SK32493A3 - Benzimidazole derivatives, process for their preparation and pharmaceutical compositions with their contents - Google Patents

Abstract

The invention relates to substituted benzimidazoles of the general formula <IMAGE> in which R1 to R4 are as defined in Claim 1, their 1- and 3-isomer mixtures, their quaternary N-alkyl salts and their salts which have useful properties. These compounds have useful pharmacological properties, in particular angiotensin-antagonistic actions, preferably angiotensin II-antagonistic actions.

Description

Benzimidazole derivatives, process for their preparation and pharmaceutical compositions containing them

Field of the invention

The present invention relates to benzimidazole derivatives and processes for their preparation. Said compounds are very effective substances which antagonize angiotensin, in particular angiotensin II, and therefore can be used for the treatment of elevated blood pressure and cardiac insufficiency.

BACKGROUND OF THE INVENTION

In European patent no. No. 468,470 some benzimidazole derivatives have been described which effectively antagonize angiotensin.

SUMMARY OF THE INVENTION

The present invention relates to novel benzimidazole derivatives of the general formula I (D wherein H, fluoro, chloro or bromo, chloromethyl, difluoromethyl, trifluoromethyl or alkyl,

_R2 is imidazol-2-yl, optionally substituted in the 1 radical R _a, wherein

R _a represents a phenyl or phenylalkyl group, the phenyl ring of which is optionally mono- or di-substituted by an alkyl, hydroxy or alkoxy group, wherein the substituents may be the same or differently C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl carbon in which the alkyl moiety is optionally substituted by a group which is metabolizable in vivo to a carboxyl, trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or from the 2-position hydroxy, alkoxy, amino, piperidino, amino group, alkylamino .

A 5,5-spirocyclopentadihydroimidazol-4-one-2-yl group, an imidazolium-2-yl group substituted at the 1-position and 3 by the radicals R 1, which may be the same or different,

R ^ represents a phenylalkyl group in which the phenyl moiety is optionally mono- or disubstituted by an alkyl, hydroxy or alkoxy group, the substituents being the same or different, or an alkyl group having 1 to 6 carbon atoms, optionally substituted in the alkyl moiety by a metabolizable group. in vivo to a carboxyl, trifluoromethyl, carboxyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, oxazol-2-yl or thiazol-2-yl group, the above imidazol-2-yl, imidazolium-2-yl, oxazol-2-yl, oxazol-2-yl The 2-yl or thiazol-2-yl moieties may be substituted at the 4, 5-positions with a C 1 -C 5 alkyl group or a phenyl group, which substituents may be the same or different, or may be attached at the 4, 5-positions by n- propylene or n-butylene bridge, oxazolin-2-yl or imidazolin-2-yl group pin, substituted in the 4 substituents R q and R in position 5 and substituent R O 'P ^r ICOM imino group may be substituted by further radicals denoted by R _and or group of formula

R ₈ CO- (R ₉ CR ₁₀ ) -NR _and -CO-, wherein R _a is as defined above a

R 8 to R 8, the same or different, are hydrogen, C 1 -C 5 alkyl or phenyl,

R1 is C1-C5alkyl, C3-C5cycloalkyl, C1-C4alkoxyalkylthio;

R 4 represents a hydrogen atom or a group of the general formula

-CH- - wherein in vivo means a group metabolizable in vivo to a carboxyl group, a carboxyl group, a cyano group,

2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 1H-tetrazolyl, 1-triphenylmethyltetrazolyl or 2-triphenylmethyltetrazolyl, all of the above groups and alkoxy groups having 1 to 3 carbon atoms, provided that: they do not directly mention the number of carbon atoms, and in vivo metabolizable to a carboxyl group means, for example, ester groups of the formula

- CO-OR,

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

- CO - O - (HCR) - O - CO - OR where

R represents a straight or branched chain alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 5 to 7 carbon atoms, benzyl,

1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl,

R is hydrogen or methyl; and

R is a straight or branched chain alkyl radical of 1 to 6 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, phenyl, benzyl, 1-phenylethyl,

2-phenylethyl or 3-phenylpropyl as well as 3 isomers thereof, mixtures of their 1- and 3- isomers, as well as their salts.

In particular, the novel compounds of the formula I in which R1 represents a group which can be converted metabolically into a carboxyl group, a carboxyl group or a 1H-tetrazole group in vivo, have significant pharmacological properties and are capable of antagonizing angiotensin, angiotensin II. Other compounds of formula I wherein R ₄ is hydrogen or R 8 is cyano, 1-triphenylmethyltetrazolyl or 2-triphenylmethyltetrazolyl are valuable intermediates in the preparation of the above active ingredients.

The present invention also provides novel intermediates of formula (I) and salts thereof, novel compounds of formula (I), antagonize the effect of angiotensin II, and physiologically acceptable salts thereof, and pharmaceutical compositions containing them, which are particularly useful in the treatment of elevated blood pressure; cardiac insufficiency and also for the treatment of ischemic peripheral blood flow disorders, cardiac muscle ischemia, for the prevention of worsening of cardiac insufficiency after heart attack, for the treatment of diabetic nephropathy, glaucoma, certain digestive diseases, bladder, prevention of atherosclerotic changes after atherosclerotic changes operationally widening the bottlenecks on the vessels. The invention also relates to processes for the preparation of the novel compounds.

Among the above-mentioned meanings of the radicals to R1, the following meanings are possible, for example:

it may be hydrogen, fluorine, chlorine or bromine, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl or isopropyl,

R2 may be 5,5-spirocyclopentanodihydroimidazol-4-on-2-yl, 1-methyl-5,5-spirocyclopentanodihydroimidazol-4-on-2-yl, 1-ethyl-5,5-spirocyclopentanodihydroimidazol-4-on-2 -yl, 1-n-propyl-5,5-spirocyclopentanodihydroimidazol-4-yl-2-yl, 1-isopropyl-5,5-spirocyclopentanodihydroimidazol-4-one-2-yl,

4,5-dimethyloxazol-2-yl, 4-methyl-5-ethyloxazole, propyloxazol-2-yl, 4-methyl-5-n-butyloxazol-2-yl. -pentyloxazol-2-yl, 4-methyl-5-phenyl-oxazol-2-yl oxazol-2-yl, 4-ethyl-5-n-propyloxazol-2-yl, butyloxazol-2-yl, 4-ethyl-5- n-pentyloxazol-2-yl-phenyloxazol-2-yl, 4,5-di-n-propyloxazol-2-yl,

4-Methyl-5-n4-methyl-5-n4,5-diethyl4-ethyl-5-n4-ethyl-5-n4-n-propyl-5n-butyloxazol-2-yl, 4-n-propyl-5- n-pentyloxazol-2-yl, 4-n-propyl-5-phenyloxazol-2-yl, tyl-4-n-propyloxazol-2-yl, tetrahydrobenzoxazol-2-yl,

5-methyl-4-ethyl-oxazol-2-yl, 5-methyl-4,5-diphenyloxazol-2-yl, 5,6,7,84,5-dimethyl-thiazol-2-yl, 4-methyl-5-ethyl-thiazol-2-yl, 4- methyl-5-n-propylthiazol-2-yl, 4-methyl-5-phenylthiazol-2-yl, 4,5-diethylthiazol-2-yl, 4-ethyl-5-n-propylthiazol-2-yl, 4-ethyl- 5-Phenylthiazol-2-yl, 4,5-di-n-propylthiazol-2-yl, 4,5-di-n-isopropylthiazol-2-yl, 4-n-propyl-5-phenylthiazol-2-yl, 4,5-diphenylthiazol-2-yl, 5,6,7,8-tetrahydrobenzothiazol-2-yl, 4-methyloxazolin-2-yl, 4-ethyloxazolin-2-yl, 4-nopropylloxazolin-2-yl, 4- isopropyloxazolin-2-yl, 4-n-butyloxazolin-2-yl, 4-isobutyloxazolin-2-yl, 4-benzyloxazolin-2-yl, 4-phenyloxazolin-2-yl, 4,4-dimethyloxazolin-2-yl, 4-methyl-5-phenyloxazolin-2-yl, 4,4-dimethyl-5-n-propyloxazolin-2-yl, 4,5-tetramethyleneoxazolin-2-yl, 4-methylimidazolin-2-yl, 4,5-dimethylimidazoline- 2-yl, 4,5-tetramethylenimidazol-2-yl, 4-methylimidazol-2-yl, 4,5-dimethylimidazol-2-yl, 1,4,5-trimethylimidazol-2-yl, 1-ethyl-4, 5-dimethylimidazol-2-yl, 1n-propyl-4,5-dimethylimidazol-2-yl, 1-isopropyl-4,5-dimethylimidazol-2-yl, 1n-butyl-4,5-dime tylimidazol-2-yl, 1-isobutyl-4,5-dimethylimidazol-2-yl, 1-cyclopropyl-4,5-dimethylimidazol-2-yl, 1-cyclobutyl-4,5-dimethylimidazol-2-yl, 1- cyclopentyl-4,5-dimethylimidazol-2-yl, 1-cyclohexyl-4,5-dimethylimidazol-2-yl, 1-cyclohexyl-4,5-dimethylimidazol-2-yl, 1-benzyl-4,5-dimethylimidazol-2- yl, 1- (2-phenylethyl) -4,5-dimethylimidazol-2-yl, 1-carboxymethyl-4,5-dimethylimidazol-2-yl, 3-methoxycarbonylmethyl-4,5-dimethylimidazol-2-yl, 1 -oxycarbonylmexyl-4,5-dimexylimidazol-2-yl, 1-n-propoxycarbonylmethyl-4,5-dimexylimidazol-2-yl,

1-isopropoxycarbonylmethyl-4,5-dimethylimidazol-2-yl, 1-aminocarbonylmethyl-4,5-dimexylimidazol-2-yl, 1-methoxylaminocarbonylmethyl-4,5-dimethylimidazol-2-yl, 1-methylaminocarbonylmethyl-4,5- dimethylimidazol-2-yl, 1-n-propylaminocarbonylmethyl-4,5-dimethylimidazol-2-yl, 1-isopropylcarbonylmethyl-4,5-dimexylimidazol-2-yl, 1-dimexylaminocarbonylmexyl-4,5-dimethylimidazol-2-yl, 1-diethylaminocarbonylmethyl-4,5-dimethylimidazol-2-yl, 1-di-n-propylaminocarbonylmethyl-4,5-dimethylimidazol-2-yl, 1-diisopropylaminocarbonylmethyl-4,5-dimethylimidazol-2-yl,

1-N-4,5-meXyleXylaminokarbonylmeXyl dimeXylimidazol-2-yl,

1- (2-carboxymethyl) -4,5-dimethylimidazol-2-yl, 1- (2-methoxycarbonylexyl) -4,5-dimethylimidazol-2-yl, 1- (2-exoxycarbonylexyl) -4,5-dimethylimidazole- 2-yl, 1- (2-n-propoxycarbonyloxy) -4,5-dimethylimidazol-2-yl, 1- (2-isopropoxycarbonyloxy) -4,5-dimethylimidazol-2-yl, 1- (2-aminocarbonyloxy) - 4,5-dimethylimidazol-2-yl, 1- (2-methoxylaminocarbonyloxy) -4,5-dimethylimidazol-2-yl, 1- (2-exylaminocarbonyloxy) -4,5-dimethylimidazol-2-yl, 1- (2 -n-propylaminocarbonylexyl) -4,5-dimethylimidazol-2-yl, 1- (2-isopropylaminocarbonylexyl) -4,5-dimexylimidazol-2-yl, 1- (2-dimethylaminocarbonyloxy) -4,5-dimethylimidazol-2- yl, 1- (2-dixylaminocarbonylexyl) -4,5-dimethylimidazol-2-yl, 1- (2-dipropylaminocarbonylexyl) -4,5-dimethylimidazol-2-yl, 1- (2-diisopropylaminocarbonylexyl) -4, 5-Dimethylimidazol-2-yl, 1- (2-N-methoxylaminocarbonylexyl) -4,5-dimethylimidazol-2-yl, 1- (3-carboxypropyl) -4,5-dimexylimidazol-2-yl, 1- (3 -methoxycarbonylpropyl) -4,5-dimethylimidazol-2-yl, 1- (3-methoxycarbonylpropyl) -4,5-dimethylimidazol-2-yl, 1- (3-n-propoxyaminocarbo) nylpropyl) -4,5-dimethylimidazol-2-yl, 1- (3-isopropoxycarbonylpropyl) -4,5-dimethylimidazol-2-yl, 1- (3-aminocarbonylpropyl) -4,5-dimethylimidazol-2-yl, 1 - (3-Methylaminocarbonylpropyl) -4,5-dimethylimidazol-2-yl, 1- (3-methylaminocarbonylpropyl) -4,5-dimexylimidazol-2-yl, 1- (3-n-propylaminocarbonylpropyl) 8

-4,5-dimethylimidazol-2-yl, -4,5-dimethylimidazol-2-yl, -4,5-dimethylimidazol-2-yl, -4,5-dimethylimidazol-2-yl,

1- (3-Isopropylaminocarbonylpropyl)

1- (3-dimethylaminocarbonylpropyl) 1- (3-diethylaminocarbonylpropyl) 1- (3-di-n-propylaininocarbonylpropyl) -4,5-dimethylimidazol-2-yl, 1- (3-diisopropylaminocarbonylpropyl) -4,5-dimethylimidazole- 2-yl, 1- (3-N-methylethylaminocarbonylpropyl) -4,5-dimethylimidazol-2-yl, 1- (2,2,2-trifluoroethyl) -4,5-dimethylimidazol-2-yl, 1- (2 -hydroxyethyl) -4,5-dimethylimidazol-2-yl, 1- (3-hydroxypropyl) -4,5-dimethylimidazol-2-yl, 1- (4-hydroxybutyl) -4,5-dimethylimidazol-2-yl, 1- (2-methoxyethyl) -4,5-dimethylimidazol-2-yl, 1- (3-methoxypropyl) -4,5-dimethylimidazol-2-yl, 1- (4-methoxybutyl) -4,5-dimethylimidazol-2-yl, 1- (2-ethoxyethyl) -4,5-dimethylimidazol-2-yl, 1- (3-ethoxypropyl) -4,5-dimethylimidazol-2-yl, 1- (4-ethoxybutyl) -4,5-dimethylimidazole- 2-yl, 1- (2-isopropoxyethyl) -4,5-dimethylimidazol-2-yl, 1- (3-n-propoxypropyl) -4,5-dimethylimidazol-2-yl, 1- (4-isopropopoxybutyl) - 4,5-Dimethylimidazol-2-yl, 1- (2-pyrrolidinetyl) -4,5-dimethylimidazol-2-yl, 1- (3-pyrrolidinopropyl) -4,5-dimethylimidazol-2-yl, 1- (4 -pyrrolidinbutyl) -4,5-dimethyl-imidazol-2-yl, 1- (2-pip eridinetyl) -4,5-dimethylimidazol-2-yl, 1- (3-piperidinopropyl) -4,5-dimethylimidazol-2-yl, 1- (4-piperidinobutyl) -4,5-dimethylimidazol-2-yl, 1 - (2-morpholinoethyl) -4,5-dimethyl-imidazol-2-yl,

1- (3-morpholinopropyl) -4,5-dimethylimidazol-2-yl, 1- (4-morpholinobutyl) -4,5-dimethylimidazol-2-yl, 1-phenyl-4,5-dimethylimidazol-2-yl 1-benzyl-4,5-dimethylimidazol-2-yl, 1- (1-phenylethyl) -4,5-dimethylimidazol-2-yl, 1- (2-phenylethyl) -4,5-dimethylimidazol-2-yl 1- (1-phenylpropyl) -4,5-dimethylimidazol-2-yl, 1- (2-phenylpropyl) -4,5-dimethylimidazol-2-yl, 1- (3-phenylpropyl) -4,5-dimethylimidazole 2-yl, 1-methyl-4,5-diethylimidazol-2-yl,

