room temperature and pressure of 0.5 MPa. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The crude product obtained is used in the next reaction without further purification.

Yield: 600 mg (100% of theory)

Rf value: 0.23 (silica gel, methylene chloride / methanol = 9: 1)

f) 2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) benzimidazole

600 mg (2.1 mmol) of 2-butyrylamino-3-amino-5- (1-methylimidazol-4-yl) -toluenol was heated to reflux in 10 ml of glacial acetic acid for one hour. It is then evaporated under vacuum, the residue is mixed with about 15 ml of water, made alkaline with ammonia and extracted four times with about 10 ml of acetate each. The organic extracts are washed with about 15 ml of water, dried and then evaporated. The crude product thus obtained is allowed to react further for purification.

Yield: 420 mg (79% of theory)

Rf value: 0.37 (silica gel, methylene chloride / methanol = 9: 1)

(g) 4 '- [(2-n-propyl-4-methyl) -6- (1-methyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid tert-butyl ester

To a solution of 200 mg (0.79 mmol) of 2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) benzimidazole and 90 mg (0.8 mmol) of tert. potassium butylate in 5 ml of dimethylsulfoxide, 280 mg (0.8 mmol) of tert-butyl 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester are added and the mixture is stirred at room temperature for 90 minutes, then stirred in about 40 ml of water. in each case about 10 ml of acetate, then the organic extracts are washed with 10 ml of water, dried and evaporated to dryness. The crude product thus obtained was purified by column chromatography (100 g silica gel, eluent: dichloromethane / methanol = 30: 1). Yield: 230 mg (56% of theory)

Rf value: 0.61 (silica gel, methylene chloride / methanol = 9: 1)

h) 4 '- [(2-n-Propyl-4-methyl) -6- (1-methyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

4 '- [(2-n-Propyl-4-methyl) -6- (1-methyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid tert-butyl ester solution (230 mg (0.44 mmol) and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane are stirred at room temperature overnight and then dried to dryness. The residue is dissolved in about 5 ml of dilute sodium hydroxide, the solution is neutralized with acetic acid, washed with water and dried. Yield: 120 mg (59% of theory)

Melting point: 293-295 ° C

Rf value: 0.39 (silica gel, methylene chloride / methanol = 9: 1)

Example B - Comparative Example

4 '- [(2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (lH-tetrazol-5-yl) biphenyl -hydrate

(a) 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] -2-cyanobiphenyl

To a solution of 200 mg (0.79 mmol) of 2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) -benzimidazole and 90 mg (0.8 mmol) of potassium tert-butylate in 6 ml of dimethylsulfoxide 218 mg (0.8 mmol) of 4'-bromomethyl-2-cyanobiphenyl are added and the mixture is stirred at room temperature for 14 hours. It is then added to about 40 ml of water, extracted four times with about 10 ml of acetate each time, the organic extracts are washed with about 10 ml of water, dried and evaporated to dryness. The crude product thus obtained was purified by column chromatography (100 g silica gel, eluent: dichloromethane / ethanol = 50: 1).

Yield: 240 mg (67% of theory)

Rf value: 0.38 (silica gel, methylene chloride / ethanol = 19: 1)

b) 4 '- [(2-n-propyl-4-methyl-6- (1-methyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) ) biphenyl-hydrate

A solution of 222 mg (0.5 mmol) of 4 '- [(2-n-propyl-4-methyl-6- (1-methylimidazol-4-yl) benzimidazol-1-yl) methyl] -2-cyanobiphenyl 660 mg ( 10 mmol) of sodium azide and 540 mg (10 mmol) of ammonium chloride in 12 ml of pure dimethylformamide were heated at 140 ° C for 18 hours. The solution was then evaporated to near dryness and the product was isolated by column chromatography (60 g silica gel, eluent: dichloromethane with 10% ethanol). The product thus obtained is taken up in about 10 ml of dilute ammonia solution and the pH of the solution is adjusted to pH 6 with acetic acid. A viscous precipitate is formed which is added by addition of a small amount of acetate and crystallized after stirring for several hours. The crystalline product is filtered off with suction, washed with about 5 ml of water and dried.

Yield: 61.0 mg (24.0% of theory)

Mp: 255-257 ° C

Analysis for C ^ I ^ ^x ^ GNG 2θ (506.62) calculated: 68.75% C, 5.97% H, 22.12% N Found: 68.90% C, 5.97% H, 22 , 03% N

Rf value: 0.24 (silica gel, methylene chloride / methanol = 9: 1)

Example 1

4 '- [(2-n-Propyl-4-methyl-6- (1-cyclopentylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1-cyclopentylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Example 2

4 '- [(2-n-Propyl-4-methyl-6- (1-cyclohexylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1-cyclohexylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Example 3

4 '- [(2-n-Propyl-4-methyl-6- (1- (4-fluorobenzyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1- (4-fluorobenzyl) imidazol-4-yl) -benzimidazol-1-yl) - methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

i N.

Analogous to Example 3, the following compounds can be obtained:

4 '- [(2-n-Propyl-4-methyl-6- (1- (3-chlorobenzyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid,

4 '- [(2-n-Propyl-4-methyl-6- (1- (3,5-dimethoxybenzyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid,

4 '- [(2-n-Propyl-4-methyl-6- (1- (4-methylbenzyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid,

4 '- [(2-n-Propyl-4-methyl-6- (1- (4-trifluoromethylbenzyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid.

Example 4

4 '- [(2-n-Propyl-4-methyl-6- (1- (2-phenylethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1- (2-phenylethyl) imidazol-4-yl) -benzimidazol-1-yl) - methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Example 5

4 '- [(2-n-Propyl-4-methyl-6- (1- (2,2,2-trifluoroethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from tert-butyl 4 '- [(2-n-propyl-4-methyl-6- (1- (2,2,2-trifluoroethyl) imidazol-4-yl) benzimidazol-1-yl) ester. yl) methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Example 6

4 '- [(2-n-Propyl-4-methyl-6- (1- (3,3,3-trifluoropropyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from tert-butyl 4 '- [(2-n-propyl-4-methyl-6- (1- (3,3,3-trifluoropropyl) imidazol-4-yl) benzimidazol-1-yl) ester. yl) methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Example 7

4 '- [(2-n-Propyl-4-methyl-6- (1-aminocarbonylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1-aminocarbonylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Example 8

4 '- [(2-n-Propyl-4-methyl-6- (1-cyclobutylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1-cyclobutylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Example 9

4 '- [(2-n-Propyl-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 59.0% of theory

Melting point: 279-280 ° C

Elemental analysis for ¢32 ^ 32 ^ 4.02 (504.64) calculated: 76.16% C, 6.39% H, 11.10% N found: 76.41% C, 6.37% H, 11.20 % N

Rf value: 0.44 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum: m / e = 504.

