CA2100927A1 - Benzimidazoles, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents

Abstract

Abstract Benzimidazoles The invention relates to benzimidazoles of formula I

(I) (wherein R1, R2, R3 and R4 are as defined in any one of claims 1 to 5) and the 1-, 3-isomer mixtures and the salts thereof.
Such compounds have valuable properties, particularly angiotensin-antagonistic effects.

Description

2 ~ IJ

59912.564 Benzimidazoles The present invention relates to new henzimidazoles, processes for their preparation and pharmaceutical compositions containing them.

It has been found that certain novel benzimidazoles have valuable pharmacological properties, in particular, angiotensin-antagonistic activities.

Thus, viewed from one aspect, the present invention provides compounds of formula I:

R2- ~ ~ R3 R

~H2 1/~=\

(I) (wherein R1 denotes a hydrogen, fluorine, chlorine or bromine atom or a C13-alkyl, C37-cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group;
'' R2 denotes a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene group in a homophthalimino group may be substituted by one or two C13-alkyl groups, or R2 denotes a 5-, 6- or 7-membered alkyleneimino group (optionally substituted by one or two Cl3-alkyl groups) 2'7 in which a methylene group is replaced by a carbonyl or sulphonyl group, or R2 denotes a maleic acid imido group optionally mono-or disubstituted by a C13-alkyl group or by a phenyl group, wherein the substituents may be identical or di~ferent, or R2 denotes a benzi.midazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group optionally substituted in the 1-position by a C16-alkyl group or by a C35-cycloalkyl group or in the phenyl nucleus thereof by a fluorine atom or by a methyl or trifluoromethyl group, or R2 denotes an imidazo~2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin 2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, 3-chloro-5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl, imidazo[l,2 a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[l,2-a]pyrazin-2-yl, imidazo[l,2-b]-pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or a carbon-attached pyrrolidine, piperidine or pyridine ring wherein a phenyl group may be condensed on to the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or R2 denotes an R7-NR6-CO-NR5- group wherein Rs denotes a hydrogen atom or a C1s-alkyl, cyclohexyl or benzyl group, R6 denotes a hydrogen atom or a C16-alkyl, allyl, cyclohexyl, benzyl or phenyl group, 2 ~

R7 denotes a hydrogen atom or a C13-alkyl group, or R6 and R7 together with the nitrogen atom between them denote an unbranched cyclic C46-alkyleneimino group or a morpholino group, or R5 and R6 together denote a C23-alkylene group;

R3 denotes a C15-alkyl, C3s-cycloalkyl or C13-alkoxy group; and R4 denotes a tetrazolyl group substituted in the 1- or 2-position by an Ra-CO-O-CH2- group, or an Rb-CO-O-(RcCH)-O-CO-, RaO-CO- or RbO-CO-O-(RCCH)-O-CO-group, wherein Ra denotes a straight-chained or branched C16-alkyl group or a Cs7-cycloalkyl, benzyl, l-phenylethyl, . 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, Rb denotes a straight-chained or branched Cl6-alkyl group or a Cs7-cycloalkyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group and Rc denotes a hydrogen atom or a methyl group, or if (i) R3 denotes an alkoxy group, R4 may also denote a carboxy, lH-tetrazolyl or 2H-tetrazolyl group or, if (ii) R2 is other than a l-methyl-benzimidazol-2-yl group and R3 denotes a cyclopropyl group, R4 may also represent a carboxy group or, if 2 ~ 2 7 (iii) R2 denotes a butanesultam-l-yl group, R4 may also denote a carboxy group or, if (iv) R2 denotes a 1-methyl-5-fluoro-benzimidazol-2-yl group and R3 denotes an ethyl group, R4 may also represent a carboxy, lH-tetrazolyl or 2H-tetrazolyl group) and the tautomers and the salts thereof.

Examples of the definitions of groups R1, R2, R3 and R4 mentioned hereinbefore include the following:

R1 may denote a hydrogen atom or in the 4-position a fluorine, chlorine or bromine atom, a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, difluoromethyl or trifluoromethyl group;