1,4,5-triethylimidazol-2-yl, 1-ethyl-4-isopropyl-5-methylimidazol-2-yl, 1-ethyl-4-isobutyl-5-methylimidazol-2-yl, 1-n-propyl- 4-Isopropyl-5-methyl-imidazol-2-yl, 1-n-propyl-4-isobutyl-5-methyl-limidazol-2-yl, 1,4-diisopropyl-5-methyl-imidazol-2-yl, 1-iso-propyl-4- isobutyl-5-methylimidazol-2-yl, 1- (2-dimethylaminoethyl) -4-isopropyl-5-methylimidazol-2-yl, 1- (2-dimethylaminoethyl) -4-isobutyl-5-methylimidazol-2-yl, 1- (3-dimethylaminopropyl) -4-isopropyl-5-methylimidazol-2-yl, 1- (3-dimethylaminopropyl) -4-isobutyl-5-methylimidazol-2-yl, 1,5-dimethyl-4-ethylimidazol-2- yl, 1,5-dimethyl-4-n-propylimidazol-2-yl, 1,5-dimethyl-4-isopropylimidazol-2-yl, 1,5-dimethyl-4-isobutylimidazol-2-yl,

1,5-dimethyl-4-phenylimidazol-2-yl, 1-methyl-4,5-diphenylimidazol-2-yl, 1-ethyl-4,5-diphenylimidazol-2-yl, 1-n-propyl-4, 5-diphenylimidazol-2-yl, 1-isopropyl-4,5-diphenylimidazol-2-yl, 1-carboxymethyl-4,5-diphenylimidazol-2-yl, 1-methoxycarbonylmethyl-4,5-diphenylimidazol-2-yl, 1-ethoxycarbonylmethyl-4,5-diphenylimidazol-2-yl, 4,5-trimethylenimidazol-2-yl, 1-methyl-4,5-trimethylenimidazol-2-yl, 5,6,7,8-tetrahydrobenzimidazole-2- yl, 1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-ethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-n-propyl-5,6,7, 8-tetrahydrobenzimidazol-2-yl, 1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1H-butyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-isobutyl-5, 6,7,8-tetrahydrobenzimidazol-2-yl, 1H-pentyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1H-hexyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- cyclopropyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-cyclobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-cyclopentyl-5,6,7,8-tetrahydrobenzimidazole-2- yl, 1-cyclohexyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-cyano loheptyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-methoxycarbonylmethyl-5,6,7,8-tetrahydrobenzimidazole-2- yl, 1-ethoxycarbonylmethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-n-propoxycarbonylmethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-isopropoxycarbonylmethyl-5,6,7 , 8-tetrahydrobenzimidazol-2-yl, 1-aminocarbonylmethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-methylaminocarbonylmethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-ethylaminocarbonylmethyl-5 6,7,8-tetrahydrobenzimidazol-2-yl, 1-n-propylaminocarbonylmethyl10

-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-isopropylaminocarbonylmethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-dimethylaminocarbonylmethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl , 1-diethylaminocarbonylmethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-di-n-propylaminocarbonylmethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1-diisopropylaminocarbonylmethyl-5,6,7 , 8-tetrahydrobenzimidazol-2-yl, 1'-methylethylaminocarbonylmethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-carboxyethyl) 5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2) -methoxycarbonylethyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-ethoxycarbonylethyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-n-propoxycarbonylethyl) - 5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-isopropoxycarbonylethyl) -5,6,

7,8-tetrahydrobenzimidazol-2-yl, 1- (2-aminocarbonylethyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-methylaminocarbonylethyl-5,6,7,8-tetrahydrobenzimidazole-2) -yl, 1- (2-ethylaminocarbonylethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-n-propylaminocarbonylethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl), 1- ( 2-isopropylaminocarbonylethyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-dimethylaminocarbonylethyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-diethylaminocarbonylmethyl) -5 , 6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-di-n-propylaminocarbonylethyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-diisopropylaminocarbonylethyl) -5,6 , 7,8-tetrahydrobenzimidazol-2-yl, 1- (2-N-methylethylaminocarbonylethyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (3-carboxypropyl-5,6,7,8-tetrahydrobenzimidazole- 2-yl, 1- (3-methoxycarbonylpropyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl,

1- (3-ethoxycarbonylpropyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl

- (3-n-propoxycarbonylpropyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (3-isopropoxycarbonylpropyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (3- aminocarbonylpropyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (3-methylaminocarbonylpropyl) -5,6,7,8-tetrahydrobenzimidazol-2-yl, 1- (3-ethylaminocarbonylpropyl) -5,6,7 , -8-tetrahydrobenzimidazol-2-yl, 1- (3-n-propylaminocarbonylpropyl) -5,6,7,8-XeXrahydrobenzimidazol-2-yl, 1- (3-isopropylaminocarbonylpropyl) -5,6,7,8 1- (3-dimethylaminocarbonylpropyl) -5,6,7,8-xetrahydrobenzimidazol-2-yl, 1- (3-dimethylaminocarbonylpropyl) -5,6,7,8-xetrahydrobenzimidazol-2-yl 1- (3-di-n-propylaminocarbonylpropyl) -5,6,7,8-Xexrahydro-benzimidazol-2-yl, 1- (3-diisopropylaminocarbonylpropyl) -5,6,7-xeXrahydrobenzimidazol-2-yl 1- (3-N-methoxy-aminocarbonylpropyl) -5,6,7,8-XeXrahydrobenzimidazol-2-yl, 1- (2,2,2-xrifluorexyl) -5,6,7,8-xeXrahydrobenzimidazol-2-yl , 1-phenyl-5,6,7-xeXrahydrobenzimidazol-2-yl, 1-benzyl-5,6,7,8-Xexrahydrobenzimidazol-2-yl, 1- ( 1-phenylexyl) -5,6,7,8-XeXrahydrobenzimidazol-2-yl, 1- (2-phenylethyl) -5,6,7,8-XeXrahydrobenzimidazol-2-yl, 1- (1-phenylpropyl) - 5,6,7,8-xexrahydrobenzimidazol-2-yl, 1- (2-phenylpropyl) -5,6,7,8-XeXrahydrobenzimidazol-2-yl,

1- (3-phenylpropyl) -5,6,7,8-xeXrahydrobenzimidazol-2-yl, 1,3-dimethyl-5,6,7,8-XeXrahydrobenzimidazol-2-yl, 1,3-diethyl-5, 6,7,8-xeXrahydrobenzimidazolium-2-yl, 1,3-di-n-propyl-5,6, -7,8-XeXrahydrobenzimidazolium-2-yl, or 1,3-dibenzyl-5,6, -7 8-XeXrahydrobenzimidazolium-2-yl may be, for example, methyl, ethyl, n-propyl, isopropyl, isobuxyl, n-buxyl, 1-methoxy-n-propyl, X-tert-butyl, n-penxyl,

1-methoxy-n-butyloxy, 2-methoxy-n-butyloxy, cyclopropyl, cyclobenzyl, cyclopentyl, methoxy, exoxy, n-propoxy, isopropoxy, n-buxoxy, isobloxy, isobutyl, propyl, n-bexyloxy, n-bexyloxy, n-bexyloxy, n-bexyloxy,

R @ 1 may be carboxyl, cyano, tetra -tetrazolyl, 1-triphenylmethyltetrazolyl, 2-triphenylmethyltetrazolyl, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, isobutyloxycarbonyl, isobutyloxycarbonyl, -hexyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, 1-phenylethyloxycarbonyl,

Fenyletyloxykarbonyl 2, 3-phenylpropyloxycarbonyl, metoxymetoxykarbonyl, cinnamyloxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymetoxykarbonyl, izobutyryloxymetoxykarbonyl, n pentanoyloxymetoxykarbonyl, izopentanoyloxymetoxykarbonyl, pivaloyloxymethoxycarbonyl, n hexanoyloxymetoxykarbonyl, cyklopentanoyloxymetoxykarbonyl, cyklohexanoyloxymetoxykarbonyl, fenylacetoxymetoxykarbonyl, 1-fenylpropionyloxymetoxykarbonyl, 2-fenylpropionyloxymetoxykarbonyl,

3-phenylbutyryloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, 1-acetoxyethoxycarbonyl, 1-propionyloxyethoxycarbonyl, 1-n-butyryloxyethoxycarbonyl, 1-isobutyryloxyethoxycarbonyl, 1-n-pentanoyloxyethoxycarbonyl, 1-isopentanoyloxyethoxycarbonyl, 1-isopentanoyloxyethoxycarbonyl cyklohexanoyloxyetoxykarbonyl.

1-fenylacetoxyetoxykarbonyl, 1- (1-phenylpropionyloxy) ethoxycarbonyl, 1- (2-phenylpropionyloxy) etoxykarbonyl1- (3-phenylbutyryloxy) etoxykarbony1, 1-benzoyloxyetoxykarbonyl, metoxykarbonyloxymetoxykarbonyl, etoxykarbonyloxymetoxykarbonyl, n propyloxykarbonyloxymetoxykarbonyl, izopropyloxykarbonyloxymetoxykarbonyl, n butyloxykarbonyloxymetoxykarbonyl, izobutyloxykarbonyloxymetoxykarbonyl, t butyloxycarbonyloxymethoxycarbonyl, n-pentyloxycarbonyloxymethoxycarbonyl, isoamyloxycarbonyloxymethoxycarbonyl, n-hexyloxycarbonyloxymethoxycarbonyl, cyclopentyloxycarbonyloxymethoxycarbonyl, cyclohexyloxycarbonyloxymethoxycarbonyl, benzyloxycarbonyloxy

1-phenyloxycarbonyloxymethoxycarbonyl, 2-phenylethoxycarbonyloxy13 methoxycarbonyl, 3-phenylpropyloxycarbonyloxymethoxycarbonyl, cinnamyloxycarbonyloxymethoxycarbonyl, 1- (mexoxycarbonyloxy) ethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyloxy, 1- (ethoxycarbonyloxy) ethoxycarbonyl) (n-butyloxycarbonyloxy) ethoxycarbonyl, 1-isobutyloxycarbonyloxy) ethoxycarbonyl, 1- (tert-butyloxycarbonyloxy) ethoxycarbonyl, 1- (n-pentyloxycarbonyloxy) ethoxycarbonyl, 1- (isoarnyloxycarbonyloxy) ethoxycarbonyl, 1- (n-n-butoxycarbonyloxy) ethoxycarbonyl cyclopentyloxycarbonyloxy) ethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 1- (benzyloxycarbonyloxy) ethoxycarbonyl, 1- (1-phenylethoxycarbonyloxy) ethoxycarbonyl, 1- (cinnamyloxycarbonyloxy) dimethylaminocarbonyl, aminocarbonyl, ethylaminocarbonyl, aminocarbonyl, methylaminocarbonyl di-n-propylaminocarbonyl, diisopropylaminocarbonyl, N-methylethylaminocarbonyl, N-ethylisopropylaminocarbonyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl.

Preferred compounds of the above formula

I are substances in which:

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

R ₂ is an imidazol-2-yl group optionally substituted at the 1-position with R _a , wherein

R _a represents a phenyl group, a phenylalkyl of 1 to 3 carbon atoms in the alkyl moiety, a cycloalkyl of 5 to 7 carbon atoms or an alkyl of 1 to 5 carbon atoms, wherein the alkyl moiety may be substituted by an in vivo metabolizable to carboxyl group, trifluoromethyl , carboxy, methoxycarbonyl, ethoxyocarbonyl, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl, or from position 2 hydroxy, methoxy, ethoxy, amino, methylamino, pyrrolidine, piperidine or morphol

5,5-spirocyclopentadihydroimidazol-4-one-2-yl, imidazolium-2-yl, optionally substituted in the 1 and 3 positions, which may be the same or different, where

R 3 is alkyl or phenylalkyl, in each case having 1 to 3 carbon atoms in the alkyl group, oxazol-2-yl or thiazol-2-yl, in the imidazol-2-yl, imidazolium-2-yl, oxazol-2-yl or thiazole groups The -2-yl groups are optionally substituted at the 4,5-position with a C1-C4 alkyl group or a phenyl group, which substituents may be the same or different, or the 4,5-positions may be linked by an n-butylene bridge, oxazoline-2- yl or imidazolin-2-yl, substituted by R ₁₀ and R imino group which may be further substituted by R _a and R, R _{q, and} R _represents hydrogen or alkyl of 1 to 4 carbon atoms,

R 3 is C 2 -C 5 alkyl, C 3 -C 5 cycloalkyl, alkoxy or C 2 -C 4 alkylthio, and

R1 is a radical of formula

wherein it represents a group metabolizable in vivo to a carboxyl group, a carboxyl group, a cyano group,

2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 1H-tetrazolyl, 1-triphenylmethyltetrazolyl or 2-triphenylraethyltetrazolyl, the group in vivo metabolizable to a carboxyl group being, for example, an ester group of formula

- CO-OR,

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

- CO - O - (HCR) - O - CO - OR where

R represents a straight or branched chain alkyl radical of 1 to 4 carbon atoms or a cycloloalkyl of 5 to 7 carbon atoms,

R is hydrogen or methyl; and

R represents straight or branched chain alkyl of 1 to 4 carbon atoms or cycloalkyl of 5 to 7 carbon atoms, as well as the 3-isomers of these compounds, a mixture of the 1-isomer and the 3-isomer of the salt thereof.

Particularly preferred are those compounds of formula I in which and R 4 are as defined above, R 2 in the 6-position is as defined above and in the 4-position is fluorine, chlorine or bromine, trifluoromethyl or alkyl of 1 to 3 carbon atoms.

Particularly preferred compounds are those wherein R 2 at the 6-position is imidazolyl, optionally substituted as described above, and the 3-isomers of these compounds, mixtures of the 1-isomer, the 3-isomer, and salts thereof.

In particular, the following compounds are preferred compounds of the invention:

a) 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2- carboxylic acid,

b) 4- [2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl- 2-carboxylic acid,

c) 4- [2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-4-yl) methyl] -2- (lH-tetrazol-5-yl) biphenyl,

d) 4- [2-n-propyl-4-methyl-6- (1-benzyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl] biphenyl 2-carboxylic acid,

e) 4- [2-Ethyl-4-methyl-6- (1-benzyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-4-yl) methyl] biphenyl-2 carboxylic acid,

f) 4- [2-n-propyl-4-methyl-6- (1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl- 2-carboxylic acid,

g) 4- [2-ethyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -4-benzimidazol-1-yl) methyl] -2- (1H) tetrazol-5-yl) biphenyl,

(h) 4- [2-n-propyl-4-methyl-6- (4,4-dimethyloxazolin-2-yl) -4-benzimidazol-1-yl) - (methyl) biphenyl-2-carboxylic acid;

i) 4- (2-n-propyl-4-methyl-6- (1,5-dimethyl-4-phenylimidazol-2-yl) -1H-benzimidazol-1-yl) - (methyl) biphenyl-2 carboxylic acid,

k) 4- (2-n-propyl-4-methyl-6- (4-isopropyl-1,5-dimethylimidazol-2-yl) -4-benzimidazol-1-yl) - (methyl) biphenyl-2 carboxylic acid, and salts thereof.

The present invention also provides processes for the preparation of novel compounds. These substances can be produced, for example, by one of the following processes:

a) In the preparation of compounds of the formula I in which R 2 is oxazol-2-yl, thiazol-2-yl or imidazol-2-yl, in which the 4, 5 positions are linked by an n-butyl bridge and in addition the imidazole imino group may be of a ring substituted with a C 1 -C 6 alkyl group, a C 1 -C 3 phenylalkyl group or a phenyl group is carried out by reacting a compound of formula II

R

R (II)

where

R ₃ , R ₃ and R 4 are as defined above and

X represents an oxygen atom or a sulfur atom or an imino group optionally substituted by a C1 -C6 alkyl radical, a C1 -C3 phenylalkyl radical or a phenyl radical with an alpha-haloketone of the formula III

(III) wherein it represents a halogen atom, for example chlorine.

The reaction is preferably carried out in the presence of a suitable solvent, for example dimethylformamide, diethylene glycol dimethyl ether or sulfolane, optionally in the presence of a base, for example potassium carbonate, pyridine, triethylamine, N-ethyldiisopropylamine or N-ethyldicyclohexylamine at 0 to 150 ° C.