Example 10 '- [(2-n-Propyl-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

a) 4 '- [(2-n-propyl-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2-triphenylmethyl-tetrazol-5-yl) biphenyl

To a solution of 300 mg (1.0 mmol) of 2-n-propyl-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) -benzimidazole and 110 mg (1.0 mmol) of potassium tert-butylate in 20 mL of dimethylsulfoxide 560 mg (1.0 mmol) of 4'-bromomethyl-2- (2-triphenylmethyltetrazol-5-yl) biphenyl are added and the mixture is stirred at room temperature for 16 hours, then mixed with about 120 ml of water and extracted four times with about 15 ml each. acetate. The organic extracts are washed with about 30 ml of water, dried and then evaporated to dryness. The crude product obtained was purified by column chromatography (100 g silica gel, eluent: methylene chloride / methanol = 30: 1).

Yield: 460 mg (60% of theory)

Rf value: 0.78 (silica gel, methylene chloride / methanol = 9: 1)

b) 4 '- [(2-n-propyl-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

A mixture of 460 mg (0.6 mmol) of 4 '- [(2-n-propyl-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) -benzimidazol-1-yl) methyl] -2 (2-triphenylmethyl- tetrazol-5-yl) biphenyl and 10 mL of saturated methanolic hydrogen chloride were stirred at room temperature for one hour. It is then evaporated to dryness, the residue is dissolved in dilute ammonia solution and washed with ether. The aqueous phase is adjusted to pH 5-6 with acetic acid and then the precipitated solid is filtered off with suction. The crude product thus obtained was purified by column chromatography (100 g silica gel, eluent: methylene chloride / methanol = 15: 1).

Yield: 130 mg (41% of theory)

Melting point: amorphous substance i

^C 32 ^H 32 ^N 8 (528.67)

Rf value: 0.78 (silica gel, methylene chloride / methanol = 9: 1)

Mass Spectrum: m / e = 528

Example 11 '- [(2-n-propyl-4-methyl-6- (1-cyclobutylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared in analogy to Example 10, from 4 '- [(2-n-propyl-4-methyl-6- (1-cyclobutylmethylimidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2-triphenylmethyl-tetrazole) -5-yl) biphenyl and sodium azide in dimethylformamide.

Example 12

4 '- [(2-n-Propyl-4-methyl-6- (2-methyl-oxazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-tert-butyl ester carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 67.0% of theory

Mp .: 241-243 ° C

Elemental analysis for C29H27N3O3 (465.56) calculated: 74.82% C, 5.85% H, 9.03% N found: 74.65% C, 5.98% H, 8.85% N

Rf value: 0.27 (silica gel, methylene chloride / ethanol = 19: 1)

Example 13 '- [(2-n-Propyl-4-methyl-6- (2-methyl-oxazol-4-yl) benzimidazol-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2-triphenylmethyl) (tetrazol-5-yl) biphenyl and sodium azide in dimethylformamide.

Example 14

4 '- [(2-n-Propyl-4-methyl-6- (2-phenyl-oxazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (2-phenyl-oxazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2 -carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 87.0% of theory

Melting point: 281-283 ° C

Elemental analysis for ^C 34 ^H 29 ^N 3 ° 3 (527.63) calculated: 77.09% C, 5.54% H, 7.96% N found: 77.09% C, 5.71% H, 7 , 76% N

Rf value: 0.18 (silica gel, methylene chloride / ethanol = 19: 1)

Example 15 '- [(2-n-Propyl-4-methyl-6- (2-phenyl-oxazol-4-yl) benzimidazol-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-n-propyl-4-methyl-6- (2-phenyl-oxazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2-triphenylmethyl) (tetrazol-5-yl) biphenyl and sodium azide in dimethylformamide.

Example 16 '- [(2-Ethoxy-6- (1-isopropyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-ethoxy-6- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2-triphenylmethyl-tetrazol-5-yl) biphenyl and sodium azide in dimethylformamide.

Yield: 69.0% of theory

Melting point: 175-178 ° C

Elemental analysis for C 28 H 29 N 6 O (504.61) calculated: 69.03% C, 5.59% H, 22.21% N found: 68.85% C, 5.58% H, 21.97% N

- 40 Rf -value: 0.27 (silica gel, methylene chloride / ethanol = 9: 1) Mass spectrum: m / e = 504

Example 17

4 '- [(2-Ethoxy-6- (1-isopropyl-imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-ethoxy-6- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid tert-butyl ester and trifluoroacetic acid in methylene chloride.

Yield: 38.0% of theory

Melting point: 220-223 ° C

Elemental analysis for C 29 H 28 N 4 O 3 (480.58) calculated: C 72.48, H 5.87, N 11.66. Found: C 72.36, H 6.05, 11.41. % N

Rf value: 0.26 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 480.

Example 18 '- [(2-Ethoxy-5- (1-isopropyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-ethoxy-5- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2-triphenylmethyl-tetrazol-5-yl) biphenyl and sodium azide in dimethylformamide.

Yield: 44.0% of theory

Melting point: amorphous ^C 29 ^H 28 ^N 8 ° (504.61)

Rf value: 0.24 (silica gel, methylene chloride / ethanol = 9: 1) Mass spectrum: m / e = 504.

Example 19

4 '- [(2-n-Propyl-4-methyl-6- (1-cycloheptyl-imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1-cycloheptylimidol-4-yl) -benzimidazol-1-yl) methyl] -biphenyl tert-butyl ester -2-carboxylic methylene chloride.