R2 may denote a phthalimino, homophthalimi.no, 4,4-dimethyl-homophthalimino, 1-oxo-isoindolin-2-yl, 2-oxo-pyrrolidino, 2-oxo-piperidino, 2-oxo-hexamethyleneimino, propanesultam-1-yl, butanesultam-l-yl, pentanesultam-l-yl, maleic acid imido, 2 methyl-maleic acid imido, 2-phenyl-maleic acid imido, 2,3-dimethyl-maleic acid imido, 3-methyl-2-phenyl-maleic acid imido, 2,3-diphenyl-maleic acid imido, piperidin-2-yl, piperidin-2-on-1-yl, quinolin-2-yl, isoquinolin-l-yl, isoquinolin-3-yl, pyridin-2-yl, benzimidazol-2-yl, 1-methyl-benzimidazol-2-yl, 1-ethyl-benzimidazol-2-yl, 1-n-propyl-benzimidazol-2-yl, l-isopropyl-benzimidazol-2-yl, 1-n-butyl-benzimidazol-2-yl, l-isobutyl-benzimidazol-2-yl, 1-n-pentyl-benzimidazol-2-yl, l-n-hexyl-benzimidazol-2-yl, 1-cyclopropyl-benzimidazol-2-yl, l-cyclobutyl-benzimidazol-2-yl, l-cyclopentyl-benzimidazol-2-yl, 1-cyclohexyl-benzimidazol-2-yl, 5-2 ~ 2 !~

fluoro-l-methyl-ben~imidazol-2-yl, 6-fluoro-1-methyl-benzimidazol-2-yl, 5~trifluoromethyl-benzimidazol-2-yl, 5-trifluoromethyl-1-methyl-benzimidazol-2-yl, imidazo[l,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[l,2-a~pyridin-2 yl, 3-chloro-5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl, imidazo[l,2-a]pyrimidin-2-yl, imidazo[4,5-b~pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[2,1-b]thiazol-6-yl, imidazo[l,2-c~pyrimidin-2-yl, imidazo[l,2-a]pyrazin-2-yl, imidazo[l,2-b]pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, imidazo[4,5-d]pyridazin-2-yl, aminocarbonylamino, methylaminocarbonylamino, dimethylaminocarbonylamino, N-methylaminocarbonyl-methylamino, N-(dimethylaminocarbonyl)-methylamino, N-dimethylaminocarbonyl-ethylamino, N-dimethylaminocarbonylisopropylamino, N-(dimethylaminocarbonyl~-n-pentylamino, N-methylaminocarbonylethylamino, N-methylaminocarbonyl-n-pentylamino, N-methylaminocarbonyl-n-hexylamino, N-methylaminocarbonyl-n-octylamino, N-methylaminocarbonyl-cyclohexylamino, ethylamino-carbonylamino, N-ethylaminocarbonyl-methylamino, N-ethylaminocarbonyl-ethylamino, N-ethylaminocarbonyl-n-hexylamino, N-ethylaminocarbonyl-n-heptylamino, N-ethylaminocarbonyl-cyclohexylamino, diethylaminocarbonylamino, N-(diethylaminocarbonyl)-methylamino, N-(diethylaminocarbonyl)-ethylamino, N-(diethylaminocarbonyl)-n-butylamino, N-(diethylaminocarbonyl)-n-hexylamino, N-(diethylaminocarbonyl)-n-octylamino, isopropylaminocarbonylamino, N-isopropylaminocarbonyl-methylamino, n-butylaminocarbonylamino, N-(n-butyl-aminocarbonyl)-methylamino, N-(n-butylaminocarbonyl)-ethylamino, N-(n-butyl.,~inocarbonyl)-isopropylamino, N-(n-butylaminocarbonyl)~n-butylamino, N-(n-butylaminocarbonyl)-n-h*xylamino, N-(n-2~ ~yr~

butylaminocarbonyl)-Acyclohexylamino, N-(di-(n-butyl)-aminocarbonyl)-amino, N-(di-(n-butyl)-aminocarbonyl)-methylamino, N-(di-(n-butyl)-aminocarbonyl)-ethylamino, N-(di-(~-butyl)-aminocarbonyl)-n-butylamino, N-(di-(n-butyl)-aminocarbonyl)-n-hexylamino, N-(n-pentylaminocarbonyl)-methylamino, N-(n-pentylaminocarbonyl)-ethylamino, N-(n-hexylaminocarbonyl)-ethylamino, n-hexylaminocarbonylamino, n-heptylaminocarbonylamino, n-octylaminocarbonylamino, N-(n-hexylaminocarbonyl)-n-butylamino, N-(n-hexylaminocarbonyl)-n-pentylamino, N-(n-hexylaminocarbonyl)-n-hexylamino, N-(n-hexylaminocarbonyl)-cyclohexylamino, di-(n-hexyl)-aminocarbonylamino, N-(di-(n-hexyl)-aminocarbonyl)-methylamino, N-((n-hexyl)-methylaminocarbonyl)-amino, cyclohexylaminocarbonylamino, N-cyclohexylaminocarbonyl-methylamino, N-cyclohexylaminocarbonyl ethylamino, N-cyclohexylaminocarbonyl-n-butylamino, N-cyclohexylaminocarbonyl-isobutylamino, N-cyclohexylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbonyl-n-hexylamino, N-cyclohexylaminocarbonyl cyclohexylamino, N-(ethyl-cyclohexylaminocarbonyl)-methylamino, N-(propyl-cyclohexylaminocarbonyl)-methylamino, N (n-butyl-cyclohexylaminocarbonyl)-methylamino, allylaminocarbonylamino, benzylaminocarbonylamino, N-benzylaminocarbonyl-isobutylamino, phenylaminocarbonylamino, pyrrolidinocarbonylamino, pyrrolidinocarbonyl-methylamino, piperidinocarbonylamino, hexamethyleneiminocarbonylamino, morpholinocarbonylamino, 3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-methyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-ethyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-n-propyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-isopropyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-n-butyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-isobutyl-3,4,5,6-2 ~ 2'~