When X is an oxygen or sulfur atom, the reaction is preferably carried out in a solvent with a boiling point above 150 ° C or in a melt at 150 to 250 ° C, preferably at 175 to 225 ° C.

In the case where X is an amino group optionally substituted by an alkyl radical, the reaction is carried out in the presence of the corresponding amine as solvent, for example in the presence of liquid ammonia, methylamine, ethylamine, n-propylamine at a temperature in the range 0 to 100 ° C, preferably 20 to 75 ° C.

b) to prepare compounds of formula I in which R ₂ is the above mentioned imidazol-2-yl, optionally substituted in the 1-position by _{R, and} the procedure is such that the reaction of the formula IV zlúčenniny

(IV) wherein and R 4 are as defined above and R ₂ represents any of the above oxazol-2-yl, with an amine of the formula V _H2 N - R @ ₆ (V) wherein R represents a group for R _& and hydrogen atom.

The reaction is preferably carried out in the presence of an excess of amine and preferably in the presence of the corresponding formamide of the general formula HCONHR 8 as solvent, optionally under pressure at a higher temperature, for example in the range 100 to 250, preferably in the range 175 to 225 ° C.

During this reaction, it is possible to simultaneously convert a substituted carboxyl group of R 4 to a carbixyl group or an optionally substituted tetrazolyl group to a 1H-tetrazol-5-yl group.

c) In the preparation of the benzimidazoles of the formula I in which R 4 is a group of the formula

The reaction is carried out by reacting a benzimidazole derivative of the general formula VI

(VI) where

R2, R3 and R4 are as defined above and

R ₂ 'means the same groups as mentioned for R ₂ except for the unsubstituted imidazol-2-yl and imidazolin-2-yl groups at the 1-position with the biphenyl derivative of the general formula VII (VII)

wherein it has the meaning given above and

Z2 is a nucleophilic leaving group, for example a halogen atom such as chlorine, bromine or iodine or a substituted sulfonyloxy group such as methanesulfonyloxy, phenylsulfonyloxy or p-toluenesulfonyloxy.

The reaction is preferably carried out in a solvent or mixture of solvents such as methyl 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, tert-butanol. . potassium butoxide, triethylamine or pyridine, both of which may be used simultaneously / as solvents. The reaction is preferably carried out at 0 to 100 ° C, for example at room temperature to 50 ° C.

As a reaction product, a mixture of 1α and 3-isomers is usually obtained, which mixture can then be separated, preferably by chromatography using a carrier, for example silica gel or alumina, to give the corresponding 1- and 3-isomers.

d) In the preparation of the compounds of the formula I in which R1 is a carboxyl group, a compound of the formula VIII is converted

where

R | to the above meaning and is a group which can be converted by hydrolysis, heat treatment or hydrogenolysis to a carboxyl group to a compound of formula I in which R @ 1 is a carboxyl group.

For example, functional derivatives of a carboxyl group such as unsubstituted or substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides, nitrile groups or tetrazolyl groups can be converted by carboxylic acid hydrolysis or esters with tertiary alcohols, e.g. butyl esters by heat treatment of the carboxyl group or it is possible to convert to the carboxyl group esters with arylalkanols, for example benzyl esters, by hydrogenolysis.

The hydrolysis may be carried out in the presence of an acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, trichloroacetic or trifluoroacetic acid, optionally in the presence of substances which may favorably influence the reaction, e.g. hexadecyltributylphosphonium bromide in a suitable solvent, e.g. ethanol, a mixture of water and ethanol, water and isopropanol or water and dioxane at a temperature of -10 to 120 ° C, for example at room temperature to the boiling point of the reaction mixture.

When in the compound of formula (VIII) is cyano or aminocarbonyl, these groups can also be converted to the carboxyl group by treatment with sodium nitrite, for example sodium nitrite, in the presence of an acid, for example sulfuric acid, preferably used as a solvent. is carried out at a temperature of 0 to 50 ° C.

When R zlúčen in the compound of formula VIII is, for example, a tert-butyloxycarbonyl group, tert. The butyl group is also cleaved by treatment with heat, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, preferably in the presence of a catalytic amount of an acid such as trifluoroacetic acid, p-toluenesulfonic acid, sulfuric, phosphoric or polyphosphoric. it is preferably carried out at the boiling point of the solvent used, for example at a temperature in the range of 40 to 100 ° C.

When R VIII in a compound of formula VIII is, for example, a benzyloxycarbonyl group, the benzyl group may also be cleaved by hydrogenolysis in the presence of a hydrogenation catalyst such as palladium on activated carbon in a suitable solvent such as methanol, ethanol, ethanol / water, ice acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at a temperature in the range of 0 to 50 ° C, for example at room temperature and at a hydrogen pressure of 1 to 5 bar. In the case of hydrogenolysis, other residues may be simultaneously reduced or replaced by a hydrogen atom, for example a nitro group can be converted in this manner to an amino group, benzyloxy group to hydroxy group, vinylidene group to the corresponding alkylidene group or cinnamic acid residue to phenyl propionic acid. a halogen atom by a hydrogen atom.

e) to prepare compounds of formula I, wherein _R2 is 5,5-spirocyklopentanodihydroimidazol-4-on-2-yl group, the benzimidazole derivative of the formula IX

where

R1, R1 and R1 are as defined above and

_R2 is imidazol-2-yl, wherein in the 4, 5 is connected to n-butylene bridge, with a base in the presence of air and light.

The reaction is carried out by treatment with a base such as sodium or potassium hydroxide in a suitable solvent such as water, a mixture of water and methanol, ethanol, a mixture of water and ethanol, water and isopropanol or water and dioxane at a temperature of -10 to 120 ° C. at room temperature to the boiling point of the reaction mixture.

The reaction simultaneously converts the optionally present R 4 group to the carboxyl group.

f) In the preparation of a compound of formula I wherein ktorom-tetrazolyl is a protecting group in a compound of formula X

where

R 1, R ₂ and R 3 are as defined above and

R 1 represents a protecting group ΙΗ-tetrazolyl or 2H-tetrazolyl group in the 1 or 2-position.

Suitable protecting groups are, for example, triphenylmethyl, the tributyltin residue or the triphenyltin residue.

The protecting group used is preferably cleaved in the presence of hydrogen halide, especially hydrogen chloride, and in the presence of a base such as sodium hydroxide or ammonia in alcohol, the process is carried out in a suitable solvent such as methylene chloride, methanol, methanol / ammonia, ethanol and isopropanol. 0 to 100 ° C, preferably at room temperature or when the reaction is carried out in the presence of an alcoholic ammonia solution even at a higher temperature, for example in the range 100 to 150 ° C, preferably 120 to 140 ° C.

g) For the preparation of compounds of the formula I in which znamená-tetrazolyl is a group, it is possible to proceed by reacting the compounds of the formula XI

wherein R 1 and R 3 are as defined above, with hydrochloric acid or its salts.

The reaction is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at a temperature in the range of 80 to 150 ° C, preferably 125 ° C. Typically, the nitric acid is liberated from an alkali metal azide such as sodium azide during the reaction in the presence of a weak acid such as ammonium chloride or is reacted with a hydrochloric acid salt, preferably aluminum azide or tributyltin azide, in the reaction mixture. are preferably formed directly in the reaction mixture by reacting aluminum chloride or tributyltin chloride with an alkali metal azide, for example sodium azide, which the tetrazolide salt obtained is liberated by acidification with a dilute acid, for example 2N hydrochloric or sulfuric acid.

h) to prepare compounds of formula I wherein R ₂ is imidazol-2-yl, optionally substituted in the 1-position by phenyl, wherein the phenyl radical is optionally substituted by alkyl, hydroxy or alkoxy, wherein the phenyl radical may carry up to two substituents which may be the same or different, or an alkyl group having 1 to 6 carbon atoms, optionally further substituted by a group which can be converted in vivo to a carboxyl group, a trifluoromethyl group, an alkoxycarbonyl group, an aminocarbonyl group, an alkylaminocarbonyl or dialkylaminocarbonyl group or R ₂ means any one of the above imidazolium-2-yl groups is carried out by reacting a compound of formula XII

where

R1 and R3 are as defined above,

R ₂ is an unsubstituted imidazol-2-yl group in the 1-position, and

R @ 1 represents a carboxyl group or a group which can be converted to a carboxyl group by hydrolysis, heat treatment or hydrogenolysis or a protected 1H-tetrazolyl or 2H-tetrazolyl group with a compound of the formula XIII of ₃ -R _? (XIII) where

Ry represents a phenylalkyl group in which the phenyl radical may be mono- or di-substituted by an alkyl or alkoxy group, the substituents being the same or different or an alkyl group having 1 to 6 carbon atoms, the alkyl group being optionally further substituted by a group which is can be converted in vivo to a carboxyl group, a trifluoromethyl group, a carboxy group, an alkoxycarbonyl group, a aminocarbonyl group, an alkylaminocarbonyl group or a dialkylaminocarbonyl group, and

Z ₃ represents a nucleophilic leaving group, for example an atom

halogen such as a chlorine atom, or j ode, with subsequent potential cleavage used protective groups. reaction sa preferably carry out e in a solvent or

in a solvent mixture such as methylene chloride, diethyl ether, tetrahydrofuran, dioxine, dimethylsulfoxide, dimethylformamide or benzene, optionally in the presence of an acid-binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride, potassium tert-butoxide or triethylamine; the latter may also be used as solvents, the reaction preferably being carried out at a temperature in the range of 0 to 100 ° C, for example at a room replicate to 50 ° C.

When the reaction is carried out in the presence of an excess of a compound of formula XIII, an imidazolium-2-yl derivative of formula I is obtained simultaneously.

Final cleavage of the protecting groups may be accomplished by hydrolysis, heat treatment or hydrogenolysis.

The hydrolytic cleavage of the protecting group employed is preferably treated with an acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, trichloroacetic or trifluoroacetic acid, optionally in the presence of a reaction aid such as hexadecyltributylphosphonium bromide in a suitable solvent such as water, a mixture of water and water. , ethanol, a mixture of water and ethanol, water and isopropanol or water and dioxane. The process is carried out at -10 to 120 ° C, for example at room temperature to the boiling point of the reaction mixture.

For the cleavage of the protecting group by the action of heat, as is done, for example, in the case of a tert-butyloxycarbonyl group, the cleavage is conveniently carried out in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, preferably in the presence of a catalytic amount of acid, e.g. -toluenesulfone, sulfur, phosphoric or polyphosphoric. The reaction is preferably carried out at the boiling point of the solvent used, for example at a temperature in the range of 40 to 100 ° C.

Hydrogenolytic cleavage of a protecting group such as a benzyloxycarbonyl group is carried out in the presence of a hydrogenation catalyst such as palladium on charcoal in a suitable solvent such as methanol, ethanol, ethanol and water, in glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at 0 to 50 ° C, for example at room temperature and at a hydrogen pressure of 1 to 5 bar.

i) For the production of compounds of formula I, wherein R 2 is imidazol-2-yl radical substituted by radicals R to R @ _10, wherein one of the radicals R and R q is hydrogen, the procedure is such that the reaction of the amino of the of formula XIV

(xiv) where

R 1, R 1, R 2 and R 8 through R 6 are as defined above, but one of R 8 or R 8 must be hydrogen and

R _a is as defined above for R _a or may be hydrogen, with the ammonium salt of a lower aliphatic carboxylic acid.

The reaction is carried out using an ammonium salt of a lower aliphatic carboxylic acid, such as ammonium acetate or an ammonium salt of propionic acid, preferably in the presence of a solvent such as glacial acetic acid or propionic acid at elevated temperature, preferably at boiling point. temperature in the range of 100 to 150 ° C.

j) In the preparation of a compound of formula I wherein R 2 is oxazolin-2-yl or imidazolin-2-yl as defined above, dehydration of the compound of formula XV is performed

where

R 1, R 2, R 4 and R 8 through R 6 are as defined above and a

Y is OH or NHR _and wherein

R _a is as defined above.

The dehydration is carried out in the presence of a water scavenger such as phosphorous oxychloride, sulfuric acid, polyphosphoric acid or thionyl chloride, and these are preferably used as solvents. The process is carried out at higher temperatures, for example at the boiling point of the dehydrating agent used, for example at a temperature in the range of 105 to 150 ° C.

a) to prepare compounds of formula I wherein _R2 is imidazolin-2-yl radical as defined above in the reaction of a compound of formula XVI

II II t

1 \

R (XVI) wherein, R 1 and R 4 are as defined above, and R 2 is an oxazoli-2-yl radical as defined above, substituted with R 8 and R 6 q as defined above, with an amine of formula XVII

₃ N - (RGCH) - (R _g CH _l0) - NH ₂ (XVII) wherein

R 8 to R 10 are as defined above.

The reaction is carried out in a solvent such as toluene, dimethylformamide or dimethylsulfoxide, preferably in an excess of the amine XVII used at elevated temperatures, for example at a temperature in the range of 100 to 150 ° C. The reaction is preferably carried out without the use of a solvent.

1) In the preparation of compounds of the formula I in which R ₂ is an oxazol-2-yl radical as defined above, substituted by the radicals R 8 to R 6, the process is carried out by dehydrating the aminoketone of the general formula XVIII

where

R 1, R 3, R 6 and R 8 to R 6 are as defined above, but R 8 or R 10 must be hydrogen.

The dehydration is carried out in the presence of a water-removing agent, for example phosphorous oxychloride, sulfuric acid or phosphoric acid, which are simultaneously used as solvents. The process is carried out at higher temperatures, for example at the boiling point of the dehydrating agent used, for example at a temperature in the range of 105 to 150 ° C. Using phosphorus oxychloride, it is possible simultaneously to cleave any tert-butyl ester group present.

m) to prepare compounds of formula I wherein R ₂ is imidazol-2-yl radical to as defined above, substituted by radicals R and R q proceed by the dehydrogenated compounds of the formula XIX

(xix) wherein R _3, R and R are as defined above, and

R 2 is imidazolin-2-yl radical as defined above in R ₂ and the radicals substituted by R 10 to ^R "but one of the radicals R or R gmusí be hydrogen.

The dehydrogenation is carried out by treatment with a dehydrogenating agent such as palladium on charcoal, barium manganate or selenium dioxide in a suitable solvent, for example toluene or methyl chloride, at a higher temperature, for example at the boiling point of the solvent used, for example 110-150 ° C.

n) The preparation of the compounds of the formula I in which R 6 represents a 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group is carried out by carrying out the reaction, optionally directly in the reaction mixture. a mixture of the formed amidoxime derivative of general formula XX

wherein R 1 -R 1 are as defined above, with a compound of formula XXI

From ₄ - CO - OR _{1: 1} (XXI) where

Z ^ represents a nucleophilic leaving group, for example a halogen atom such as a chlorine, bromine or iodine atom; and

R 14 represents an alkyl, aryl or aralkyl group, preferably a lower alkyl group, for example methyl, ethyl, n-propyl or isopropyl, followed by cyclization of the thus obtained acylated amidoxime derivative.

The reaction is preferably carried out in a solvent such as methyl chloride, chloroform, tetrahydrofuran, dioxane or acetonitrile, preferably in the presence of an inorganic base such as sodium or potassium carbonate or an organic base such as triethylamine or pyridine, the latter two being used simultaneously as solvents. The reaction is carried out at a temperature in the range of 0 to 20 ° C.

The final cyclization of the thus obtained acylated amidoxime is preferably carried out in an organic solvent, for example benzene, toluene, xylene, tetrahydrofuran or dioxane at higher temperatures, for example at a temperature in the range of 50 to 100 ° C, preferably at the boiling point of the solvent used.

The starting amidoxime is preferably obtained by reacting the corresponding nitrile of formula XI with hydroxylamine in the presence of a solvent such as methanol, ethanol, methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or dioxane in the presence of a suitable base such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine sodium methoxide, sodium ethoxide or sodium hydride at a temperature in the range of 50 to 100 ° C.

Optionally, reactive groups such as hydroxy, amino or alkylamino groups present in the reactions described above may be protected during the reaction by suitable protecting groups which are cleaved again after the reaction is complete.