Yield: 79.0% of theory

Melting point: from 190 ° C (decomposition) ^ 35 ^ 38 ^ 4θ2 (546,71)

Rf value: 0.36 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 546.

Example 20 '- [(2-n-propyl-4-methyl-6- (1-cycloheptyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) ) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-n-propyl-4-methyl-6- (1-cycloheptyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2-triphenylmethyl) tetrazol-5-yl) biphenyl. Yield: 27.0% of theory

Melting point: 198 - 201 ° C ^C 35 ^H 38 ^N 8 ( ⁵⁷⁰ · ⁷⁵ )

Rf value: 0.48 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 570.

Example 21

4 '- [(2-n-propyl-4-methyl-6- (1- (1-n-propyl-n-butyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2- carboxylic acid

Prepared in analogy to Example A from tert-butyl ester of 4 '- [(2-n-propyl-4-methyl-6- (1- (1-n-propyl-n-butyl) imidazol-4-yl)) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 28.0% of theory

Melting point: 236-238 ° C ^C 35 ^H 40 ^N 4 ° 2 (548.73)

Rf value: 0.61 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 548.

Example 22

4 '- [(2-n-Propyl-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1- (1-cyclopropylmethylimidazol-4-yl) -benzimidazol-1-yl) methyl] biphenyl) -2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 52.0% of theory

Melting point: 172-173 ° C

Elemental analysis for ^c 31 ^H 30 ^N 4 <> 3 (506.6D calculated: 73.50% C, 5.97% H, 11.06% N found: 73.36% C, 5.94% H, 11.65, 30% N

Rf value: 0.52 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 506.

Example 23 '- [(2-Ethoxy-4-methyl-6- (1-cyclopropylmethyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-ethoxy-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2-triphenylmethyl-tetrazol-5-yl) ) biphenyl.

Yield: 42.0% of theory

Melting point: amorphous substance ^C 31 ^H 30 ^N 8 ° ( ⁵³⁰ - ⁶⁴ )

Rf value: 0.50 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 530.

Example 24 '- [(2-n-propyl-4-methyl-6- (1- (1-n-propyl-n-butyl) -imidazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (lH-tetrazol-5-yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-n-propyl-4-methyl-6- (1- (1-n-propyl-n-butyl) imidazol-4-yl) -benzimidazole-1-). yl) methyl] -2- (2-triphenylmethyl-tetrazol-5-yl) biphenyl. Yield: 12.0% of theory

Melting point: 150 ° C (sintered) ^C 35 ^H 40 ^N 8 (572.76)

Rf value: 0.34 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 572.

Example 25

4 '- [(2-n-Propyl-4-methyl-6- (1,2-dimethyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid hydrate

(a) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid tert-butyl ester

A solution of 2.8 g (11 mmol) of 2-n-propyl-4-methyl-6- (2-methyloxazol-4-yl) benzimidazole and 1.7 g (15 mmol) of potassium tert-butylate was stirred at 60 DEG C. for 15 min. ml of dimethylsulfoxide at room temperature. Then 5.2 g (15 mmol) of tert-butyl 4'-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester are added and the mixture is further stirred at room temperature for 14 hours. The solution is stirred into about 150 ml of saturated sodium chloride solution, the precipitated crude product is filtered off with suction and purified by column chromatography (400 g of silica gel, eluent: methylene chloride with 1-2% ethanol).

Yield: 3.5 g (61.4% of theory)

Melting point: amorphous substance

Rf value: 0.90 (silica gel, methylene chloride / ethanol = 4: 1)

b) 4 '- [(2-n-Propyl-4-methyl-6- (1,2-dimethylimidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid hydrate

A mixture of 1.5 g (3 mmol) of 4 '- [(2-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl tert-butyl ester -2-carboxylic acid, 10 ml of a 40% solution

Of N-methylamine and 15 ml of N-methylformamide was autoclaved at 200 ° C for 10 hours. After cooling, the contents of the autoclave are mixed with about 40 ml of water, the pH of this suspension is adjusted to 6.5 with acetic acid, then the precipitated crude product is filtered off with suction and dissolved in 1N sodium hydroxide. The solution was washed successively with 25 ml of acetate and diethyl ether each time. The pH is adjusted to 6 with 20% citric acid. The precipitated product is filtered off with suction, washed with about 30 ml of water and dried, then triturated with diethyl ether and dried under high vacuum.

Yield: 950 mg (68% of theory)

Mp: 239-240 ° C

Elemental analysis for C 30 H 30 N 4 O 2 x H 2 O (496.62) calculated: 72.55% C, 6.49% H, 11.28% N found: 72.62% C, 6.62% H, 11.54% N

Rf value: 0.70 (silica gel, methylene chloride / ethanol = 4: 1)

Example 26

4 '- [(2-n-Propyl-4-methyl-6- (1- (1,2-dimethyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazole-) hydrate 5-yl) biphenyl ^a ) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (1H) tetrazol-5-yl) biphenyl

A solution of 2.8 g (11 mmol) of 2-n-propyl-4-methyl-6- (2-methyloxazol-4-yl) benzimidazole and 1.7 g (15 mmol) of potassium tert-butylate in 60 ml of dimethylsulfoxide is stirred 15 minutes at room temperature. 6.0 g (11 mmol) of 4 &apos; -bromomethyl-2- (2-triphenylmethyl-tetrazol-5-yl) biphenyl are then added and the mixture is stirred at room temperature for a further 3 hours. The solution is stirred into about 150 ml of saturated solution, the precipitated crude product is filtered off with suction and purified by column chromatography (500 g of silica gel, eluent: petroleum ether / acetate = 1: 1). Yield: 3.6 g (45% of theory)

b) 4 '- [(2-n-propyl-4-methyl-6- (1,2-dimethyl-imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (1H-tetrazole-5-) hydrate yl) biphenyl

A mixture of 3.6 g (4.9 mmol) of 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) -benzimidazol-1-yl) -methyl] - 2- (1H-tetrazol-5-yl) biphenyl, 20 ml of a 40% solution of N-methylamine and 30 ml of N-methylformamide were heated at 200 ° C for 10 hours in an autoclave. After cooling, the contents of the autoclave are mixed with about 50 ml of water,

The pH of this suspension is adjusted to 6.5 with 20% citric acid, the precipitated crude product is filtered off with suction and purified by column chromatography (200 g of silica gel, eluent: methylene chloride with 5 to 20% ethanol).