tetrahydro-2-pyrimidon-1-yl, 3-n-pentyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-n-hexyl-3,4,5,6~
tetrahydro-2-pyrimidon-1-yl, 3-cyclopentyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-cyclohexyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-cycloheptyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-benzyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3,~,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-methyl-3,4,5,6-tetrahydro-2~lH)-pyrimidon-l-yl, 3-ethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon 1-yl, 3-n-propyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-1-yl, 3-isopropyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl, 3-(2~phenylethyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl or 3-(3-phenylpropyl)-3,4,5,6-tetrahydro-2(lH)-pyrimidon-l-yl group;

R3 may denote a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl, l-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy or isopropoxy group; and R4 may denote a hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, tert.butyloxycarbonyl, n-pentyloxycarbonyl, isoamyloxycarbonyl, n-hexyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, 1-phenylethyloxycarbonyl, 2-phenylethyloxycarbonyl, 3-phenylpropyloxycarbonyl, methoxymethoxycarbonyl, cinnamyioxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, n-pentanoyloxymethoxycarbonyl, isopentanoyloxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl, n-hexanoyloxymethoxycarbonyl, cyclopentanoyloxy-2 ~ f~

methoxycarbonyl, cyclohexanoyloxymethoxycarbonyl,phenylacetoxymethoxycarbonyl, 2-phenylpropionyloxy-methoxycarbonyl, 3-phenylpropionyloxymethoxycarbonyl, 4-phenylbutyryloxymethoxycarbonyl,benzoyloxymethoxycarbonyl, l-acetoxyethoxycarbonyl, 1-propionyloxyethoxycarbonyl, l-n-butyryloxyethoxy-carbonyl, l-isobutyryloxyethoxycarbonyl, l-n-pentanoyloxyethoxycarbonyl, 1-isopentanoyloxyethoxycarbonyl, l-pivaloyloxyethoxy-carbonyl, 1-n-hexanoyloxyethoxycarbonyl, 1-cyclopentanoyloxyethoxycarbonyl, 1-cyclohexanoyloxyethoxycarbonyl, 1-phenylacetoxyethoxycarbonyl, 1-(1-phenylpropionyloxy)-ethoxycarbonyl, 1-(2-phenylpropionyloxy)-ethoxycarbonyl, 1-(3-phenylbutyryloxy)-ethoxycarbonyl, 1-benzoyloxyethoxycarbonyl, methoxycarbonyloxy-methoxycarbonyl, ethoxycarbonyloxymethoxycarbonyl, n-propyloxycarbonyloxymethoxycarbonyl, isopropyloxycarbonyloxymethoxycarbonyl, n-butyloxy-carbonyloxymethoxycarbonyl, isobutyloxycarbonyloxy-methoxycarbonyl, tert.butyloxycarbonyloxy-methoxycarbonyl, n pentyloxycarbonyloxymethoxycarbonyl, isoamyloxycarbonyloxymethoxycarbonyl, n-hexyloxycarbonyloxymethoxycarbonyl, cyclopentyloxycarbonyloxymethoxycarbonyl, cyclohexyloxycarbonyloxymethoxycarbonyl, benzyloxycarbonyloxymethoxycarbonyl, 1-phenylethoxycarbonyloxymethoxycarbonyl, 2-phenylethoxy-carbonyloxymethoxycarbonyl, 3-phenylpropyloxy-carbonyloxymethoxycarbonyl, cinnamyloxycarbonyloxymethoxycarbonyl, 1-(methoxycarbonyloxy)-ethoxycarbonyl, 