Protective groups for the hydroxyl group are, for example, trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl, among the amino-protecting groups in particular acetyl, ethoxycarbonyl or benzyl.

The final optional deprotection is preferably carried out by hydrolysis in an aqueous solvent, for example water in a mixture of isopropanol and water, tetrafuran and water or dioxane and water in the presence of an acid, for example hydrochloric or sulfuric acid or in the presence of an alkali metal-containing base. sodium hydroxide or potassium hydroxide at a temperature in the range of 0 to 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 by treatment with hydrogen in the presence of a catalyst such as palladium on charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally in the presence of an acid such as hydrochloric acid at 0 to 50. ° C, preferably at room temperature and at a hydrogen pressure of 0.1 to 0.7, preferably 0.3 to 0.5 MPa.

The mixture of isomers of the formula I thus obtained can, if desired, be separated, preferably by chromatography on a support, for example silica gel or alumina.

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

In addition, the novel compounds of the formula I thus obtained, if they contain a carboxyl or 1H-tetrazolyl group, can optionally be converted to salts with inorganic or organic bases, in particular to salts which are pharmaceutically acceptable and therefore physiologically inert. Suitable bases for use herein are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The starting materials for the preparation of the compounds according to the invention, the compounds of the formulas II to XXI are partly known from the literature or can be partly obtained by processes described in the literature.

For example, compounds of formulas II, IV, VI, VIII, IX, X, or XII may be obtained by acylation of the corresponding o-phenylenediamine followed by cyclization or acylation of the corresponding o-aminonitro compound followed by reduction of the nitro group and cyclization. by alkylation of the corresponding substituted biphenyl derivative with the corresponding substituted biphenyl derivative to the 1-substituted compound in the corresponding manner, followed by optional cleavage of the protecting groups.

The described conversions of oxazol-2-yl derivatives of formula IV to imidazol-2-yl compounds substituted in the 1-position can be carried out according to Angew. Chem. 71, 761 (1959), which describes the synthesis of IH-imidazole, i.e. the conversion of oxazoles to IH-imidazole using a mixture of formamide and ammonia.

The oxazole derivatives of formulas IV, VI, VIII, X and XI may be obtained by acylating the corresponding alpha-aminoketone with the corresponding carboxylic acid chloride or anhydride followed by cyclization according to J. Chem. Soc., 95, 2167 (1909) and Synthesis, 1970, 648, wherein a strong acid such as sulfuric acid, phosphoric acid, hydrofluoric acid or phosphorous oxychloride is used as condensation agent.

The starting material of formula XV may be obtained by acylating the corresponding beta-aminoalcohol and the compound of formula XVI may be obtained by cyclizing the compound of formula XV thus obtained.

The above acylated alpha-aminoketones can be converted directly to the corresponding substituted imidazoles by treatment with ammonium acetate in glacial acetic acid according to the method of Chem, Ber., 106, 2415 (1973).

The starting compounds of formula (XIV) and (XVIII) may be prepared by acylating the corresponding alpha-aminoacetate derivative with the corresponding activated benzimidazolecarboxylic acid, and the alpha-aminoacetone derivative required for carrying out the reaction may be obtained according to Dakin, Vest, Chem. Rev., 17, 91 (1988) from the corresponding alpha-amino acids.

The starting compounds of formula (XIX) can be obtained by acylating the corresponding beta-amino alcohols with the corresponding activated benzimidazolecarboxylic acid, whereby the compound thus obtained is cyclized and then reacted with the corresponding ethylenediamine derivative.

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

In particular, the following compounds of the invention were tested for biological activity in the following manner:

A: 4- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid .

B: 4- [2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydro-benzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl (biphenyl-) 2-carboxylic acid,

C: 4- [2-n-propyl-4-methyl-6- (1,5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- ( H-tetrazol-5-yl) biphenyl,

D: 4- [2-n-propyl-4-methyl-6- (1-benzyl-5,6,7,8-tetrahydro-benzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2 carboxylic acid,

E: 4- (2-n-ethyl-4-methyl-6- (1-phenyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl hydrate biphenyl-2-carboxylic acid,

F: 4- [2-n-Propyl-4-methyl-6- (1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl biphenyl-2-carboxylic acid,

G: 4- [2-n-ethyl-4-methyl-6- (1-ethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2 - (lH-tetrazol-5-yl) bifenylhydrát.

H: 4- (2-n-propyl-4-methyl-6- (4,4-dimethyloxazolin-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2-carboxylic acid di-trifluoroacetate,

I: 4- [2-n-propyl-4-methyl-6- (1,5-dimethyl) -hydrate

-4-phenyl-imidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2-carboxylic acid;

K: 4- [2-n-propyl-4-methyl-6- (4-ixopropyl-1,5-dimethylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid x 1.25 water.

Binding to angiotensin II receptors

The tissue (rat lung) is homogenized in a tris buffer containing 50 mmol tris, 150 mmol sodium chloride and 5 mmol EDTA at pH 7.40, then the tissue is centrifuged twice at 20,000 g for 20 minutes each. The resulting pellet is suspended in incubation buffer containing 50 mmoles of magnesium chloride and 0.2% BSA, pH 7.40 at a ratio of 1:85 based on the wet weight of the tissue. 0.1 ml of homogenate is incubated for 60 minutes at 37 ° C with 50 µM of β-angiotensin II (NEN, Dreieich, Germany) with 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 filter was washed with 4 ml of buffer containing 25 ml of tris, 2.5 mmol of magnesium chloride and 0.1% BSA, pH 7.40 at 0 ° C. The bound radioactive material is determined by a gamma counter. From the dose-response curve, the corresponding IC 50 value is determined.

The IC 50 values for compounds A to K obtained as described above are shown in the following table:

compound

12.0

3.8

2.6

6.0

46.0

38.0

1.6

37.0

3.2

19.5

No toxic side effects, such as no negative inotropic effect as well as any cardiac rhythm disturbances, were observed with the intravenous administration of the compounds up to 30 mg / kg. That is, the compounds of the invention are well tolerated.

The compounds according to the invention and their physiologically acceptable salts, due to their pharmacological properties, are suitable for the treatment of elevated blood pressure and cardiac insufficiency, further for the treatment of ischemic disorders of peripheral blood circulation, angina pectoris ischemic heart disease, for the prevention of cardiac insufficiency after myocardial infarction, for the treatment of diabetic nephropathy, glaucoma and certain diseases of the digestive system and bladder.

Furthermore, the novel compounds of the invention and their physiologically acceptable salts are useful in the treatment of certain pulmonary diseases, such as pulmonary edema and chronic bronchitis, to prevent re-narrowing of the arteries after angioplasty, to prevent vascular wall changes after vascular surgery, arteriosclerosis and in diabetic angiopathy. Because of the effect of angiotensin in the brain on influencing acetylcholine and dopamine release, new angiotensin antagonists are also useful for the treatment of certain central nervous system disorders such as depression, Alzheimer's disease, Parkinson's syndrome, bulimia and cognitive impairment.

In order to achieve the desired effect in adults, the effective dose is usually in the range of 0.5 to 100, preferably 1 to 70 mg, and 0.1 to 200, preferably 1 to 100 mg, 1 to 3 mg per oral administration. x daily. The novel compounds of the formula I can be formulated, optionally in admixture with other active substances, such as blood pressure lowering agents, ACE inhibitors, diuretics and / or calcium antagonists. The dosage forms may contain one or more conventional pharmaceutical carriers and / or diluents, such as corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, a mixture of water and ethanol, water, and water. glycerol, water and sorbitol, or water and polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxylmethylcellulose or fatty substances such as hardened fat or suitable fat blends. The usual dosage form is tablets, dragees, capsules, powders, suspensions or lace.

Other active substances which may be mentioned are, for example, bendrofluometiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzthiazide, cyclotiazide, ethacrinic acid, furosemide, metoprolol, prazosin, atenolol, propranolo, (di) hydralazine hydrochloride, diltipine, nilipipine, felodipine, felodipine, felodipine, felodipine, captopril, enalapril, lisinopril, cilazapril, quinapril, fosinopril and ramipril. The dose of these active substances is usually 1/5 of the usually lowest dose to the usual dose, for example 15 to 200 mg for hydrochlorothiazide, 125 to 2000 mg for chlorothiazide, 15 to 200 mg for etacrinic acid, 5 to 80 mg for furosemide, 20 to 20 mg. 400 mg for propanolo, 5 to 60 mg for nifedipine or 5 to 60 mg for nitrendipine.

The invention is illustrated by the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

a) 4 - [(2-n-propyl-4-methyl-6-amidin-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid methyl ester

To a solution of 6.2 g, 14.6 mmol of 4 - [(2-n-propyl-4-methyl-6-cyano-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid methyl ester in 750 mL of absolute The reaction mixture was stirred at room temperature for 3 hours at room temperature. After removal of the solvent, the mixture was evaporated in vacuo, the residue was dissolved twice in a mixture of 50 ml of ethanol and 50 ml of ether and evaporated again. The residue is then dissolved in 750 ml of absolute methanol and 30 g of ammonium carbonate are added. After standing at room temperature for 12 hours, 50 g of silica gel with an average particle humidity of 0.06-0.3 mm are added. After filtration and evaporation of the filtrate, the residue is chromatographed on silica gel with a particle size of 0.032-0.063 mm using an increasing polarity mixture of methylene chloride and ethanol (9: 1, 4: 1, 3: 3) as eluent. 1 to 1: 1. The individual fractions were combined and evaporated.

Yield 4.3 g, 57% of theory.

A foam was obtained with 0.14 using silica gel and methylene chloride / ethanol 9: 1.

b) 4- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2- methyl ester carboxylic acid

0.5 g, 1.0 mmol of methyl 4- (2-n-propyl-4-methyl-6-amidino-1H-benzimidazol-1-yl) methyl / biphenyl-2-carboxylic acid methyl ester, 0.13 g, 1 mmol of 2-chlorocyclohexanone and 10 ml of liquid ammonia are heated in a bomb at 60 ° C for 15 hours.

After cooling and evaporation of the ammonia, the residue is dissolved in a 2: 1 mixture of methanol and methyl chloride and the solution is chromatographed on silica gel with a particle size of 0.032-0.063 mm, eluting with increasingly polar mixtures of methyl chloride and ethanol (19). : 1 to 9:

1. Combine the appropriate fractions and evaporate.

Yield: 0.1 g, 19% of theory.

A foamed product of 0.50 was obtained using silica gel and a 9: 1 mixture of methylene chloride and ethanol.

Example 2

4- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid,

0.1 g, 0.2 mmol of methyl 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl ester (methyl) biphenyl-2-carboxylic acid and 10 mg, 0.02 mmol of hexadecyltributylphosphonium bromide are mixed with 10 ml of 48% hydrobromic acid and the mixture is heated at 110 ° C for 15 minutes. After cooling, the mixture was covered with 20 ml of ether and diluted with 10 ml of water. After extraction, the organic phase is separated and the aqueous phase is adjusted to pH 7 with ammonia, the precipitate formed is suction filtered, washed with water and then dissolved in a 4: 1 mixture of methylene chloride and ethanol. The solvent was evaporated, the residue was triturated with ethanol and dried. The crude product is chromatographed on silica gel with a particle size of 0.032-0.063 mm using a 9: 1 mixture of methyl chloride and ethanol. The appropriate fraction was combined and evaporated. The residue is triturated with ether and dried.

Yield: 64 mg, 64% of theory.

Melting point: 231-235 ° C with decomposition.

^ 32 ^Β 32 ^ 4θ2 'molecular weight 504, 64.

Mass Spectrum: (M + H) ⁺ = 505

Example 3

4- [2-n-Propyl-4-methyl-6- (5,5-spirocyclopentano-dihydroimidazol-4-on-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2- hemihydrate carboxylic acid

0.05 g, 0.1 mmol of methyl 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl ester (methyl) biphenyl-2-carboxylic acid was dissolved in 4 ml of ethanol, 2 ml of 1N sodium hydroxide was added and the mixture was stirred at room temperature for 4 days. 4 ml of water are added and the pH is adjusted to 6 by addition of glacial acetic acid. The resulting precipitate was filtered off with suction, washed with water and then dried with potassium hydroxide. The crude product is chromatographed on silica gel with a particle size of 0.032-0.063 mm, eluting with a mixture of methyl chloride, ethanol and glacial acetic acid first in a ratio of 50: 1: 0.1 and then in a ratio of 30: 1: 0.1. Product containing fractions were combined and evaporated. The residue is triturated with ether and then dried.

Yield: 30 mg, 59% of theory.

The melting point is 310 ^ 32 ^ 32 ^ 4θ3 moleku molecular

Mass Spectrum: (M @ + to + 111 DEG C. with decomposition).

weight 520, 64.

H ^{@ +} = 521.

Example 4

4- (2-n-Propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2- tert-butyl ester carboxylic acid

a) n-Propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazole

2-n-propyl-4-methyl-6-aminocarbonyl-4-benzimidazole (2.17 g, 10 mmol) and 2-chlorocyclohexanone (10.25 g, 77 mmol) were heated at 190 ° C for 1 h. After cooling to room temperature, the reaction mixture was triturated with ether and suction filtered. The residue was dissolved in water and concentrated ammonia was added. The resulting mixture is extracted with methylene chloride, the organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel with a particle size of 0.032-0.063 mm, eluting with increasingly polar mixtures of methyl chloride and ethanol to a ratio of 50: 1, 25: 1 and finally 20: 1. The fractions containing the resulting product are combined and evaporated.

Yield: 1.9 g, 64% of theory.

A foamed product is obtained with an Rf of 0.20 using silica gel and ethyl acetate.

b) 4- [2-n-Propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-tert-butyl ester 2-carboxylic acid

3.30 g, 11 mmol of 2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazole are dissolved in 15 ml of dimethylformamide and at a temperature of 5-10 ° C. ° C, potassium tert-butoxide (1.5 g, 13.2 mmol) was added portionwise to the solution. After standing at 5 ° C for 15 minutes, 4.6 g (13.2 mmol) of tert-butyl ester are added.

-brómmetylbifenyl-2-carboxylic acid. After an additional 45 minutes at 5 ° C, 200 ml of water are added to the reaction mixture. The precipitate formed is filtered off with suction, washed with water and dissolved in 200 ml of ethyl acetate. The solution was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel with a particle size of 0.032-0.063 mm, eluting with a 50: 1 mixture of methyl chloride and ethanol. The fractions containing the resulting product are combined and evaporated.

Yield: 4.8 g, 78% of theory.

A foamed product is obtained with an Rf of 0.23 using silica gel and a 49: 1 mixture of methyl chloride and ethanol.

Example 5

4- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid,

2.0 g, 3.56 mmol of 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazole-1) tert-butyl ester -yl (methyl) biphenyl-2-carboxylic acid, 16 ml, 40 mmol of formamide and 40 ml of liquid ammonia were heated in a bomb at 200 ° C for 14 hours. After cooling, the reaction mixture is diluted with water, and the precipitate formed is suction filtered.

The filtrate is adjusted to pH 6 by the addition of glacial acetic acid, the precipitate formed is collected by centrifugation and washed with water. Dissolve the residue in 50 ml of N hydrochloric acid. The pH is adjusted to 6 by addition of concentrated ammonia, the precipitate formed is suction filtered, washed with water and dried.

Yield: 1.3 g, 72% of theory.

Melting point:> 235 ° C with decomposition.

Example 6

4- [2-n-propyl-4-methyl-6- (1,3-dimethyl-5,6,7,8-tetrahydro-benzimidazolium) -idyl] -1H-benzimidazol-1-yl (methyl) biphenyl-2-carboxylic acid sulfoxide, 570 mg, 4.0, are added at a temperature of potassium tert-butoxide

0.85 g, 1.7 mmol of 4- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] acid methyl / biphenyl-2-carboxylic acid is dissolved in 9 ml of dimethyl 5 ° C, 420 mg, 3.7 mmol are added and the mixture is stirred for 10 minutes. Methyl iodide (mmol) was then added and the reaction mixture was heated at 70 ° C for 25 min. After cooling, the mixture is poured into ice pulp, the precipitate formed is suction filtered and washed with water. The residue is dissolved in 50 ml of ethanol, 12 ml of 1N sodium hydroxide is added and the mixture is stirred at room temperature for 5 days. The solvent was evaporated in vacuo, ice was added to the residue and the mixture was acidified with 5% aqueous citric acid. The precipitate formed is filtered off with suction, washed with water and dried.