Yield: 1.0 g (41% of theory)

Melting point: from 195 ° C sintered

Elemental analysis for C ^ gH GNG x H ₂ 0 (520.6) calculated: 69.21% C, 6.19% H, 21.52% N Found: 68.99% C, 6.26% H, N, 21.37

Mass spectrum: m / e = 502

Example 27

4 '- [(2-Ethyl-4-methyl-6- (1- (2-methoxyethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-ethyl-4-methyl-6- (1- (1- (2-methoxyethyl) imidazol-4-yl) -benzimidazol-1-yl)) - tert-butyl ester] -methyl] -biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 49.0% of theory

Melting point: 165-167 ° C

Elemental analysis for C ^ qHH qNNOj (494.60) calculated: C, 72.85; H, 6.11; N, 11.33. Found: C, 72.62; 35% N

Mass spectrum: m / e = 494.

Example 28

4 '- [(2-Cyclopropyl-4-methyl-6- (1- (2-methoxyethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-cyclopropyl-4-methyl-6- (1- (2-methoxyethyl) imidazol-4-yl) -benzimidazol-1-yl) tert-butyl ester methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride. Yield: 78.0% of theory.

Melting point: 179-181 ° C

Elemental analysis for (506.61) calculated: 73.50% C, 5.97% H, 11.06% N found: 73.37% C, 6.02% H, 11.02% N

Mass spectrum: m / e = 506.

Example 29

4 '- [(2-n-Propyl-4-methyl-6- (1-aminocarbonylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1- (1-aminocarbonylmethyl-imidazol-4-yl) -benzimidazol-1-yl)) - tert-butyl ester -methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride Yield: 26.0% of theory.

Melting point: 190-192 ° C ^C 30 ^H 29 ^N 5 ° 3 (507.60)

Rf value: 0.44 (silica gel, methylene chloride / methanol = 8: 2).

Example 30

4 '- [(2-n-Propyl-4-methyl-6- (1-ethoxycarbonylmethylimidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1- (1-ethoxycarbonylmethyl-imidazol-4-yl) -benzimidazol-1-yl) -benzimidazol-1-yl) - methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride. Yield: 18.0% of theory.

Melting point: 223-224 ° C ^C 30 ^H 29 ^N 5 ° 3 (536.63)

Rf value: 0.69 (silica gel, methylene chloride / methanol = 8: 2). Mass spectrum: m / e = 536

Example 31

4 '- [(2-Cyclopropyl-4-methyl-6- (1- (2-hydroxyethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

A solution of 500 mg (1.0 mmol) of 4 &apos; - [(2-cyclopropyl)

4-Methyl-6- (1- (2-methoxyethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid and 1.5 g (6.0 mmol) of boron tribromide are stirred for 16 hours at room temperature, then mixed with about 30 ml of water and stirred vigorously for another 10 minutes. This mixture is evaporated to dryness and the residue is heated in refluxing about 40 ml of ethanol for 10 minutes. Evaporate to dryness, dissolve the residue in about 30 ml of 2N ammonia solution and adjust to pH 5-6 with 2N acetic acid. The crude product precipitates, which is filtered off with suction and purified by column chromatography (80 g silica gel, elution). reagent: methylene chloride / methanol = 4: 1).

Yield: 150 mg (30% of theory)

Melting point: 220-222 ° C ^C 30 ^H 28 ^N 4 ° 3 (492.58)

Rf value: 0.20 (silica gel, methylene chloride / methanol = 9: 1). Mass spectrum: m / e = 492.

Example 32

4 '- [(2-n-Propyl-4-methyl-6- (1- (2-N-morpholinoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1- (2-N-morpholinoethyl) imidazol-4-yl) benzimidazole) tert-butyl ester. 1-yl) methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride. Yield: 54% of theory.

Melting point: 259-261 ° C

Elemental analysis for ^C 34 ^H 37 ^N 5 ° 3 (563.70) calculated: 72.44% C, 6.62% H, 12.42% N found: 76.68% C, 6.65% H, 12 , 53% N

Mass spectrum: m / e = 563.

Example 33

4 '- [(2-n-Propyl-4-methyl-6- (1- (2-methoxyethoxy-2-ethyl) -imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

- 48 Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1- (2-methoxyethoxy-2-ethyl) -imidazol-4-yl)) - tert-butyl ester benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride. Yield: 49% of theory.

Melting point: 192-194 ° C

Elemental analysis for ^C 33 ^H 36 ^N 4 ° 4 (552.67) calculated: 71.72% C, 6.57% H, 10.14% N found: 71.52% C, 6.36% H, 10.25 % N

Rf value: 0.36 (silica gel, dichloromethane / methanol = 9: 1). Mass spectrum: m / e = 552.

Example 34

4 '- [(2-n-propyl-4-methyl-6- (1- (3-dimethylaminopropyl) -imidazol-4-yl) benzimidazol-yl) methyl] biphenyl-2-carboxylic acid pentahydrate

Prepared in analogy to Example A from 4 '- [(2-n-propyl-4-methyl-6- (1- (1- (3-dimethylaminopropyl) imidazol-4-yl) benzimidazole-1-yl) benzimidazole-1-) ester. yl) methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride Yield: 12% of theory

Melting point: from 128 C (decomposition) ^C 33 ^H 37 ^N 5 ° 2 ^{x 2 HCl x 5 H} 2 ° ( ⁵³⁵ > ^7θ )

R.f-value: 0.20 (silica gel, dichloromethane / methanol = 9: 1). Mass spectrum: m / e = 535.

Example 35

4 '- [(2-n-Propyl-4-methyl-6- (2-methyl-thiazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from tert-butyl 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-thiazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2 -carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 32%

Melting point: 248-250 ° C

Elemental analysis for C 28 H 27 N 3 O 2 S (481.62) calculated: 72.32% C, 5.65% H, 8.72% N found: 72.21% C, 5.83% H, 8.67% N

Rf value: 0.26 (silica gel, dichloromethane / methanol = 9: 1). Mass spectrum: m / e = 481.