1-(ethoxycarbonyloxy)-ethoxycarbonyl, 1-(n-propyloxycarbonyloxy)-ethoxycarbonyl, 1-(isopropyloxycarbonyloxy)-ethoxycarbonyl, l-(n-butyloxycarbonyloxy)-ethoxycarbonyl, 1-(isobutyloxycarbonyloxy)-ethoxycarbonyl, 1-3 t~ ~ 7 g (tert.butyloxycarbonyloxy)-ethoxycarbonyl, l-(n-pentyloxycarbonyloxy)-ethoxycarbonyl, 1-(isoamyloxycarbonyloxy)-ethoxycarbonyl, 1-(n-hexyloxycarbonyloxy)-ethoxycarbonyl, 1-(cyclopentyloxycarbonyloxy)~ethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)-ethoxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl, 1-(benzyloxycarbonyloxy)-ethoxycarbonyl, 1~
phenylethoxycarbonyloxy)-ethoxycarbonyl, 1-(2-phenylethoxycarbonyloxy)-ethoxycarbonyl, 1-(3-phenylpropyloxycarbonyloxy)-ethoxycarbonyl, 1-(cinnamyloxycarbonyloxy)-ethoxycarbonyl, cyano, lH-tetrazolyl, 1-triphenylmethyl-tetrazolyl, 2-triphenylmethyl-tetrazolyl, 1-acetoxymethyl-tetrazolyl, 2-acetoxymethyl-tetrazolyl, 1-propionyloxymethyl-tetrazolyl, 2-propionyloxymethyl-tetrazolyl, 1-butyryloxymethyl-tetrazolyl, 2-butyryloxymethyl-tetrazolyl, l-isobutyryloxymethyl-tetrazolyl, 2-isobutyryloxymethyl-tetrazolyl, l-pivaloyloxymethyl-tetrazolyl, 2-pivaloyloxymethyl-tetrazolyl, 1-ethoxycarbonyloxymethyl-tetrazolyl, 2-ethoxycarbonyloxymethyl-tetrazolyl, 1-[1-(ethoxycarbonyloxy)-ethyl]-tetrazolyl, 2-[1-(ethoxycarbonyloxy)-ethyl]-tetrazolyl, 1-[1-(cyclohexyloxycarbonyloxy)-ethyl]-tetrazolyl or 2-[1-(cyclohexyloxycarbonyloxy)-ethyl]-tetrazolyl group.

Preferred compounds according to the invention include those of formula I wherein R1 denotes a hydrogen atom or in the 4-position a chlorine atom, a Cl3-alkyl group or a trifluoromethyl group;

Rz denotes a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group, 2 ~ 2 ~

or R2 denotes a 5-, 6- or 7-membered alkyleneimino group in which a methylene group is replaced by a carbonyl or sulphonyl group, or R2 denotes a maleic acid imido grcup optionally mono-or disubstituted by a methyl or phenyl group, wherein the substituents may be identical or dif~erent, or R2 denotes a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group optionally substituted in the 1-position by a C16-alkyl group or by a cycloalkyl group or in the phenyl nucleus thereof a fluorine atom or a methyl or trifluoromethyl group, or R2 denotes an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, 3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a~pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[l,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or R2 denotes an R7-NR6-CO-NRs- group wherein Rs denotes a hydrogen atom or a C15-alkyl, cyclohexyl or benzyl group, R6 denotes a hydrogen atom or a C16-alkyl, allyl, cyclohexyl, benzyl or phenyl group, R7 denotes a hydrogen atom or a Cl3-alkyl group, or R6 and R7 together with the nitrogen atom between them denote a straight-chained C4 6-alkyleneimino 2 ~ 2 7 group or a morpholino group, or R5 and R6 together denote a Cz3-alkylene group;