Yield: 470 mg, 42% of theory. Mp .: 240-242 ° C dec.

H, 5.65; N, 8.48 ^. Found: C, 61.69; H, 5.88; N, 8.72.

Example 7

4- [2-n-Propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl- hydrate 2-carboxylic acid

The title compound was obtained in a similar manner to the product of Example 5 using 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazole tert-butyl ester) 1-yl / methyl / biphenyl-2-carboxylic acid and a mixture of N-methylformamide and methylamine.

Yield: 27% ‘of the theoretical amount.

Mp: 183-186 ° C.

Analysis for C33H34N4O2 x H ₂ 0 (536.68) calculated C 73.85, H 6.76, N 10.44% Found C 74.22, H 6.97, N 10.48%.

Example 8

- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- (1H-tetrazole-5) yl) bifenylhemihydrát

a) 4- [2-n-Propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- (1- triphenylmethyl-tetrazol-5-yl) biphenyl

This product was obtained by the method of Example 4b using 2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazole and 4-bromomethyl-2- (1 triphenylmethyltetrazol-5-yl) biphenyl. It is an oily substance.

Rf 0.67 using silica gel and ethyl acetate.

b) 4- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- (1H-tetrazole- 5-yl) bifenylhernihydrát

The resulting product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -4-benzimidazol-1-yl) methyl 2- (1-triphenylmethyltetrazol-5-yl) biphenyl and a mixture of formamide and ammonia.

Yield: 70% of theory.

Melting point: above 230 DEG. Analysis for ^C 32 ^H 32 ^N 8 x 0.5 H ₂ 0 (537, , 68) calculated C 71.48, H 6.19, N 20.84 % found C 71.43, H 6.46, N 21.20 %.

Example 9

- [2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- (1H) tetrazol-5-yl) bifenylhemihydrát

Λ

The resulting product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -4-benzimidazol-1-yl) methyl 2- (1-triphenylmethyltetrazol-5-yl) biphenyl and a mixture of N-methylformamide and methylamine.

yield

Temperature of theoretical quantity.

Melting point: above 240 ° C with decomposition.

Analysis calculated for the found ^C 33 ^H 34 ^N 8 C 71.84, C 71.63, x 0.5 H ₂ 0 (551.71)

H 6.40, N 20.31%

H, 6.45; N, 20.64%.

Example 10

4- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid,

1.2 g, 24 mmol of 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid is dissolved in 25 ml of methylene chloride, 8.5 ml of trifluoroacetic acid is added and the mixture is stirred at room temperature for 3 hours. Thereafter, the solvent was evaporated in vacuo, the residue was mixed with ice grit, and the mixture was basified with concentrated ammonia. After an hour of standing, the pH is adjusted to 5 by the addition of citric acid. The resulting precipitate is filtered off with suction, washed with water and dried. The crude product obtained is purified by chromatography on silica gel with a particle size of 0.032-0.063 nm, eluting with ethyl acetate. The fractions containing the product were combined and evaporated.

Yield: 33% of theory.

Melting point: 229-232 ° C with decomposition.

^C 32 ^H 31 ^N 3 ° 3 (505.62)

Mass Spectrum: M ⁺ = 505.

Example 11

- [2-ethyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- (1H-tetrazole) 5-yl) bifenylhemihydrát

(a) 2-ethyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazole

The product was obtained according to the method of Example 4a) from 2-ethyl-4-methyl-6-aminocarbonyl-1H-benzimidazole and 2-chlorocyclohexane.

Yield: 60% of theory.

It is an oil, Rf = 0.17 using silica gel and ethyl acetate.

b) 4- [2-ethyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- (1-triphenylmethylterazole); 5-yl) biphenyl

The product is obtained by the method of Example 4b) with ingestion

2-ethyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazole and 4-bromomethyl-2- (1-triphenylmethyltetrazol-5-yl) biphenyl.

Yield: 63% of theory.

It is an oil, Rf = 0.69 using silica gel and ethyl acetate.

c) 4- [2-ethyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- ( 1 H-tetrazol-5-yl) bifenylhydrát

The product was obtained in a similar manner to Example 5 using 4- (2-ethyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazol-1-yl) methyl 2- (2-triphenylmethyltetrazol-5-yl) biphenyl and a mixture of N-methylformamide and methylamine.

Yield: 51% of theory.

Melting point: above 180 ° C with decomposition.

Analysis for £ 32 ^ 32 ^ 8 ^x b ₂ 0 (546.69) calculated C 70.31, H 6.27, N 20.50% Found C, 70.07; H, 6.55; N, 20.60%.

Mass Spectrum: M ⁺ = 528.

Example 12

4- [2-Ethyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid hydrate

a) 4- (2-Ethyl-4-methyl-6- (5,6,7,8-tetrahydro-benzoxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2-carboxylic acid tert-butyl ester

The product was obtained according to the method of example 4b) using 4-bromomethyl-biphenyl-2-carboxylic acid tert-butyl ester and 2-ethyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) - 1H-benzimidazole.

Yield: 77% of theory.

Melting point: 160-162 ° C.

b) 4- [2-Ethyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl- 2-carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-ethyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester. methyl / biphenyl-2-carboxylic acid and mixtures of N-methylformamide and methylamine.

Yield: 34% of theory. Mp .: 292-300 ° C with decomposition. Analysis for ύ ₃₂ Η32 4θ2 ^ ^x ^ 2θ (522.66) calculated C 73.54, H 6.56, N 10.72 Found C 73.38, H 6.76, N 10.67

Mass Spectrum:

504th

Example 13

4- [2-Ethyl-4-methyl-6- (1-phenyl-5,6,7,8-tetrahydrobenzimidazol-1-yl) -1H-benzimidazol-1-yl] methyl] -biphenyl-2 hydrate carboxylate

The product was obtained according to the method of Example 5 using 4- [2-ethyl-4-methyl-6- (5,6,7,8-tetrahydro-benzothiazol-2-yl) -1H-benzimidazol-1-yl] tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-formylanilide and aniline.

Yield: 13% of theory.

Melting point: 255-257 ° C with decomposition.

Analysis for C37H34N4O2 x H ₂ 0 (584.73) calculated C 76.00, H 6.20, N 9.58% found C 76.36, H 6.18, N 9.59%.

Mass Spectrum: M ⁺ = 566.

Example 14

4- [2-n-Propyl-4-methyl-6- (1-phenyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl- hemihydrate 2-carboxylic acid

The product was obtained according to the method of Example 5 using 4- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydro-benzoxazol-2-yl) -1H-benzimidazol-1-yl] tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-formylanilide and aniline

Yield: 23% of theory.

Melting point: 258-260 ° C with decomposition.

Analysis for C ^ g ^ GH ^ C x H ₂ 0 (589.75) calculated C 77.39, H 6.32, N 9.50 Found C 77.03, H 6.30, N 9.39% .

Mass Spectrum: M ⁺ = 580.

Example 15

4- [2-n-propyl-4-methyl-6- (1-benzyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -4-benzimidazol-1-yl] methyl] biphenyl- 2-carboxylic acid.

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydro-benzoxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-benzylformamide and benzylamine.

Yield: 54% of theory.

Melting point: 256-258 ° C with decomposition.

Analysis for C ^ C ^ ghjg x H ₂ 0 requires C 78.76, H 6.44, found C 78.50, H 6.49, (594.77): N 9.42% N 9.35%.

Mass Spectrum: M ⁺ = 594.

Example 16

4- [2-n-Propyl-4-methyl-6- (1-ethyl-5,6) -acetic acid sesquihydrate,

7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (5,6,7,857 tetrahydrobenzoxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester. methyl / biphenyl-2-carboxylic acid; and a mixture of N-ethylformamide and ethylamine.

Yield: 17% of theory.

Melting point: above 228 ° C with decomposition.

Analysis for C34 ^H 36 ^N 4 ° 2 ^x - ^{1 '5} ° ^H 2 (559.71) calculated C 72.96, H 7.02, N 10.01% found C 73.04, H 6.90, N 9.77%

Mass Spectrum: M ⁺ = 532.

Example 17

4- [2-Ethyl-4-methyl-6- (1-benzyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl-2 acid carboxylic acid.

The product was obtained according to the method of Example 5 using 4- (2-ethyl-4-methyl-6- (5,6,7,8-tetrahydro-benzoxazol-2-yl) -1H-benzimidazol-1-yl) -methyl / tert-butyl ester biphenyl-2-carboxylic acid and a mixture of N-isopropylformamide and isopropylamine.

Yield: 2% of theory.

Melting point: 197 ° C.

^C 34 ^H 36 ^N 4 ° 2 (532.69)

Mass Spectrum: M ⁺ = 532.

Example 18

4- [2-n-propyl-4-methyl-6- (1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl- 2-carboxylic acid.

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydro-benzoxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of isobutylamine and water.

Yield: 5% of theory.

^c 36 ^H 40 ^N 4 ° 2 (560.75)

Mass Spectrum: (M + H) ⁺ = 561.

Example 19

4- [2-n-Propyl-4-methyl-6- (1,3-dibenzyl-5,6,7,8-tetrahydrobenzimidazolium acetate-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl- 2-carboxylic acid

The product was obtained according to the method of Example 6 using 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2-carboxylic acid and a mixture of benzyl bromide, sodium hydroxide and glacial acetic acid.

Yield: 76% of theory.

Melting point: product sintered above 80 ° C.

Analysis for C ₄ gH ₄₄ N ₄ O 2 x V H COOH x 1.2 H2 O requires C 76.47, H 6.55, N 7.43% (753.95) náj Dené

C 76.46, H 6.65, N 7.76

Mass Spectrum: M ⁺ = 684.

Example 20

4- [2-n-Propyl-4-methyl-6- (1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] -methyl] biphenyl hemihydrate 2-carboxylic acid.

The product was obtained according to the method of Example 6 using 4- [2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid and a mixture of ethyl bromoacetate and sodium hydroxide.

Yield: 34% of theory.

Mp: 239-242 ° C.

For C34H34N4O4 (571.69) calculated C 71.43, found C 71.39,

Mass Spectrum: M ⁺

Example 21

H 6.17, N 9.80% H 6.19, N 9.81% = 562.

4- [2-Cyclopropyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid hemihydrate

The product was obtained in an analogous manner to Example 5 using 4- (2-cyclopropyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benzimidazole) tert-butyl ester. 1-yl (methyl) biphenyl-2-carboxylic acid and a mixture of N-methylformamide and methylamine.

Yield: 50% of theory. Melting point: 285-289 ° C.

H, 6.33; NC, 75.24; H, 6.44, N. Analysis for the calculated found: ^C 33 ^H 32 ^N 4 ° 2 ^{x 1/2 H} 2 ° C

Mass Spectrum: M ⁺ - 516.

In an analogous manner, the following (525.66) 10.66% 10.42% examples can also be obtained as in the previous compounds:

1) 4/2-cyclopropyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydroberisimidazol-2-yl) -ΙΗ-benzimidazol-1-yl/ -methyl/-2-( 1H- tetrazol-5-yl) biphenyl,

2) 4- [2-ethoxy-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl- 2-carboxylic acid,

3) 4- [2-ethoxy-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- (1H- tetrazol-5-yl) biphenyl,

4) 4 H-2-ethyl-4-methyl-6- (1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl / methyl-2- (1H-tetrazole- 5-y1) biphenyl,

5) 4-n-Propyl-4-methyl-6- (1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid .

6) 4H-2-n-propyl-4-methyl-6- (1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl / methyl] -2- (lH-tetrazol-5-yl) biphenyl,

7) 4-ethyl-4-methyl-6- (1-isobutyl-5,6,7,8-tetrahydro-benzimidazol-2-yl) -1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid .

8) 4H-2-ethyl-4-methyl-6- (1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl / methyl] -2- (1H) tetrazol-5-yl) biphenyl,

9) 4H-2-n-propyl-4-methyl-6- (1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl / methyl] -2- (1 H-tetrazol-5-yl) biphenyl,

10) 4-n-propyl-4-methyl-6- (1-carboxymethyl-5,6,7,8-tetrahydro-61-benzimidazol-2-yl) -1H-benzimidazol-1-yl / methyl-2 (1H- tetrazol-5-yl) biphenyl,

11) 4 H-2-n-propyl-4-methyl-6- (1-methyl-4,5-trimethylenimidazol-2-yl) -1 H -benzoimidazol-1-yl / methyl / biphenyl-2-carboxylic acid;

12) 4 H-2-n-propyl-4-methyl-6- (1-methyl-4,5-trimethyleninidazol-2-yl) -1H-benzimidazol-yl / methyl] -2- (1H-tetrazole-5) yl) biphenyl.

Example 22

4 // 2-ethyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -1 H-benzimidazol-l-yl / methyl / 2- (lH-tetrazol-5-yl ) biphenyl

The product was obtained according to the method of Example 10 using 4 H-2-ethyl-4-methyl-6- (5,6,7,8-tetrahydro-benzoxazol-2-yl) -1 H -benzoimidazol-1-yl / methyl / -2 - (1-triphenylmethyltetrazol-5-yl) biphenyl and hydrochloric acid in methanol.

Yield: 15% of theory.

Melting point: 140-142 ° C with decomposition.

^C 31 ^H 29 ^N 7 ° (515.63)

Mass Spectrum: (M + H) ⁺ = 516.

Example 23 // 2-Ethyl-4-methyl-6- (1-ethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl / methyl] -2- (1H- tetrazol-5-yl) bifenylhydrát

The product was obtained according to the method of Example 5 using 4 H-2-ethyl-4-methyl-6 - (- 5,6,7,8-tetrahydrobenzoxazol-2-yl) -1 H -benzimidazol-1-yl (methyl) - 2- (2-triphenylmethyltetrazol-5-yl) biphenyl and a mixture of N-ethylformamide and ethylamine.

Yield: 25% of theory. Melting point: above 180 ° C with decomposition.

Analysis for ^C 33 ^H 34 ^N 7 x H ₂ 0 (560.72) calculated C 70.68, H 6.47, N 19.99 % found C 70.46, H 6.44, N 19.56 %

Mass spectrum:

Example 24

M = 542.

4 H-2-n-Propyl-4-methyl-6- (4,4-dimethyloxazolin-2-yl) -1 H -benzoimidazol-1-yl / methyl] biphenyl-2-carboxylic acid di-trifluoroacetate

The product was obtained according to the method of Example 10 using 4 H-2-n-propyl-4-methyl-6- (4,4-dimethyloxazolin-2-yl) -1 H -benzoimidazol-1-yl (methyl) tert-butyl ester biphenyl-2-carboxylic acid and trifluoroacetic acid.

Yield: 60% of theory. Melting point: 158-159 ° C.

Analysis for calculated found

30 ^H 31 ^N 3 ° 3 57.55, H 57.76, H x 2 CF ₃ COOH (709.64) 4.69, N 5.92%

4.72, N 6.02%.

Mass spectrum

Example 25

4- [2-n-Propyl-4-methyl-6- (1,5-dimethyl-4-phenylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid hydrate

a) 4/2-n-Propyl-4-methyl-6- [N (1-benzoylethyl) methylaminocarbonyl] -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid tert-butyl ester

To a solution of tert-butyl [2-n-propyl-4-methyl-6-chlorocarbonyl-1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid tert-butyl ester in 20 ml of methylene chloride was added 20 ml of toluene and 0.504 g, 2.2 mmol of 2-methylaminopropiophenone are added. The reaction mixture is heated to 85 ° C and 10 ml of pyridine are added dropwise over 4 hours at this temperature. Then, the reaction mixture is evaporated, the residue is mixed with a mixture of water and ice and the resulting mixture is extracted twice with methylene chloride. The organic phases are combined, dried over magnesium sulphate and evaporated. The crude product is purified by chromatography on silica gel with a particle size of 0.032-0.063 mm, eluting first with methylene chloride and then with a mixture of methylene chloride, ethanol and ammonia in a ratio of initially 50: 1: 0.25 and then 25: 1: 0.01. The appropriate fractions were combined and evaporated.