Example 36

4 '- [(2-n-Propyl-4-methyl-6- (2-methyl-thiazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl dihydrochloride

Prepared in analogy to Example 10 from 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-1-thiazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (2) triphenylmethyl-tetrazol-5-yl) biphenyl.

Yield: 91.0% of theory

Melting point: from 219 ° C (decomposition)

Elemental analysis for C 29 H 29 Cl 2 N 7 S (578.58) calculated: 60.20% C, 5.05% H, 16.95% N, 12.25% Cl found: 59.96% C, 5.19% H, 16, N, 12.42%

Rf value: 0.32 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 505.

Example 37

4 '- [(2-Ethyl-4-methyl-6- (1- (2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from tert-butyl ester of 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-morpholinoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 27% of theory

Melting point: 201-202 ° C

Elemental analysis for ^C 33 ^H 35 ^N 5 ° 3 (549.65) calculated: 72.11% C, 6.42% H, 12.74% N found: 72.00% C, 6.48% H, 12 , 62% N

Rf value: 0.36 (silica gel, dichloromethane / methanol = 9: 1). Mass spectrum: m / e = 549.

Example 38

4 '- [(2-ethyl-4-methyl-6- (1- (2-N-morpholinoethyl) imidazol-4-yl) benzimidazol-1-yl) -4-methyl] -2- (1H-tetrazole-5-) hydrate yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-yl) methyl] -2- (2- triphenylmethyl-tetrazol-5-yl) biphenyl. Yield: 14.0% of theory

Melting point: from 180 ° C (decomposition)

Elemental analysis for C 33 H 35 N 9 O x H 2 O (573.68) calculated: 66.98% C, 6.30% H, 21.31% N found: 66.87% C, 6.36% H, 21.22% N

Rf value: 0.31 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 573.

Example 39

4 '- [(2-Ethyl-4-methyl-6- (1- (2-aminocarbonylethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-ethyl-4-methyl-6- (1- (2-aminocarbonylethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl- Of 2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 66% of theory

Melting point: from 185 ° C (decomposition)

Elemental analysis for C 3 H 29 N 5 O 3 (507.59) calculated: C 70.99, H 5.76, N 13.80. Found: C 70.73, H 5.72, N 13.66.

Mass spectrum: m / e = 507.

Example 40

4 '- [(2-ethyl-4-methyl-6- (1- (2-aminocarbonylethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-ethyl-4-methyl-6- (1- (2-aminocarbonylethyl) imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2- triphenylmethyl-tetrazol-5-yl) biphenyl.

Yield: 42%

Melting point: from 191 ° C (decomposition)

H, C ₃ Qh2 ₉ N ₉ 0 (531.63) calculated: 67.78% C, 5.50% H, 23.71% N Found: 67.79% C, 5.40% H, 23, 66% N

R-p value: 0.20 (silica gel, methylene chloride / methanol = 8: 2) Mass spectrum: m / e = 531

Example 41

4 '- [(2-Ethyl-4-methyl-6- (1- (2-N-pyrrolidinoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-pyrrolidinoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] tert-butyl ester biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 60%

Mp 215-217 ° C

Elemental analysis for C 33 H 35 N 5 O 2 (533.67) calculated: 74.27% C, 6.61% H, 13.12% N found: 74.03% C, 6.85% H, 13.11% N

Rf value: 0.30 (silica gel, methylene chloride / methanol = 8: 2) Mass spectrum: m / e = 533.

Example 42

4 '- [(2-ethyl-4-methyl-6- (1- (2-N-pyrrolidinoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-pyrrolidinoethyl) -imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2-triphenylmethyl-tetrazol-5-yl) biphenyl. Yield: 38%

Melting point: from 128 ° C (sintered)

Elemental analysis for C ₃₃ H ₃₅ N ₉ (551.71) calculated: 71.84% C, 6.39% H, 22.85% N found: 71.63% C, 6.20% H, 22.49 % N

Rf value: 0.23 (silica gel, methylene chloride / methanol = 8: 2)

Example 43

4 '- [(2-Ethyl-4-methyl-6- (1- (2-diethylaminoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid dihydrochloride

Prepared in analogy to Example A from 4 '- [(2-ethyl-4-methyl-6- (1- (2-diethylaminoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl- Of 2-carboxylic acid and trifluoroacetic acid in methylene chloride.

yield; 32% of theory

Melting point: 255 to 257 ° C (decomposition) ^C 33 ^H 37 ^N 5 ° 2 ^{x 2 HCl} ( ^6θ8 · ^6θ )

Rf value: 0.24 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum: m / e = 535.

Example 44 '- [(2-Ethyl-4-methyl-6- (1- (2-diethylaminoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) ) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-ethyl-4-methyl-6- (1- (2-diethylaminoethyl) -imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- (2) triphenylmethyl-tetrazol-5-yl) biphenyl. Yield: 51% of theory

Melting point: 191-193 ° C

Elemental Analysis for (559,70) * calculated: 70.81% C, 6.66 % H, 22.52% N found: C, 70.59; 6.66 % H, 22.58% N R-value: 0.30 (silica gel, methylene chloride / methanol = 8: 2)

Example 45

4 '- [(2-Ethyl-4-methyl-6- (1- (3-N-piperidinopropyl) imidazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid

Prepared in analogy to Example A from 4 '- [(2-ethyl-4-methyl-6- (1- (3-N-piperidinopropyl) imidazol-4-yl) benzimidazol-1-yl) methyl] tert-butyl ester biphenyl-2-carboxylic acid and trifluoroacetic acid in methylene chloride.

Yield: 19% of theory

Melting point: amorphous

Elemental analysis for C 35 H 39 N 5 O 2 (561.73) calculated: 74.84% C, 7.00% H, 12.47% N found: 74.61% C, 6.92% H, 12.31% N

Rf value: 0.34 (silica gel, methylene chloride / methanol = 8: 2).