R3 denotes a C15-alkyl, C3s-cycloalkyl, or C23-alkoxy group; and R4 denotes a tetrazolyl group substituted in the 1- or 2-position by an R~-CO-O-CH2- group, or an Rb-CO-O-(RcCH)-O-CO-, RaO-Co- or RbO-CO-O-(RcCH)-O-CO-group, wherein Ra denotes a straight-chained or branched C16-alkyl group or a C57~cycloalkyl, benzyl, l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, Rb denotes a straight-chained or branched C16-alkyl group or a C57-cycloalkyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group and Rc denotes a hydrogen atom or a methyl group, or, if (i) R3 denotes an alkoxy group, R4 may also denote a carboxy, lH-tetrazolyl or 2H-tetrazolyl group or, if (ii) R2 is other than a 1-methyl-benzimidazol-2-yl group and R3 denotes a cyclopropyl group, R4 may also represent a carboxy group or, if (iii) R2 denotes a butanesultam-1-yl group, R4 may also denote a carboxy group or, if (iv) R2 denotes a 1-me-thyl-5-fluoro-benzimidazol-2-yl 2 ~ 3 ~ 2 ~

group and R3 denotes an ethyl group, R4 may also represent a carboxy, lH-tetrazolyl or 2H-tetrazolyl group, and the tautomers and the salts thereof.

Particularly preferred compounds according to the present invention include those of formula I wherein R1 denotes a hydrogen atom or in the 4-position a methyl group;

R2 denotes an imidazo[l,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, 3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, 1-methyl-benzimidazol-2-yl, 1-methyl-5 fluoro-benzimidazol-2-yl or butanesultam-l-yl group;

R3 denotes a C24-alkyl group, a cyclopropyl group or a C23-alkoxy group; and R4 denotes a tetrazolyl group substituted in the 1- or 2-position by an Ra-CO-O-CH2- group, or an Rb-CO-O-(RcCH)-O-CO-, RaO-CO- or RbO-CO-O-(RcCH)-O-CO-group, wherein Ra denotes a straight-chained or branched C16-alkyl group or a C57-cycloalkyl, benzyl, l-phenylethyl, 2-phenylethyl) 3-phenylpropyl, methoxymethyl or cinnamyl group, Rb denotes a straight-chained or branched C16-alkyl group or a C57-cycloalkyl, phenyl, benzyl, 1-ph~nylethyl, 2-phenylethyl or 3-phenylpropyl group and Rc denotes a hydrogen atom or a methyl group;

2 ~ 2 1 and the tautomers and the salts thereof.

More particularly preferred compounds according to the invention include the following compounds of formula I:

4'-~(2-cyclopropyl-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

4'-[(2-ethoxy-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

4'-[(2-ethoxy-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl;

4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2 -a ] pyridin-2-yl)-benzimidazol-l-yl)~methyl]-biphenyl-2-carboxylic acid;

4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid;

4'-[(2-ethoxy-4-methyl-6-(imidazo[1~2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl;

1'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-2 (lH-tetrazol-5-yl)-biphenyl;

4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimida 7. ol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl;

4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid; and 4'-[(2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-l-yl)-methyl] biphenyl-2-carboxylic acid;

and the tautomers and the salts thereof.

The present invention particularly relates to the following compounds of formula I:

4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl~-methylJ-biphenyl-2-carboxylic acid;

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

4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid;

4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetxahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid; and 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl;

and the tautomers and the salts thereof.

Viewed from a further aspect, the invention provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps:

2 ~

a) cyclising a compourld of formula II

~Xl R2~"~`Yl (II) (wherein R1 and R2 are as hereinbefore defined, one of the groups X1 or Y1 represents a group of formula --NR5--CH2 ~--`~>

and the other group X1 or Y1 represents a group of formula - NH - C - R

wherein R3 and R4 are as hereinbefore defined, Rs represents a hydrogen atom or an R3CO- group, wherein R3 is as hereinbefore defined, Zl and Z2~ which may be identical or different, represent amino, hydroxy or mercapto groups optionally substituted by C16-alkyl groups, or Z1 and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C13-alkyl 2 1 ~

group, or a C23-alkylenedioxy or C23-alkylenedithio group) optionally formed in the reaction mixture, or a corresponding hydroxylamine and if required reducing a cyclized N-oxide thus obtained;

b) reacting a benzimidazole of formula III

~XN 3 H

, (III) (wherein R1, R2 and R3 are as defined hereinbefore) with a biphenyl compound of formula IV

Z3- CH2 ~

(IV) (wherein R4 is as hereinbefore defined and Z3 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group);

c) (to prepare a compound of formula I wherein R4 represents a carboxy group) converting a compound of formula V

2 ~ 2 7 ~N R
~H2 ~r ~

(v) (wherein R1, Rz and R3 are as hereinbefore defined, and R4' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) by hydrolysis, thermolysis or hydrogenolysis;

d) tto prepare a compound of formula I wherein R"
represents a lH-tetrazolyl group) cleaving a protecting group from a compound of formula VI