Yield: 1.0 g, 79% of theory.

The product was in the form of a foam, Rf = 0.50, using methylene chloride / ethanol 9: 1 silica gel.

b) 4/2-n-Propyl-4-methyl-6- (1,5-dimethyl-4-phenylimidazol-2-yl) -1H-benzimidazol-1-yl / methyl / biphenyl-2 tert-butyl ester carboxylate

Toluene 1.0 g, 1.5 mmol of tert-butyl 4 H-2-n-propyl-4-methyl-6- [N- (1-benzoylethyl) methylaminocarbonyl] -1H-benzimidazol-1-yl] methyl of biphenyl-2-carboxylic acid and 15 g of ammonium acetate in 80 ml of glacial acetic acid are heated at reflux for 2.5 hours. Then, the reaction mixture is evaporated to half its volume and the concentrated residue is mixed with a mixture of water and ice, and the resulting mixture is extracted twice with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulphate and evaporated. The crude product obtained is chromatographed on silica gel with a particle size of 0.032-0.063 mm, eluting with methylene chloride with an increasing amount of ethanol, initially 3%, then 10% and finally 20%. The appropriate fractions were combined and evaporated.

Yield: 0.68 g, 74% of theory.

The product is in the form of a foam, = 0.40 using silica gel and a 19: 1 mixture of methylene chloride and ethanol.

c) 4/2-n-Propyl-4-methyl-6- (1,5-dimethyl-4-phenylimidazol-2-yl) -1H-benzimidazol-1-ylmethyl / biphenyl-2-carboxylic acid hydrate

The product was obtained in an analogous manner to Example 10 using 4/2-n-propyl-4-methyl-6- (1,5-dimethyl-4-phenylimidazol-2-yl) methyl / biphenyl-2 tert-butyl ester -carboxylic acid and trifluoroacetic acid.

Yield: 90% of theory. Melting point: above 152 ° C with decomposition.

Analysis calculated for the found ^C 36 ^H 33 ^N 4 ° 2 C 75.50, HC 75.95, H x H ₂ 0 (572.72) 6.34, N 9.78% 6.48, N 9.92 %.

Mass Spectrum: M ⁺ = 554.

Example 26

4/2-n-Propyl-4-methyl-6- (1-methyl-4,5-diphenylimidazol-2-yl) -1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid sesquihydrate

a) 4/2-n-Propyl-4-methyl-6- (1-methyl-4,5-diphenylimidazol-2-yl) -1H-benzimidazol-1-yl (methyl) biphenyl-2-tert-butyl ester carboxylate

The product was obtained according to the method of Example 25b) using 4/2-n-propyl-4-methyl-6- [N- (1-benzoylbenzyl) methylaminocarbonyl] -1H-benzimidazol-1-yl / methyl / biphenyl tert-butyl ester -2-carboxylic acid and ammonium acetate in glacial acetic acid.

yield; 27% of the theoretical quantity.

It is an oil, 0.40, using silica gel and a 19: 1 mixture of methylene chloride and ethanol.

b) 4/2-n-Propyl-4-methyl-6- (1-methyl-1,4,5-diphenylimidazol-2-yl) -1H-benzimidazol-1-yl / methyl / biphenyl-2- carboxylic acid

The product was obtained by the method of Example 10 using 4H-2-n-propyl-4-methyl-6- (1-methyl-4,5-diphenylimidazol-2-yl) -1H-benzimidazole-1- tert -butyl ester yl (methyl) biphenyl-2-carboxylic acid and trifluoroacetic acid.

Yield: 60% of theory.

Melting point: 325 to 328 ° C with decomposition.

Analysis Calculated for ^C náj Dené 41 ^H 36 ^N 4 ° 2 ^{x 1 »5} C 76.49, H 6.11, C 76.53, H 6.15;

H ₂ 0 (643.79)

N 8.70%

N, 8.75%.

Mass spectrum: M ⁺ = 616.

Example 27

4- [2-n-Propyl-4-methyl-6- (5-methyl-4-isopropylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid dihydrate acetate

a) 4/2-n-Propyl-4-methyl-6- (1-methyl-6- (5-methyl-4-isopropylimidazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) bipheyl-2-carboxylic acid

The product was obtained according to the method of Example 25b using 4 H-2-n-propyl-4-methyl-6- (N 1 -acetyl-2-methyl-n-propyl) methylaminocarbonyl / -1 H -benzoimidazole-1- tert -butyl ester yl (methyl) biphenyl-2-carboxylic acid and ammonium acetate in glacial acetic acid.

Yield: 45% of theory.

It is an oil with an Rf of 0.10 using silica gel and a 2: 1 mixture of ethyl acetate and petroleum ether.

b) 4/2-n-Propyl-4-methyl-6- (5-methyl-4-isopropylimidazol-2-yl) -1H-benzimidazol-1-ylmethyl / biphenyl-2-carboxylic acid dihydrate acetate

The product was obtained according to the method of Example 10 using 4 H-2-n-propyl-4-methyl-6- (5-methyl-4-isopropylimidazol-2-yl) -4-benzimidazol-1-yl tert-butyl ester. methyl / biphenyl-2-carboxylic acid and trifluoroacetic acid.

Yield: 75% of theory.

Melting point: above 155 ° C with decomposition.

Analysis for C32H34N4O2 x CH COOH x 2 H ₂ 0 (602.74) calculated C 67.75, H 7.02, N 9.30% found C 67.69, H 7.02, N 9.53%.

Mass Spectrum: M ⁺ =

506th

Example 28 4- (2-n-Propyl-4-methyl-6- (4-methylimidazolin-2-yl) -1H-benzimidazol-1-yl) methylbiphenyl-2-carboxylic acid di-trifluoroacetate

a) 4- (2-n-Propyl-4-methyl-6- (4-methylimidazolin-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2-carboxylic acid tert-butyl ester

A mixture of 0.43 g, 0.8 mmol of 4- (2-n-propyl-4-methyl-6- (4,4-dimethyloxazolin-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester of methyl / biphenyl-2-carboxylic acid and 0.67 ml, 5.8 mmol of 1,2-diaminopropane are heated at 120 ° C for 48 hours. The yellow solid obtained by cooling the mixture to room temperature was stirred with water for one hour, then filtered with suction and dried. This crude product is then chromatographed on silica gel with a particle size of 0.032-0.063 mm, eluting with a mixture of methyl chloride, ethanol and ammonia at a ratio of 50: 1: 0.05, then 20: 1:

0.02 and finally 7: 1: 0.07. The individual fractions were combined and evaporated.

Yield: 0.26g, 62% of theory.

It is a foam with an Rf of 0.20 using silica gel and a 9: 1 mixture of methylene chloride and ethanol with ammonia.

b) 4- [2-n-propyl-4-methyl-6- (4-methylimidazolin-2-yl) -1H-benzimidazol-1-yl] methylbiphenyl-2-carboxylic acid di-trifluoroacetate

The product was obtained according to the method of Example 10 using 4- (2-n-propyl-4-methyl-6- (4-methylimidazolin-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and trifluoroacetic acid.

Yield: 72% of theory.

Melting point: 115-180 ° C with decomposition, sintered from 100 ° C.

H, 4.64; N, 8.07%. Found: C, 57.02; H, 5.02; N, 8.13%. C29H30N4O2 * 2 CF3COOH (694.63) requires C, 57.06;

Mass Spectrum: M ⁺ = 466.

Example 29

4- [2-n-Propyl-4-methyl-6- (4-isopropyl-5-methyl-oxazol-2-yl) -4-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

3.9 g, 6.7 mmol of 4- [2-n-propyl-4-methyl-6- [N- (1-acetyl-2-methyl-n-propyl) aminocarbonyl] -1H-benzimidazole tert-butyl ester The 1-yl (methyl) biphenyl-2-carboxylic acid was dissolved in 50 ml of phosphorus oxychloride and stirred at 105 ° C for 2.5 hours. The phosphorus oxychloride is then evaporated, the residue is mixed with water at 80 ° C and, after cooling, concentrated ammonia is added. The pH is adjusted to 5 by the addition of glacial acetic acid, the precipitate formed is suction filtered, washed with water, dissolved in a 9: 1 mixture of methylene chloride and methanol and dried over magnesium sulphate. The crude product was chromatographed on silica gel with a particle size of 0.032-0.063 mm, eluting with a 1: 1 mixture of petroleum ether, ethyl acetate and glacial acetic acid. 0.002 and then a 20: 1 mixture of methyl chloride, ethanol and glacial acetic acid:

0,002. The appropriate fractions were combined and evaporated, the residue was triturated with ether and the solution was suction filtered.

Yield: 2.4 g, 71% of theory.

M.p .: 222-223 ° C.

Analysis for calculated found

32 ^H 33 ^N 3 ° 3 75.71, H 75.61, H (507.64)

6.55, N 8.28% 6.59, N 8.36%.

Mass Spectrum: M ⁺ = 507.

Example 30

4- [2-n-Propyl-4-methyl-6- (4-isopropyl-1,5-dimethylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid x 1 , 25 water

The product was obtained by the method of Example 5 using 4- [2-n-propyl-4-methyl-6- (4-isopropyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl] tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-methylformamide and methylamine.

Yield: 38% of theory.

Melting point: above 150 ° C with decomposition.

Analysis of the x 1.25 H ₂ 0 (543.20) calculated C 72.97, H 7.14, N 10.32% Found C 72.95, H 7.02, N 9.94%.

Mass Spectrum: M ⁺ = 520.

Example 31

The

4- [2-n-Propyl-4-methyl-6- (1-ethyl-4-isopropyl-5-methylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxy acid Lova

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isopropyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-methylformamide and ethylamine.

Example 32

4- [2-n-Propyl-4-methyl-6- (1-isopropyl-4-isopropyl-5-methylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid

The product was obtained by the method of Example 5 using 4- [2-n-propyl-4-methyl-6- (4-isopropyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-isopropylformamide and isopropylamine.

Example 33

4- [2-n-Propyl-4-methyl-6- (1-cyclohexyl-4-isopropyl-5-methylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid

The product was obtained by the method of Example 5 using 4- [2-n-propyl-4-methyl-6- (4-isopropyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-cyclohexylformamide and cyclohexylamine.

Yield: 10% of theory.

Formula C 58 H 55 N 2 O 5 (588.80) = 0.24 using silica gel and methylene chloride / ethanol / acetic acid 9: 1: 0.01

Mass Spectrum: (M + H) ⁺ = 589.

Example 34

4- [2-n-Propyl-4-methyl-6- [1 - [(2-dimethylaminoethyl) -4-isopropyl-5-methylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl hemihydrate biphenyl-2-carboxylic acid

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isopropyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N- (2-dimethylaminoethyl) formamide and 2-dimethylaminoethylamine.

Yield: 48% of theory.

Mp .: 192-195 ° C.

Analysis for C36H43N5O2 x 0.5 H ₂ 0 (586.79) calculated C 73.69, H 7.56, N 11.93% Found C 73.53, H 7.55, N 11.94%.

Mass Spectrum: M ⁺ = 577.

Example 35

4- [2-n-Propyl-4-methyl-6- (1,5-dimethyl-4-isobutylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid x 0 , 75 water

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-methylformamide and methylamine.

Yield: 64% of theory.

M.p .: 155-197 ° C.

Analysis calculated for the found ^C 34 ^H 38 ^N 4 ° 2 C 74.49, HC 74.45, H x 0.75 H ₂ 0 (548.22)

7.28, N 10.22%

7.29, N 10.35%.

Mass Spectrum: M

534th

Example 36

4- [2-n-Propyl-4-methyl-6- (1-ethyl-4-isobutyl-5-methylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid x 0.25 water

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-ethylformamide and ethylamine.

Yield: 62%.

Mp: 239-241 ° C.

Analysis for C33H35N3O3 x 0.25 H ₂ 0 (526.17) calculated C 75.33, H 6.80, N 7.29% Found C 75.35, H 6.75, N 7.96%.

Mass Spectrum: M ⁺ = 527.

Example 37

4- [2-n-propyl-4-methyl-6- (1-tert-butyl-4-isobutyl-5-methylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2 acid carboxylic acid

The product was obtained according to the method of Example 5 using 4- [2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazole-1] tert-butyl ester. - (methyl) biphenyl-2-carboxylic acid and a mixture of N-tert-butylformamide and tert-butyl amine.

Example 38

4- [2-n-Propyl-4-methyl-6- (1-benzyl-4-isobutyl-5-methylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isobutyl-5-methyloxazol-2-yl) -1H-benzimidazole-1-) tert-butyl ester and methyl-biphenyl-2-carboxylic acid and a mixture of N-benzylformamide and benzylamine.

Example 39

4- [2-n-propyl-4-methyl-6- [1- (2-morpholinoethyl) -4-isobutyl-5-methylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl / biphenyl-2 acid carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N- (2-morpholinoethyl) formamide and 2-morpholinoethylamine.

Yield: 30% of theory.

Melting point: 201-203 ° C with decomposition.

H, 7.47; N, 11.05%. Found: C, 73.65; H, 7.45; N, 11.07.

Mass Spectrum: M ⁺ =

633rd

Example 40

4- [2-n-Propyl-4-methyl-6- [1- (2-methoxyethyl) -4-isobutyl-5-methylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl] hydrate biphenyl-2-carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) bifea of 2-methoxyethylamine.

Yield: 29% of theory.

Melting point: 135-137 ° C with decomposition, sintering from 110 ° C

Analysis for £ 3584 ^ 403 x H ₂ 0 (596.78) calculated C 72.46, H 7.43, N 7.43% Found C 72.50, H 7.45, N 9.77%.

Mass Spectrum: M ⁺ = 578.

Example 41

4- [2-n-Propyl-4-methyl-6- [1- (2-hydroxyethyl) -4-isobutyl-5-methylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl / biphenyl-2 acid carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) (methyl) biphenyl-2-carboxylic acid and a mixture of N- (2-hydroxyethyl) formamide and 2-hydroxyethylamine.

Example 42

4- [2-n-propyl-4-methyl-6- [1- (3-dimethylaminopropyl) -4-isobutyl-5-methylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl] - biphenyl-2-carboxylic acid

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N- (3-dimethylaminopropyl) formamide and 3-dimethylaminopropylamine.

Example 43

4- [2-n-Propyl-4-methyl-6- (1-carboxymethyl-4-isobutyl-5-methylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl-2- carboxylic acid

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of N-formylglycine ethyl ester and glycine ethyl ester.

Example 44

4- [2-n-Propyl-4-methyl-6- (1-aminocarbonylmethyl-4-isobutyl-5-methylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl-2- carboxylic acid

The product was obtained according to the method of Example 5 using 4- [2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazole-1- tert -butyl ester yl / methyl) biphenyl-2-carboxylic acid and a mixture of N-formylglycine and glycine.

Example 45

4- [2-n-Propyl-4-methyl-6- [1- (2-carboxyethyl) -4-isobutyl-5-methylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl] - biphenyl-2-carboxylic acid

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4-isobutyl-5-methyl-oxazol-2-yl) -1H-benzimidazol-1-yl) tert-butyl ester (methyl) biphenyl-2-carboxylic acid and a mixture of ethyl ester

3-formylaminopropionic acid and ethyl 3-aminopropionate.

The following resultant compounds can also be prepared in an analogous manner:

- // 2-n-propyl-4-methyl-6- (1,5-dimethyl-4-isobutylimidazo-2-yl) -lH-benzimidazol-Ι-yl / methyl / - (1H-tetrazol-5-yl ) biphenyl,

- // 2-n-propyl-4-methyl-6- (1-n-propy1-4-isobutyl-5-methyl-imidazol-2-yl) -1 H-benzimidazol-1-yl / methyl / - (1 H-tetrazol 5-yl) biphenyl,

- [2-n-propyl-4-methyl-6- [1- (2-dimethylaminoethyl) -4-isobutyl-5-methylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl] - (1H) tetrazol-5-yl) biphenyl.