Example 46 '- [(2-ethyl-4-methyl-6- (1- (3-N-piperidinopropyl) imidazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazole-5- yl) biphenyl

Prepared in analogy to Example 10 from 4 '- [(2-ethyl-4-methyl-6- (1- (3-N-piperidinopropyl) imidazol-4-yl) -benzimidazol-1-yl) methyl] -2- ( 2-triphenylmethyl-tetrazol-5-yl) biphenyl. Yield: 71%

Melting point: from 140 ° C (decomposition)

Elemental analysis for C 35 H 39 N 9 (585.76) calculated: 71.77% C, 6.71% H, 21.52% N found: 71.58% C, 6.68% H, 21.44% N

Rf value: 0.22 (silica gel, methylene chloride / methanol = 8: 2)

In the following examples of pharmaceutical use, all suitable compounds of formula I can be used as the active ingredient, especially those in which R @ 1 represents a carboxy- or ΙΗ-tetrazolyl group.

Example I

Ampoules containing 50 mg of active substance per 5 ml

active substance 50 mg kh ₂ Mon ₄ 2 mg Na ₂ HPO ₄ x 2H ₂ 0 50 mg NaCl 12 mg water for injection into 5 ml

Production

Powder substances and the isotonic component are dissolved in some of the water. The active substance is added and, after complete dissolution, made up to the indicated volume with water.

Example II

Ampoules containing 100 mg of active substance per 5 ml

active substance 100 mg methylglucamine 35 mg glycofurol 1000 mg polyethylene glycol-polypropylene a glycol-block polymer 250 mg water for injection into 5 ml

Production

Methylglucamine is dissolved in a portion of water and the active ingredient is transferred with stirring and heating into solution. After addition of solvent, make up to volume with water.

Example III

Tablets containing 50 mg active substances active substance 50.0 mg calcium phosphate 70.0 mg milk sugar .40,0 mg maize starch 35.0 mg polyvinylpyrrolidone 3.5 mg magnesium stearate 1.5 mg 200.0 mg

Production

The active ingredient, CaHPO4, milk sugar and corn starch are simultaneously moistened with an aqueous solution of PVP. The mass is sieved through a 2 mm sieve, dried in an air circulation oven at 50 ° C and sieved again.

After the glidant is admixed, the granulate is compressed on a tabletting machine.

Example IV

Dragee, containing 50 mg of active substance

active substance 50.0 mg lysine 25.0 mg milk sugar 60.0 mg maize starch 34.0 mg gelatin 10.0 mg magnesium stearate 1.0 mg 180.0 mg

Production

The active ingredient is mixed with excipients and moistened with a gelatin solution. After sieving and drying, the granulate is mixed with magnesium stearate and pressed into cores.

The cores thus produced are coated by known methods. A colorant may be added to the coating suspension or solution.

Example V

Dragee, containing 100 mg of active substance

active substance 100.0 mg lysine 50.0 mg milk sugar 86.0 mg maize starch 50.0 mg polyvinylpyrrolidone 2.8 mg microcrystalline cellulose 60.0 mg magnesium stearate 1.2 mg 350.0 mg

Production

The active ingredient is mixed with the excipients and moistened with an aqueous solution of PVP. The wet mass is rubbed through a 1.5 mm sieve and dried at 45 ° C. After drying, it is sieved again and magnesium stearate is admixed. This mixture is compressed into cores.

The cores thus produced are coated by known methods. Dyestuffs may be added to the coating suspension or solution.

Example VI

Capsules containing 250 mg of the active substance

active substance 250.0 mg maize starch 68.5 mg magnesium stearate 1.5 mg 320.0 mg

Production

The active ingredient and corn starch are mixed and moistened with water. The wet mass is sieved and dried. The dried granulate is sieved and mixed with magnesium stearate. The final blend is filled into size 1 hard gelatin capsules.

Example VII

Oral suspension containing 50 mg of active substance per 5 ml of active substance hydroxyethylcellulose sorbic acid sorbitol 70% glycerin aroma water to

50.0 mg 50.0 mg 5.0 mg 600.0 mg 200.0 mg 15.0 mg 5.0 ml

Production

The distilled water is heated to 70 [deg.] C. The hydroxyethylcellulose is dissolved therein with stirring. After addition of the sorbitol-glycerin solution, it is cooled to room temperature. Sorbic acid, flavor and the active ingredient are added at room temperature. Stirring is carried out under reduced pressure to deaerate the suspension. One dose = 50 mg is contained in 5 ml.

Example VIII ’

Suppositories containing 100 mg of active substance active substance 100.0 mg adeps solidus 1600.0 mg

1700.0 mg

Production

The hardened fat melts. The active ingredient is dispersed homogeneously in the melt at 40 ° C. Cool to 38 ° C and pour into pre-cooled slightly suppository molds.

Claims (10)