N R~

CH2 '~

(VI) (wherein R1, R2 and R3 are as hereinbefore defined and R4" represents a lH-tetrazolyl group protected in the 1-or 3-position by a protecting group);

e) (to prepare a compound of formula I wherein R~
represents a lH-tetrazolyl group) reacting a compound of formula VII

21 ~ ~ ~ 2 7 2~CN~P~3 CN

(VII) (wherein R1, R2 and R3 are as hereinbefore de~ined) with hydrazoic acid or a salt thereof;

f) (to prepare a compound of formula I wherein R4 denotes a tetrazolyl group substituted in the l or 2-position by an Ra-CO-O-CH2- group, or R4 denotes an RaO-CO-, Rb-CO-O-(RcCH)-O-CO- or RbO-CO-O-(RcCH)-O-CO- group) reacting a compound of formula VIII

R

2 ~N~R3 R4 CH2 --~ =

(VIII) (wherein R1, R2 and R3 are as hereinbefore defined and R4~ denotes a carboxy, lH-tetrazolyl or 2H-tetrazolyl group) with a compound of formula IX

Z4 Y2 (IX) (wherein Y2 denotes an Ra-CO-O-CH2-, Rb-CO-O-(RcCH)-, RbO-CO-O-(RcCH)- or Ra~ group, wherein Ra~ Rb and Rc are as 2 ~ 2 ~

hereinbefore defined ar.d Z4 denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom, or, if Y denotes an Ra~ group, Z4 may also represent a hydroxy group);

g) resolving a 1-, 3-isomer mixture of a compound of formula I thus obtained into the 1- and 3-isomers thereof;

h) converting a compound of formula I thus obtained into a salt thereof, more particularly, for pharmaceutical use, into a physiologically acceptable salt thereof with an inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound;
and i) performing a process as defined in any one of steps (a) to (h) above on a corresponding protected compound and subsequently removing the protecting group used.

The cyclisation of step (a) is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benæene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, e.g. at temperatures between 0 and 250C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally in the presence of a base such as potassium ethoxide or ~otassium tert.-butoxide.

2 ~ 2 r~

However, the cyclisation may also be carried out without a solvent and/or condensing agent.

It is particularly advantageous to carry out the reaction of step (a) by preparing a compound of formula II in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of formula R3COOH, or by acylation of a corresponding o-diamino compound. When the reduction of the nitro group is broken off at the hydroxylamine stage, the N-oxide of a compound of formula I is obtained in the subsequent cyclisation. The rasulting N-oxide is then converted by reduction into a corresponding compound of formula I.

The subsequent reduction of the N-oxide of the compound of formula I is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic acid, hydrochloric acid or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel, at temperatures between 0 and 50C, but preferably at ambient temperature.

The reaction of step (b) is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethyl-sulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, sodium hydride, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, preferably at temperatures between 0 and 100C, e.g. at temperatures 2~1 between ambient temperature and 50C.

In the reaction of step (b), a mixture of the 1- and 3-isomers is preferably obtained which can if desired subsequently be resolved into the corresponding 1- and 3- isomers, by crystallisation or chromatography using a substrate such as silica gel or aluminium oxide.

In step (c), functional derivatives of the carboxy group such as the unsubstituted or substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides, the nitrile group or the tetrazolyl group may, for example, be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. the tert.butylester, may, for example, be converted by thermolysis into a carboxy group and esters with aralkanols, e.g. the benzylester, may, for example, be converted by hydrogenolysis into a carboxy group.

The hydrolysis of step (c) is appropriately carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol, water/dioxane, methylene chloride or chloroform, at temperatures between -10C and 120C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups present may simultaneously be converted into a corresponding acyloxy group such as the trifluoroacetoxy group.

If R4' in a compound oE formula V represents a cyano or aminocarbonyl group, these groups may also be converted 2 ~ 2 ~

into a carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which may simultaneously also be used as solvent, at tem~eratures between 0 and 50C.

If R4' in a compound of formula V represents for example a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40C and lOO~C.

If R4' in a compound of formula V represents, for example, a benzyloxycarbonyl group the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50C, e.g. at ambient temperature, under a hydrogen pressure of 1 to 5 bar. During hydrogenolysis, other groups may be reduced at the same time, e.g. a nitro group may be reduced to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.

Suitable protecting groups for use in step (d) include, for example, the triphenylmethyl, tributyl tin or triphenyl tin groups. The cleaving of a protecting group used is preferably carried out in the presence of a hydrohalic acid, preferably in the presence of 2~a~ 7 hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia, in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, at temperatures between 0 and lOODC, but preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and 150C, preferably at temperatures between 120 and 140C.