Example 46

4- [2-n-Propyl-4-methyl-6- (4-methylimidazol-2-yl) -1H-benzimidazol-4-yl] biphenyl-2-carboxylic acid methyl ester.

A solution of 0.35, 0.7 mmol of methyl 4- (2-n-propyl-4-methyl-6- (4-methylimidazolin-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2 of carboxylic acid in 10 ml of toluene was heated to reflux with 0.16 g of palladium (10% palladium on charcoal) under a nitrogen atmosphere for 66 hours. The toluene is evaporated, the residue is dissolved in methyl chloride, the solution is filtered and the filtrate is evaporated. The crude product is chromatographed on silica gel with a particle size of 0.032-0.063 mm, eluting first with methyl chloride and then with a mixture of methylene chloride, ethanol and ammonia in successive 50: 1: 0.05, 20: 1: 0.02, 10: 1: 0.01 and 5: 1: 0.005. The appropriate fractions were combined and evaporated.

Yield: 0.30 g, 9% of theory.

Mass Spectrum: M ⁺ = 478.

Example 47

4- (2-n-Propyl-4-methyl-6- (1,4,5-trimethylimidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2-carboxylic acid x 0.25 H ₂ 0

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-dimethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of N-methylformamide and methylamine.

Yield: 61% of theory.

Melting point: 217-219 ° C with decomposition.

Analysis for C 32 ^ 3 ^ 02 ^x θ '25 _H2 0 (497.13) calculated C 74.90, H 6.59, N 11.27% Found C 74.84, H 6.58, N 11, 26%.

Mass Spectrum: M ⁺ =

429th

Example 48

4- [2-n-propyl-4-methyl-6- (1-ethyl-4,5-dimethylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-dimethyl-oxazol-2-yl) -1H-benzimidazol-1-yl) -methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of N-ethylformamide and ethylamine.

Example 49

- // 2-n-propyl-4-mety1-6- (1-methyl-4,5-dietylimidazol-2-yl) -1 H-benzimidazol-1-yl / methyl / 2- (lH-tetrazol-5 yl) biphenyl

The product was obtained according to the method of Example 5 with 4- (2'-propyl-4-methyl-6- (4,5-diethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl] -2- (2- triphenylmethyltetrazol-5-yl) biphenyl and a mixture of N-methylformamide and methylamine.

Example 50

- // 2-n-propyl-4-methyl-6- (1-ethyl-4,5-dimethyl-imidazol-2-yl) -1 H-benzimidazol-1-yl / methyl / 2- (lH-tetrazol-5 yl) biphenyl

The product was obtained according to the method of Example 5 with 4- (2-n-propyl-4-methyl-6- (4,5-diethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl] -2- (2- triphenylmethyltetrazol-5-yl) biphenyl and a mixture of N-ethylformamide and ethylamine.

Example 51

4- [2-n-Propyl-4-methyl-6- (1-isopropyl-4,5-dimethylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-dimethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl tert-butyl ester biphenyl-2-carboxylic acid; and a mixture of N-isopropylformamide and isopropylamine.

Example 52

4- [2-n-Propyl-4-methyl-6- [1- (2-dimethylaminoethyl) -4,5-dimethylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl / biphenyl -2 carboxylic acid

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-dimethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of N- (2-dimethylaminoethyl) formamide and 2-dimethylaminoethylamine.

Example 53

4- [2-n-Propyl-4-methyl-6- [1- (2-morpholinoethyl) -4,5-dimethylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl / biphenyl-2- carboxylic acid

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-dimethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of N- (2-morpholinoethyl) formamide and 2-morpholinoethylamine.

Example 54

- // 2-n-propyl-4-methyl-6- (1- (2-morpholinoethyl) -4,5-dimethyl-imidazol-2-yl) -lH-benzimidazol-1-yl / methyl / 2- (IH-tetrazol 5-yl) biphenyl

The product was obtained according to the method of Example 5 with 4- (2-n-propyl-4-methyl-6- (4,5-diethoxyoxazol-2-yl) -1H-benzimidazol-1-yl) methyl] -2- (2- triphenylmethyltetrazol-5-yl) biphenyl; and a mixture of N- (2-morpholinoethyl) formamide and morpholinoethylamine.

Example 55

4- [2-n-Propyl-4-methyl-6- [1- (2-methoxyethyl) -4,5-dimethylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-dimethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of N- (2-methoxyethyl) formamide and 2-methoxyethylamine.

Example 56

- // 2-n-propyl-4-methyl-6- / 1- (2-methoxyethyl) -4,5-dimety1imidazol-2-yl) -1 H-benzimidazol-1-yl / methyl / -2 (H tetrazol-5-yl) biphenyl

The product was obtained according to the method of Example 5 with 4- (2-n-propyl-4-methyl-6- (4,5-dimethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl] -2- (2- triphenylmethyltetrazol-5-yl) biphenyl; and a mixture of N- (2-methoxyethyl) formamide and 2-methoxyethylamine.

Example 57

4- [2-n-propyl-4-methyl-6- [1- (2-carboxyethyl) -4,5-dimethylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl] -2-biphenyl- carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-dimethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of ethyl N-formyl-3-aminopropionate and ethyl 3-aminopropionate.

Example 58

4- [2-n-Propyl-4-methyl-6- (1-methyl-4,5-diethylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid x 0 ., 25 H ₂ 0

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-diethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of N-methylformamide and methylamine.

Yield: 65% of theory.

Melting point: 247-249 ° C with decomposition.

Analysis of the x 0.25 H ₂ 0 (526.18) calculated C 75.47, H 7.01, N 10.67% Found C 75.43, H 7.11, N 10.68%.

Mass Spectrum: M ⁺ =

520th

Example 59

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

The product is obtained by heating tert-butyl 4- [2-n-propyl-4-methyl-6- [2- (2-methylamino) ethylaminocarbonyl] -4-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid tert-butyl ester in phosphorus oxychloride followed by isolation of the product by the method of Example 10.

Yield: 30% of theory.

Formula C29H3QN4O2 (466.59)

Rf = 0.50 using 2: 1: 0.02 methylene chloride, methanol and acetic acid

Mass Spec: (M + H) ⁺ = 467.

Example 60

4- [2-n-Propyl-4-methyl-6- [1- (2-dimethylaminoethyl) -4,5-diethylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl / biphenyl-2 dihydrate carboxylate

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-diethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of N- (2-dimethylaminoethyl) formamide and 2-dimethyl aminoethylamine.

Yield: 14% of theory.

Melting point: &gt; 210 ° C with decomposition.

Analysis for 3 x 2 HCl x H ₂ 0 (723.21) calculated C 59.79, H 6.97, N 9.69, Cl 14.71% Found C 59.28, H 6.92, N 9, 75 Cl 14.26%.

Mass Spectrum: M ⁺ = 577.

Example 61

4- [2-n-Propyl-4-methyl-6- [1- (2-morpholinoethyl) -4,5-diethylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl / biphenyl-2-acid carboxylic acid

The product was obtained by the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-diethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of N- (2-morpholinoethyl) formamide and 2-morpholinoethylamine.

Yield: 41% of theory.

Melting point: &gt; 196 DEG C. with decomposition.

Formula C _3g H ₄₅ N ₅ O ₃

Example 62

4- [2-n-propyl-4-methyl-6- [1- (2-methoxyethyl) -4,5-diethylimidazol-2-yl] -1H-benzimidazol-1-yl] methyl] biphenyl-2 acid carboxylic acid

The product was obtained according to the method of Example 5 using 4- (2-n-propyl-4-methyl-6- (4,5-diethyloxazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl tert-butyl ester -2-carboxylic acid and a mixture of N- (2-methoxyethyl) formamide and 2-methoxyethylamine.

Example 63

4- [2-n-Propyl-4-methyl-6- (4,5-diethyloxazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid

The product was obtained according to the method of Example 29 using 4- (2-n-propyl-4-methyl-6- (N- (1-propionyl-n-propyl) aminocarbonyl) -1H-benzimidazol-1-yl) tert-butyl ester) methyl / biphenyl-2-carboxylic acid and phosphorus oxychloride.

Yield: 97% of theory. Melting point: 250-255 ° C. H, 6.55; N, 8.28. Found: C, 75.77; H, 6.59; N, 8.46.

Mass Spectrum: M ⁺ = 507.

Example 64

- // 2-n-propyl-4-methyl-6- (4,5-diéty1-1H-imidazol-2-yl) -1H-benzimidazol-1-yl / methyl / 2- (lH-tetrazol-5-yl ) biphenyl

The product was obtained by the method of Example 25b) using 4- [2-n-propyl-4-methyl-6- [N- (1-propionyl-n-propyl) aminocarbonyl] -1H-benzimidazol-1-yl] methyl 2- (2-triphenylmethyltetrazol-5-yl) biphenyl and a mixture of ammonium acetate and glacial acetic acid.

Yield: 27% of theory.

Melting point: 221-223 ° C.

Analysis calculated for ^C 32 ^H 34 ^N 8 C 70.05, found C 70.79,

Mass Spectrum: M ⁺

x h ₂ o (530.69) H 6.61; N 20.43% H 6.98. N 18.83%

= 530.

Example 65

4- [2-n-Propyl-4-methyl-6- (4,5-dimethyloxazol-2-yl) -1H-benzimidazol-1-yl] methyl / biphenyl-2-carboxylic acid

The product was obtained according to the method of Example 29 using 4- (2-n-propyl-4-methyl-6- [N- (lacetylethyl) aminocarbonyl) -1H-benzimidazol-1-yl] methyl / biphenyl- 2-carboxylic acid and phosphorus oxychloride.

Yield: 88% of theory.

Melting point: 259-260 ° C with decomposition.

Analysis calculated for the found ^C 29 ^H 3 ° 3 C 74.44, C 74.33, x 0.25 H ₂ 0 (484.09)

H 6.14, N 8.68%

H, 6.14; N, 8.69%.

Mass Spectrum: M ⁺ = 479.

Example 66

- [2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- (2 , 5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl

a) 4- [2-n-Propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2 - (hydroxycarbamimidoyl) biphenyl

To a solution of 8.4 g (0.12 mol) of hydroxylamine hydrochloride in ml of dimethyl sulfoxide was added dropwise 30 ml of a 30% solution of sodium ethoxide in methanol at room temperature. After a further 10 minutes, 4.5 g of 10 mmol of 4- [2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H] are added. -benzimidazol-1-yl / methyl) -2-cyanobiphenyl, the resulting suspension is then heated at 90 ° C for 12 hours. After cooling to room temperature, the reaction mixture is poured into 200 ml of a mixture of water and ice, the precipitate is filtered off with suction, washed with water, dissolved in methylene chloride and chromatographed on silica gel with a particle size of 0.023-0.063 mm. ethanol and concentrated ammonia successively in the ratio of 19: 1: 0.06, 19; 1: 0.08, 19: 1: 0.1 and 19: 1: 0.2. Appropriate fractions were combined, evaporated, triturated with ether and dried.

Yield: 1.2 g, 25% of theory.

Melting point: 221-224 ° C with decomposition.

b) 4- [2-n-propyl-4-methyl-6- (1-methyl-6- (1-methyl-5,6,7,8-tetrahydro-benzimidazol-2-yl) -1H-benzimidazole- 1-yl / methyl / 2- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl

To a solution of 0.5 g, 1 mmol of 4- [2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazole-1- yl (methyl) -2- (hydroxycarbamidoyl) biphenyl and 0.14 ml, 1 mmol of triethylamine in 40 ml of tetrahydrofuran are added dropwise at 5 ° C a solution of 0.1 ml, 1 mmol of ethyl chloroformate in 1 ml of methylene chloride. After 2 hours at room temperature, the precipitate formed is filtered off with suction. The filtrate is evaporated, the residue is dissolved in 5 ml of xylene and the solution is heated at reflux for 90 minutes. After cooling to room temperature, the reaction mixture was treated with 20 mL of ethyl acetate, washed with water and dried over magnesium sulfate. The crude product is chromatographed on silica gel with a particle size of 0.032-0.063 mm, eluting with methylene chloride with increasing amounts of ethanol up to 10%.

ARE YOU

Appropriate fractions were combined, evaporated, triturated with ether and dried.

Yield: 80 mg, 14% of theory.

Melting point: &gt; 199 DEG C. with decomposition.

Rf: 0.33 using silica gel and a 3: 1 mixture of ethyl acetate and methanol.

Formula C34H34N6O2 (558.69)

Mass Spectrum: (M-H) - = 557

In a similar manner to Example 66, the following compound can also be obtained:

- [2-n-propyl-4-methyl-6- (1,4,5-trimethylimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -2- (2,5-dihydro-5-yl) oxo-l, 2,4oxadiazol-3-yl) biphenyl.

In the following examples where pharmaceutical compositions are mentioned, any compound of formula I can be used as the active ingredient, especially those in which it represents a group metabolizable in vivo to a carboxyl group or a ΙΗ-tetrazolyl group.

Example I

Ampoule containing 50 mg of active substance in 5 ml

active substance 50 mg kh ₂ Mon ₄ 2 mg Na ₂ HP0 ₄ x 2H ₂ 0 50 mg NaCl 12 mg water for injection 5 ml

Method of production:

Buffer and isotonic solution are dissolved in a portion of the water. The active substance is then added and, after complete dissolution, the volume is made up to 5 ml with water.

Example II

Ampoule containing 100 mg of active substance in 5 ml of active substance methylglucamine glycofurol polymers of polyethylene glycol and polypropylene glycol water for injections

100 mg 35 mg

1000 mg

250 mg to 5 ml.

Method of production:

Methylglucamine is dissolved in a portion of water and the active ingredient is then dissolved with stirring and heating. After addition of solvent, make up to 5 ml with water.

Example III

Tablets containing 50 mg of the active substance active substance calcium hydrogen phosphate milk sugar corn starch polyvinylpyrrolidone magnesium stearate

50.0 mg 70.0 mg 40.0 mg 35.0 mg 3.5 mg 1.5 mg 200.0 mg

Method of production

The active ingredient, dicalcium phosphate, milk sugar and corn starch are equally moistened with an aqueous solution of polyvinylpyrrolidone. The mass is passed through a sieve with a mesh diameter of 2 mm, dried in a drying oven at 50 ° C and sieved again.

After the glidant has been added, the granulate is compressed into a tabletting machine.

Example IV

Holds containing 50 mg of active substance active substance 50.0 mg lysine 25.0 mg milk sugar 60.0 mg corn starch 34.0 mg gelatin 10.0 mg magnesium stearate 1.0 mg

180.0 mg

Method of production:

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

The cores thus produced can be coated in a known manner. Dyestuffs 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

Method of production:

The active ingredient is mixed with excipients and the mixture is moistened with an aqueous solution of polyvinylpyrrolidone. The wet material is passed through a 1.5 mm mesh screen and dried at 45 ° C. After drying, the material is passed through a sieve, magnesium stearate is added and the mixture is pressed into dragee cores.

The cores thus obtained are coated in a known manner. The dragee suspension or solution may contain coloring agents.

Example VI

Capsules containing 250 mg of active substance

active substance 250.0 mg maize starch 68.5 mg magnesium stearate 1.5 mg 350.0 mg

Method of production:

The active ingredient and corn starch are mixed and the mixture is moistened with water. The wet mixture is then passed through a sieve and dried. The dry granulate is passed through a sieve and mixed with magnesium stearate. The resulting mixture is then filled into size I hard gelatin capsules.

Example VII

Oral suspension containing 50 mg of active substance in 5 ml

active substance 50.0 mg hydroxyethyl 50.0 mg sorbic acid 5.0 mg Sorbit 70% 600.0 mg glycerol 200.0 mg aromatic substances 15.0 mg Water to 5.0 ml

Method of production:

The distilled water is heated to 70 ° C. Hydroxyethylcellulose is then dissolved in the water with stirring. Sorbitol and glycerol solution was added and the mixture was cooled to room temperature. Sorbic acid, flavorings and the active ingredient are then added at room temperature. To remove air, the suspension is placed under vacuum while stirring. A dose of 50 mg is contained in 5.0 ml of this suspension.