PATENT TOOLS 1, 2, 3, 4, 5, 6 or 7 substituted by carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl-, morpholinocarbonyl-, thiomorpholinocarbonyl- or 1-oxo-thiomorpholinocarbonyl-, alkyl of 2 to 4 atoms carbon that in position Benzimidazoles of the general formula I in which R 1 represents an alkyl group having 1 to 3 carbon atoms, a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom; R represents in the 2-position a phenyl-substituted oxazol-4-yl- or thiazol-4-yl-group or optionally in the 2-position an alkyl group having 1 to 6 carbon atoms or a phenyl-substituted imidazol-4-yl group, the imidazole- The 4-yl group is substituted in the 1-position by an alkyl group having 1 to 7 carbon atoms which may be in the 1-position. 2. A compound according to claim 1, wherein R &lt; 1 &gt; represents an alkyl group having 1 to 3 carbon atoms, a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom; R is in the 6-position attached at the 2-position by a phenyl-substituted oxazol-4-yl- or thiazol-4-yl-group or optionally in the 2-position, an alkyl group having 1 to 6 carbon atoms or a phenyl-substituted imidazol-4-yl group; wherein the imidazol-4-yl group is substituted in the 1-position by an alkyl group having 1 to 7 carbon atoms which may be substituted in the 1, 2, 3, 4, 5, 6 or 7 position by carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl-, morpholinocarbonyl-, thiomorpholinocarbonyl- or 1-oxo-thiomorpholinocarbonyl-, a (C až-C alky) alkyl group substituted in the 2, 3 or 4 position with hydroxy, alkoxy, alkoxyalkoxy, dialkylamino- , pyrrolidino-, piperidino-, hexamethylenimino-, morpholino-, thiomorpholino-, 1-oxo-thiomorpholino- or imidazol-1-yl-yl, alkyl substituted with trifluoromethyl, cycloalkyl of 3 to 7 carbon atoms or the case not fluorine or chlorine, trifluoromethyl, methyl or methoxy, mono- or disubstituted phenyl, two phenyl-substituted alkyl, wherein, unless otherwise indicated, the alkyl and alkoxy moieties each contain 1 to 3 carbon atoms, and R is C 2 -C 4 alkyl, alkoxy or C 2 -C 3 alkylthio, in each case alkyl, cyclopropyl or cyclobutyl; and R ⁴ is a carboxy-convertible group in vivo, carboxy, cyano, ΙΗ-tetrazolyl-, 1-triphenylmethyltetrazolyl or 2-triphenylmethyl-tetrazolyl, and salts thereof. 2, 3 or 4 is substituted with hydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethylenimino, morpholino, thiomorpholino, 1-oxo-thiomorpholino or imidazol-1-yl, alkyl substituted with trifluoromethyl, C 3 -C 7 cycloalkyl or optionally fluorine or chlorine, trifluoromethyl, methyl or methoxy, mono- or disubstituted phenyl, or alkyl substituted with two phenyl groups, provided that, unless otherwise specified, the alkyl and alkoxy moieties each contain 1 to 3 carbon atoms, and R is C 2 -C 4 alkyl, alkoxy or C 2 -C 3 alkylthio, in each case alkyl, cyclopropyl or cyclobutyl; and R ⁴ is a group convertible into a carboxy group in vivo, carboxy, cyano, ΙΗ-tetrazolyl, l-trifenylmetyltetrazolyl or 2-triphenylmethyl-tetrazolyl group, and the compound: (a) 4 '- [(2-n-propyl-4-methyl-6- (1- (2-phenylethyl) imidazol-4-yl) -benzimidazol-1-yl) methyl] -biphenyl-2- carboxylic acid, (b) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) benzimidazol-1-yl) methyl] -biphenyl-2-carboxylic acid; c) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazole-5) yl) biphenyl, d) 4 '- [(2-ethoxy-6- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) - biphenyl, (e) 4 '- [(2-ethoxy-6- (1-isopropyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid; (f) 4 '- [(2-ethoxy-5- (1-isopropyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) -biphenyl; (g) 4 '- [(2-n-propyl-4-methyl-6- (1-cycloheptyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid; h) 4 '- [(2-n-propyl-4-methyl-6- (1-cycloheptyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) ) biphenyl, i) 4 '- [(2-n-propyl-4-methyl-6- (1- (1'-propyl-n-butyl) -imidazol-4-yl) -benzimidazol-1-yl) -methyl] -2 - (lH-tetrazol-5-yl) biphenyl, (j) 4 '- [(2-n-propyl-4-methyl-6- (1,2-dimethyl-imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid; k) 4 '- [(2-n-propyl-4-methyl-6- (1,2-dimethyl-imidazol-4-yl) benzimidazol-1-yl) methyl] -2- (1H-tetrazole-5) yl) biphenyl, (l) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-thiazol-4-yl) benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid; and m) 4 '- [(2-n-propyl-4-methyl-6- (2-methyl-thiazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazole-5- yl) biphenyl, and salts thereof. The benzimidazoles of formula I according to claim 1, wherein: R * represents a hydrogen atom or a chlorine atom or a methyl group, R represents in position 6, in position 2 a phenyl-substituted oxazol-4-yl- or thiazol-4-yl-group or optionally in position 2 a methyl-substituted imidazol-4-yl-group which in position 1 can be substituted by an alkyl group having 1 to 7 carbon atoms which may be substituted in the 1, 2, 3, 4, 5, 6 or 7 position by carboxy-, methoxycarbonyl-, aminocarbonyl-, methylaminocarbonyl-, ethylaminocarbonyl-, n-propylaminocarbonyl-, dimethylaminocarbonyl-, morpholinocarbonyl- -, thiomorpholinocarbonyl- or 1-oxothiomorpholinocarbonyl, a (C 2 -C 4) alkyl group which is substituted at the 2, 3 or 4 position with hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino piperidino62-, morpholino- or imidazol-1-yl, or substituted with 2,2,2-trifluoroethyl-, 3,3,3-trifluoropropyl-, cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, 4-fluorobenzyl-, 3-chlorobenzyl-, 4-methylbenzyl-, 4-trifluoromethyl ylbenzyl-, 3,5-dimethoxybenzyl or 2,2-diphenylethyl; Q R represents an alkyl group having 2 to 4 carbon atoms, an alkoxy or alkylthio group having in each case 2 or 3 carbon atoms in the alkyl moiety, a cyclopropyl or cyclobutyl group; and R ⁴ represents a group convertible in vivo to a carboxy, carboxy- or 1H-tetrazolyl group, and salts thereof. 4. A compound according to claim 1, in which 10 Q R, R and R are as defined in claims 1 to 3 and R ⁴ is a carboxy group of the formula -CO-OR ', -C0-0- (HCR) -O-CO-R 'a -C0-0- (HCR) -O-CO-OR 'in which R 'denotes a straight or branched chain alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl, R is hydrogen or methyl; and R 'represents a straight or branched chain alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, phenyl-, benzyl-, 1-phenylethyl-, 2-phenylethyl- or 3-phenylpropyl and salts thereof. 