The reaction of step (e) is preferably carried out in a solvent such as benzene, toluene or dimethylformamide, at temperatures between 80 and 150C, preferably at 125C. Advantageously, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g. from sodium azide, in the presence of a weak acid such as ammonium chloride, or the tetrazolide salt obtained in the reaction mixture by reacting with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which are also conveniently prepared in the reaction mixture by reacting aluminium chloride or tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric acid or 2N sulphuric acid.

The reaction of step (f) is conveniently carried out by esterification with a corresponding alcohol or with a corresponding reactive derivative such as the halide, conveniently in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide or in an excess of the acylating agent as solvent, optionally in the presence of an acid activating or dehydrating agent such as thionylchloride, with the anhydrides, esters or halides thereof optionally in the presence of an inorganic or tertiary organic base such as sodium hydroxide, potassium carbonate, triethylamine or 2 ~ 2 ~1 pyridine, whilst the latter two may simultaneously be used as solvent, at temperatures between -25 and 100C, but preferably at temperatures between -10 and 80C.

In the reactions described hereinbefore, any reactive groups present such as hydroxy or imino groups may be protected during the reaction by means of conventional protecting groups which are split off again after the reaction.

By way of example, protecting groups for a hydroxy group may include a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and protecting groups for an imino group may include an acetyl, benzoyl, ethoxycarbonyl or benzyl group.

The optional subsequent cleaving of a protecting group used is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is preferably cleaved by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 50~C, but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar.

An isomer mixture of a compound of formula I thus obtained may if desired be resolved by chromatography using a substrate such as silica gel or aluminium oxide.

2 ~ ',,), 7 Moreover, the compounds of formula I obtained may be converted into ~he ac:Ld addition salts thereof, more particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Furthermore, the new compounds of ~ormula I thus obtained, if they contain a carboxy or lH-tetrazolyl group, may if desired subsequently be converted into the salts thereof with inorganic or organic bases, more particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of formulae II to IX used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature.

Thus, for example, a compound of formula II may be obtained by alkylation of a corresponding o-amino-acylamino compound with a compound of formula IV. The o-amino-acylamino compound required for this is preferably obtained by reduction of a corresponding o-l nitro-acylamino compound which in turn may be obtained by nitration of a corresponding acylamino-acetophenone, subsequent conversion of the resulting corresponding o-nitro-acylamino-acetophenone into the corresponding ~-bromo-acetophenone, su~sequent cyclisation of the ~-bromo-acetophenone witr~ a corresponding acid amide and subsequent reduction c~ the nitro group. Before the reduction of the nitrc group, an oxazol-4-yl compound thus obtained may be nverted into the corresponding 2 ~ ) ?,J~7 imidazol-4-yl compound by means of a corresponding amine, preferably ammonia, under pressure, or an imidazol-4-yl compound unsubstituted in the l-position obtained in this way may be converted by alkylation into a corresponding imidazol-4-yl compound alkylated in the l-position.

A starting compound of formula III may be obtained by reduction and cyclisation of an o-nitro-acylamino compound as described hereinbefore.

Starting compounds of formulae V, VI, VII and VIII may be obtained by reacting a compound of formula III with a corresponding compound of formula IV.

The new compounds of formula I and the physiologically acceptable salts thereof ha~e valuable pharmacological properties. They are angiotensin-an~agonists, particularly angiotensin-II-antagonists.

By way of example, the following compounds:

A = 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

B = 4'-[(2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid;

C = 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

D = 4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid; and 2 ~ 't~ 2 ~

E = 4'-[(2-ethoxy-4~methyl-6-(1-methyl-benzimidazol~2-yl)-benzimidazo~-l-yl)-methyl]-2-~lH-tetrazol-5-yl)-biphenyl, were investigated for their biological activities as follows:

Description of method: anqiotensin-II-rece~tor bindinq The tissue (rat's lung) is homogenised in Tris buffer (50 mMol Tris, 150 mMol NaCl, 5 mMol EDTA, pH 7.40) and centrifuged twice for 20 minutes each time at 20,000 x g. The finished pellet is resuspended in incubation buffer (50 mMol Tris, 5 mMol MgClz, 0.2% BSA, pH 7.40) 1:75, based on the moist weight of the tissue.
Each 0.1 ml of homogenate is incubated for 60 minutes at 37C with 50 pM [125I]-angiotensin-II (NEN, Dreieich, Germany) and increasing concentrations of the test substance in a total volume of 0.25 ml. The incubation is ended by rapid filtration through glass fibre filter mats. The filters are each washed with 4 ml of ice cold buffer (25 m~lol Tris, 2.5 mMol MgCl2, 0.1% BSA, pH 7.40).
The bound radioactivity is measured in a gamma-counter.
The corresponding IC50 ~alue is determined from the dosage-activity curve.