Example VIII

Lace containing 100 mg of the active substance Adeps solidus

100.0 mg 1600.0 mg 1700.0 mg

Method of production

The solid fat is melted and the finely divided active ingredient is dispersed homogeneously at 40 ° C. Then, the melt is cooled to 38 ° C and poured into slightly pre-cooled lace molds.

Claims (10)

PATENT CLAIMS What is claimed is: 1. A compound of the formula (I) EMI2.0 wherein: EMI3.0 [0000] EMI2.0 [0005] EMI2.0 [0005] R 1 represents a hydrogen, fluorine, chlorine or bromine atom, a chloromethyl, difluoromethyl, trifluoromethyl or alkyl group, _R2 is imidazol-2-yl, optionally substituted in the 1 radical R _a, wherein R _a represents a phenyl or phenylalkyl group, the phenyl ring of which is optionally mono- or di-substituted by an alkyl, hydroxy or alkoxy group, wherein the substituents may be the same or differently C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl carbon in which the alkyl moiety is optionally substituted by a group which is metabolizable in vivo to a carboxyl, trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl or from position 2 hydroxy, alkoxy, amino, piperidino, amino . 5,5-spirocyclopentadihydroimidazol-4-one-2-yl, imidazolium-2-yl substituted in the 1 and 3 positions, which may be the same or different, means a phenylalkyl group in which the phenyl residue is optionally mono- or disubstituted by alkyl, hydroxy or alkoxy, wherein the substituents may be the same or different, or alkyl having 1 to 6 carbon atoms, optionally substituted in the alkyl moiety, metabolizable in vivo to carboxyl, trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl , alkylaminocarbonyl or dialkylaminocarboxyl, oxazol-2-yl or thiazol-2-yl, wherein the aforementioned imidazol-2-yl, imidazolium-2-yl, oxazol-2-yl or thiazol-2-yl moieties may be in the positions 4, 5 substituted with C 1 -C 5 alkyl or phenyl; these substituents may be the same or different, or an n-propylene or n-butylene bridge, oxazolin-2-yl or imidazolin-2-yl substituted at the 4-position by substituents R 8 and R 6 q may be attached at positions 4, 5 or at position 5 with a substituent R? θ, the imino group may be substituted by further radicals denoted by R, or _a group of formula RgCO- (RqCRjq) -NR _a -CO-, where R _and is defined above, and R 8 to R 10, the same or different, are hydrogen, C 1 -C 5 alkyl or phenyl, R 1 represents an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, an alkoxy group or an alkylthio group having 1 to 4 carbon atoms each, and R ₄ represents a hydrogen atom or a group of the formula wherein R1 represents a group metabolizable in vivo to a carboxyl group, a carboxyl group, a cyano group, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 1H-tetrazolyl, 1-triphenylmethyltetrazolyl or 2-triphenylmethyltetrazolyl, all of the above groups and alkoxy groups having 1 to 3 carbon atoms, provided that: they do not directly indicate the number of carbon atoms and in vivo metabolizable to a carboxyl group means, for example, ester groups of the formula - CO-OR, - CO - O - (HCR) - O - CO - R a - CO - O - (HCR) - O - CO - OR where R is 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 radical of 1 to 6 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl as well as 3 isomers thereof, mixtures of their isomers 1- and 3- and also salts thereof. The benzimidazole derivatives of the general formula I according to claim 1, in which R1 is hydrogen, fluorine, chlorine or bromine, chlorine, trifluoromethyl or alkyl having 1 to 3 carbon atoms, _R2 is imidazol-2-yl, optionally substituted in the substituent R 1 _and wherein R _a represents phenyl or phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety, cycloalkyl having 5 to 7 carbon atoms or alkyl having 1 to 5 carbon atoms, wherein the alkyl moiety may be substituted by a group which is metabolizable in vivo to a carboxyl group, trifluoromethyl , carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl or, from the 2-position, hydroxy, methoxy, ethoxy, amino, methylamino, pyrrolidine, piperidine, or morphol 5,5-spirocyclopentadihydroimidazol-4-one-2-yl, imidazolium-2-yl, optionally substituted in the 1-position and 3 with the radicals R 1, which may be the same or different, where alkyl or phenylalkyl are always 1 to 1; The 3 carbon atoms in the alkyl group, the oxazol-2-yl or thiazol-2-yl groups in the imidazol-2-yl, imidazolium-2-yl, oxazol-2-yl or thiazol-2-yl groups are optionally 4-positions, 5 substituted with C 1 -C 4 alkyl or phenyl, the substituents may be the same or different or the 4, 5 positions may be linked by an n-butylene bridge, oxazolin-2-yl or imidazolin-2-yl substituted with R 8 and R @ ₁₀ wherein the imino group may be further substituted by R _a and R, R q _and R _a are hydrogen or alkyl of 1 to 4 carbon atoms, R ^ is C až-C alkyl alkyl, C až-C cyk cycloalkyl, alkoxy or Cti-C alkyl alkylthio; R 4 represents a group of the general formula -CH where R 5 is an in vivo metabolizable group to a carboxyl group, further to a carboxyl group, a cyano group, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, ΙΗ-tetrazolyl, 1-triphenylmethyltetrazolyl or 2- triphenylmethyltetrazolyl, wherein the group in vivo metabolizable to a carboxyl group means, for example, an ester group of the formula - CO-OR, - CO - O - (HCR) - O - CO - R a - CO - O - (HCR) - O - CO - OR where R represents a straight or branched chain alkyl radical of 1 to 4 carbon atoms or a cycloloalkyl of 5 to 7 carbon atoms, R is hydrogen or methyl; and R represents straight or branched chain alkyl of 1 to 4 carbon atoms or cycloalkyl of 5 to 7 carbon atoms, as well as the 3-isomers of these compounds, a mixture of the 1-isomer and the 3-isomer of the salt thereof. The benzimidazole derivatives of the general formula I according to claim 1, in which R 2 and R ₄ are as defined in Claim 2, R2 at position 6 is as defined in claim 2 a Rf at the 4-position represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an alkyl group having 1 to 3 carbon atoms. as well as mixtures of 1- and 3-isomers and salts thereof. A compound according to claim 1, wherein: R ₃ and R ₄ are as defined in claim 3 a The R ₂ at the 6-position is the imidazole moiety according to claim 3, as well as mixtures of 1- and 3-isomers and salts thereof. 5. A compound of the formula I as claimed in claim 1: a) 4- (2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2- carboxylic acid, b) 4- [2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-1-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl] biphenyl- 2-carboxylic acid, c) 4- [2-n-propyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl] -2- (1 H-tetrazol-5-y1) biphenyl, d) 4- (2-n-propyl-4-methyl-6- (1-benzyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl acid 2-carboxylic acid, e) 4- [2-ethyl-4-methyl-6- (1-benzyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl-2 acid carboxylic acid, f) 4- [2-n-propyl-4-methyl-6- (1-carboxymethyl-5,6,7,8-terrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl / biphenyl- 2-carboxylic acid, 100 g) 4- [2-ethyl-4-methyl-6- (1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl) methyl] -2- (1H) tetrazol-5-yl) biphenyl, (h) 4- [2-n-propyl-4-methyl-6- (4,4-dimethyloxazolin-2-yl) -1H-benzimidazol-1-yl] - (methyl) biphenyl-2-carboxylic acid; i) 4- [2-n-propyl-4-methyl-6- (1,5-dimethyl-4-phenylimidazol-2-yl) -1H-benzimidazol-1-yl] - (methyl) biphenyl-2 carboxylic acid, k) 4- (2-n-propyl-4-methyl-6- (4-isopropyl-1,5-dimethylimidazol-2-yl) -1H-benzimidazol-1-yl) - (methyl) biphenyl-2 carboxylic acid as well as salts of these compounds. 6. Physiologically acceptable salts of the compounds of the formula I according to at least one of claims 1 to 5 with inorganic or organic acids or bases. A pharmaceutical composition which antagonizes the effect of angiotensin, characterized in that it contains at least one compound of the formula I as claimed in claims 1 to 5 or a salt thereof according to claim 6 as an active ingredient, physiologically acceptable together with at least one inert carrier and / or diluent. Use of the compounds of the formula I according to at least one of Claims 1 to 6 for the preparation of pharmaceutical compositions which antagonize the action of angiotensin. 101 Process for the production of a pharmaceutical composition according to claim 7, characterized in that the compound of the formula I according to at least one of claims 1 to 6 is treated by mechanical means together with at least one inert carrier and / or diluent. A process for the preparation of the benzimidazole derivatives according to claims 1 to 6, characterized in that: a) the preparation of compounds of formula I wherein _R2 is oxazol-2-yl, thiazol-2-yl or imidazol-2-yl, these skuupinách is in the 4, 5 coupled n-butyl bridge and also is the imino group of the imidazole ring optionally substituted with a C 1 -C 6 alkyl, a C 1 -C 3 phenylalkyl or a phenyl moiety to react a compound of formula II R, R ₃ and R ₄ are as defined in claims 1 to 5, and X represents an oxygen atom or a sulfur atom or an imino group optionally substituted by a C1 -C6 alkyl radical, a C1 -C3 phenylalkyl radical or a phenyl radical with an alpha-haloketone of the formula III 102 (m) wherein Z 1 is a halogen atom or is a halogen atom b) the preparation of compounds of formula I, wherein R ₂ is imidazol-2-yl groups, as described in claims 1 to 5, and optionally substituted in the 1 radical in the definition of R _a, zlúčenniny by reaction of the formula IV (IV) wherein R 1, R ₂ and are as defined in claims 1 to 5 a R ₂ represents an oxazol-2-yl group as defined in claims 1 to 5, with an amine of formula V h ₂ n - r ₆ (V) Wherein R 8 is as defined in R 1 _and as defined in claims 1 to 5 or is hydrogen or s c) in the preparation of the benzimidazoles of the formula I in which R 4 is a group of the formula in which R má is as defined in claims 1 to 5, the reaction of the benzimidazole of the formula VI is carried out wherein: R 1, R 3 and R 4 are as defined in claims 1 to 5 and R 2 is the groups listed for R ₂ in claims 1 to 5 except for the imidazol-2-yl and imidazolin-2-yl unsubstituted at the 1-position with biphenyl a derivative of the general formula VII 104 Wherein R is as defined in claims 1 to 5 and Z ₂ is a nucleophilic leaving group or is d) in the preparation of the compounds of the formula I in which R @ 1 represents a carboxyl group, a compound of the formula VIII is converted wherein: R1-R3 are as defined above and R1 is a group which can be converted by hydrolysis, heat treatment or hydrogenolysis to a carboxyl group, to a compound of formula I in which R1 is a carboxyl group, or 105 (e) at. the preparation of compounds of formula I, wherein _R2 is 5,5-spirocyklopentanodihydroimidazol-4-on-2-yl, the benzimidazole derivative of formula wherein R f, R f and R 6 are as defined in claims 1 to 5 a _R2 is imidazol-2-yl, wherein in the 4, 5 is connected to n-butylene bridge, with a base in the presence of air and light, or f) in the preparation of a compound of the formula I in which R ^ represents a tet-tetrazolyl group, the protecting group is cleaved from the compound of the formula X 106 wherein ^{R1 and R2} are as defined in claims 1 to 5 and R 5 represents a ΙΗ-tetrazolyl or 2H-tetrazolyl group in the 1 or 2 position, protected by a protecting group or g) in the preparation of a compound of formula I in which R 1 represents a ΙΗ-tetrazolyl group, reacting a compound of formula XI (xi) wherein R f and R 3 are as defined in claims 1 to 5 with hydrochloric acid or one of its salts; the h) the preparation of compounds of formula I wherein R ₂ is imidazol-2-yl groups according to claims 1 to 5, optionally substituted in the 1-position by phenyl, wherein the phenyl ring is optionally further mono- or di alkylovýin radicals, hydroxy or alkoxy, wherein the substituents may be the same or different, or an alkyl group having 1 to 6 carbon atoms, optionally further substituted, in vivo metabolizable to carboxyl, trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl 2-yl groups according to claims 1 to 5, 107 reacting a compound of formula XI1 wherein R and R ₃ are as defined in claims 1 to 5, R2 represents an unsubstituted imidazol-2-yl group according to claims 1 to 5, unsubstituted at the 1-position, and R1 represents a carboxyl group, a group which can be converted to a carboxyl group by hydrolysis, heat treatment or hydrogenolysis, or a protected 1H-tetrazolyl or 2H-tetrazolyl group, with a compound of formula XIII of ₃ -R _? (XIII) where R 7 represents a phenylalkyl group in which the phenyl ring is optionally substituted by an hydroxy or alkoxy alkyl group with one or two identical or different substituents or an alkyl group having 1 to 6 carbon atoms, the alkyl group being optionally further substituted by an in vivo metabolizable group to a carboxyl group, a trifluoromethyl group, a carboxy group, an alkoxycarbonyl group, an aminocarbonyl alkylaminocarbonyl or a dialkylaminocarbonyl group, and 108 Zj denotes a nucleophilic leaving group with optional cleavage of the protecting group used or (i) in the preparation of compounds of formula I in which R2 is an imidazol-2-yl radical as claimed in claims 1 to 5, substituted by Rg to Rjq, where one of Rg or Rgg is hydrogen, reacting an aminoketone of formula XIV wherein R1, R3, R4 and R8 to R8 as defined in claims 1 to 5, wherein one of R8 or R8 represents a hydrogen atom and R _& apos _; is as defined in claims 1 to 5 for R _& apos _; or is hydrogen, with an ammonium salt of a lower aliphatic carboxylic acid, or j) in the manufacture of a compound of formula I, wherein R 2 is an oxazolin-2-yl or imidazolin-2-yl radical according to claims 1 to 5, 109 performs dehydration of a compound of formula XV wherein R 1, R 3, R 4 and R 8 to R 11 are as defined in claims 1 to 5 and Y is OH or NHR _a, wherein R _a is as defined in claims 1 to 5, or k) reacting a compound of formula XVI (xvi) in the preparation of compounds of formula I wherein R ₂ is an imidazolin-2-yl radical according to claims 1 to 5 R, where R 1, R 3 and R 4 are as defined in claims 1 to 5 and _R2 is oxazolin-2-yl radical of the claims 1 to 5, 110 with an amine of formula XVII ₃ N - (RGCH) - (R _g CH ₁₀₎ - _NH2 (XVII) wherein R 8 to R ₁₀ have the meaning given in claims 1 to 5 or se 1) in the preparation of compounds of the formula I in which R ₂ is an oxazol-2-yl radical according to claims 1 to 5, substituted by R 8 to R 8, dehydrates the aminoketone of the formula XVIII wherein: R 1, R 3, R ₄ and R 6 to R 6 are as defined in claims 1 to 5, wherein one of R 6 and R 6 is hydrogen or m) the preparation of compounds of formula I wherein R ₂ is imidazol-2-yl radical given in claims 1 to 5 and the radicals R and substituted with R q dehydrogenating a compound of formula XIX (XIX) Wherein R 3 and R 4 are as defined in claims 1 to 5 and R ₂ 'is an imidazolin-2-yl radical as defined in R ₂ as defined in claims 1 to 5 and substituted with residues R 8 to R 11, wherein at least one the radicals R 8 or R 6 q must be hydrogen or s n) in the preparation of compounds of the formula I in which R1 represents a 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group, the reaction is carried out, optionally directly in the reaction mixture of the amidoxime prepared in general wherein R 1 -R 1 are as defined in claims 1 to 5 with a compound of formula XXI CO-OR (XXI) 112 where Z3 represents a nucleophilic leaving group and R @ 1 represents an alkyl, aryl or aralkyl group, and then the acylated amidoxime thus obtained is cyclized and any protecting group used during the reaction is cleaved off or f or the compound of formula I thus obtained is converted into a salt, in particular to a physiologically acceptable salt with an inorganic or organic acid or base suitable for pharmaceutical use.