5. A compound according to claim 1, wherein R &lt; 1 &gt; represents a hydrogen atom or a methyl group, R ² represents in the 6-position attached at the 2-position a phenyl-substituted oxazol-4-yl- or thiazol-4-yl-group or optionally in the 2-position a methyl-substituted imidazol-4-yl-group which can be substituted in the 1-position (C 1 -C 7) alkyl group which may be substituted at the 1, 2, 3, 4, 5, 6 or 7 position by carboxy-, methoxycarbonyl-, dimethylaminocarbonyl- or morpholinocarbonyl-, C 2 -C 4 -alkyl; in the 2, 3 or 4 position is substituted by hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-1-yl, or is substituted with 2,2, 2-trifluoroethyl-, 3,3,3-trifluoropropyl-, cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl- or 4-fluorobenzyl, R ^ represents a (C 4-C alky) alkyl group, an ethoxy-, ethylthio-, cyclopropyl- or cyclobutyl group; and R ⁴ represents a carboxy- or 1H-tetrazolyl group, and salts thereof. 33 Compounds of formula (I) according to claim 1 which are (i) 4. '- [(2-n-propyl-4-methyl-6- (1- (2-N-morpholinoethyl)) imidazole) 4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid, 64 (ii) 4 '- [(2-n-propyl-4-methyl-6- (1- (2-methoxyethoxy-2-ethyl) -imidazol-4-yl) -benzimidazol-1-yl) -methyl] - biphenyl-2-carboxylic acid, (iii) 4 '- [(2-ethyl-4-methyl-6- (1- (2-diethylaminoethyl) -imidazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (1) H-Tetrazol-5-yl) -biphenyl, (iv) 4 '- [(2-ethyl-4-methyl-6- (1- (3-N-piperidinopropyl) -imidazol-4-yl) -benzimidazol-1) -yl) -methyl] -2- (1H-tetrazol-5-yl) biphenyl; (v) 4 '- [(2-n-propyl-4-methyl-6- (1- (3-dimethylaminopropyl)) - (vi) 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-morpholinoethyl))), (vi) 4' - [(2-ethyl-4-methyl-6- (1- (2-N-morpholinoethyl))) (vii) 4 '- [(2-ethyl-4-methyl-6- (1- (2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-1-yl) methyl] -biphenyl-2-carboxylic acid (imidazol-4-yl) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl) biphenyl; 1- (2-N-pyrrolidinoethyl) -imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid, (ix) 4 '- [(2-ethyl-4-methyl-6- ( 1- (2-N-pyrrolidinoetyl) imidazol-4-yl) benzimidazol-l-yl) methyl] -2- (lH-tetra zol-5-yl) biphenyl, (x) 4 '- [(2-ethyl-4-methyl-6- (1- (2-diethylaminoethyl) imidazol-4-yl) benzimidazol-1-yl) methyl (xi) 4 '- [(2-Ethyl-4-methyl-6- (1- (3-N-piperidinopropyl) -imidazol-4-yl) -benzimidazol-1-yl)] -biphenyl-2-carboxylic acid 1-Methyl] -biphenyl-2-carboxylic acid and salts thereof. '/ No 4-Ar' O / A compound of formula (I) according to claim 1 which is 4 '- [(2-n-propyl-4-methyl-6- (1- (2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-1-one) -yl) -methyl] -biphenyl-2-carboxylic acid and its salts. proline methyl ester. Jtx / Íu feiCbíOío ' Physiologically acceptable salts of the compounds according to at least one of claims 1 to 7 with inorganic or organic acids or bases. A process for the preparation of benzimidazoles according to claims 1 to 8, characterized in that a) optionally forming a compound of formula (II) in the reaction mixture wherein: R ^A and R are as defined in claims 1 to 7, one of the radicals or Y ³ · being a group of the formula and the other of the formula Z ¹ \ - NH where R ³ and R ⁴ are as defined in claims 1 to 7, R ^J is hydrogen or a radical R-CO wherein R is as defined above, Z 1 and T 1, which may be the same or different, represent optionally substituted amino or optionally C 1 -C 6 alkyl substituted hydroxy or mercapto groups, or Z ³ and Z 2 together with an oxygen or sulfur atom or an alkyl group having 1 to 3 carbon atoms substituted by an imino group, an alkylenedioxy or an alkylenedithio group each having 2 or 3 carbon atoms, are cyclized and optionally the N-oxide thus obtained is reduced, or b) a benzimidazole of the general formula III (III) in which H R ³ - to R ³ are as defined in claims 1 to 7, reacted with a biphenyl compound of the general formula IV R ⁴ of ³ -ch ₂ (IV) wherein R ⁴ is as defined in claims 1 to 7 and Z ³ represents a nucleophilic leaving group, or c) R ⁴ represents the production of a compound of formula I in which the carboxy group, the compound of formula V (V) wherein 1 3 R to R are as defined in claims 1 to 7 and R ⁴ represents a group convertible by hydrolysis, thermolysis or hydrogenolysis to a carboxy group, converted to the corresponding carboxy compound, or d) for the preparation of a compound of the formula I wherein R ⁴ is ΙΗ-tetrazolyl, the protecting group is cleaved from the compound of the formula VI in which: R 1, R 2 and R 2 are as defined in claims 1 to 7 and Λ ” R represents the 1-position or the 3-position of the protected 1H-tetrazolyl group; e) for the preparation of a compound of the formula I wherein R ⁴ is a 1H-tetrazolyl group, a compound of the formula VII wherein R * to R 6 are as defined in claims 1 to 7, is reacted with hydrazoic acid or its salts and optionally thereafter the compound of formula I thus obtained, in which R ⁴ is a carboxy group, is converted to the corresponding compound of formula I in which R ⁴ is a carboxy-convertible group in vivo by esterification and / or a compound of formula I in which R ^{x is obtained} means an imidazol-4-yl group substituted in the 1-position by a (C 2 -C 4) alkyl group in which the alkyl group in the 2, 3 or 4 position is substituted by an alkoxy or alkoxyalkoxy group by ether cleavage to the corresponding compound of formula ABOUT Wherein R is an imidazol-4-yl group which is substituted in the 1-position by an alkyl group having 2 to 4 carbon atoms, the alkyl group at the 2, 3 or 4 position being substituted by a hydroxy group and, if desired, cleaved off protecting group used during reactions a) to e) to protect the reaction groups and / or the 1-isomer is separated from the 1-, 3-isomer mixture of the compound of the formula I thus obtained by isomer separation or the compound of the formula I thus obtained is transformed for its salt, for pharmaceutical use for its physiologically acceptable salt with an inorganic or organic acid or base. Medicament, characterized in that it comprises a compound according to at least one of Claims 1 to 7 or a physiologically acceptable salt according to Claim 8 or, optionally, one or more inert carriers and / or diluents. ί.% / tc t'ci caž.c · / ^ 11. Use of a compound according to at least one of claims 1 to 8 for the manufacture of a medicament having an angiotensin-antagonistic effect.