Substances A to E show the following IC50 values in the test described:
Substance IC50 [nM]
_ 7.4 D 1.3 3.3 In view of their pharmacological properties, the new ~a~-~2 l compounds and the phy~iologically acceptable salts thereof are suitable for the tr~atment of hypertension and cardiac insufficiency and for treating ischaemic peripheral circulator~ disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.

Furthermore, the new compounds and the physiologically acceptable salts thereof are suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial rP-stenosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, arteriosclerosis and diabetic angiopathy. Because of the effect of angiotensin on the release of acetylcholine and dopamine in the brain, the new angiotensin antagonists are also suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's disease, Parkinson's syndrome and bulimia, as well as disorders of cognitive functions.

Thus, viewed from a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients.

Viewed from a still further aspect the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent having an angiotensin-antagonistic activity.

In particular, the inv~ntion provides the use of a compound of formula I or a physiologically acceptable r~ 9 r~

salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension and cardiac insufficiency and for treating ischaemic peripheral circulatory disorders~ myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.

More particularly, the invention provides the use of a compound of formula I or a physiologically acceptable sal~ thereof for the manufacture of a therapeutic agent for treating pulmonary diseases, for preventing arterial re-stenosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, arteriosclerosis and diabetic angiopathy, or for the treatment of depression, Alzheimer's disease, Parkinson's syndrome, bulimia and disorders of cognitive functions.

Viewed from a yet still further aspect the invention provides a method of treatment of the human or non-human animal body for the treatment of hypertension and cardiac insufficiency and for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.

More particularly, the invention provides a method of treatment of the human or non-human animal body for treating pulmonary diseases, for preventing arterial re-stenosis after angioplasty, for preventing thickening of 2 ~ 2 7 the vascular walls after vascular operations, arteriosclerosis and ~iabetic angiopathy, or for the treatment of depression, Alzheimer's disease, Parkinson's syndrome, bulimia and disorders of cognitive functions, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.

The dosage required to achieve these effects in adults is appropriately, when administered intravenously, 0.5 to 100 mg, preferably 1 to 70 mg, and, when administered orally, 0.1 to 200 mg, preferably 1 to 100 mg, 1 to 3 times a day. For this purpose, the compounds of formula I prepared according to the invention, optionally in conjunction with other active substances such as, for example, hypotensive agents, ACE inhibitors, diuretics and/or calcium antagonists, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, micro-crystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene-glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

Examples of additional active substances which may be used in the combinations mentioned above include bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzothiazide, cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosin, atenolol, propranoloI, (di)hydralazine-hydrochloride, dlltiazem, felodipine, nicardipine, nifedipine, nisoldipine, nitrendipine, captopril, ~ a ~?~rl enalapril, lisinopril, cilazapril, quinapril, fosinopril and ramipril. The dosage of these active substances is conveniently 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dosage, that is for example 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorothiazide, 15 to 200 mg of ethacrinic acid, 5 to 80 mg of furosemide, 20 to 480 mg of propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipine or 5 to 60 mg of nitrendipine.

The following non-limiting Examples are provided to illustrate the invention. Unless otherwise specified, all percentages and ratios are by weight, other than eluant or solvent ratios which are by volume.

Example 1 4'-[(2-Ethyl-4-methyl-6~ methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2 carboxylic acid a) 2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazole A mixture of 4.5 g (21 mMol) of 1-methylamino-2-amino-4-fluoro-benzene-dihydrochloride and 4.3 g (21 mMol) of 2-ethyl-4 methyl-benzimidazol-6-yl-carboxylic acid is stirred for four hours at 140C in 100 g of polyphosphoric acid, then stirred into about 300 g of ice water and made alkaline with concentrated ammonia solution. The crude product precipitated is suction filtered, dried and then purified by column chromatography (300 g of silica gel; methylene chloride/ethanol = 95:5).
Yield: 3.1 g (48% of theory), Rf value: 0.24 (silica gel; methylene chloride/ethanol =
19 : 1 ) b) Tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate 616 mg (5.5 mMol) of potassium tert.butoxide are added to a solution of 1.55 g (5 mMol) of 2-ethyl-4-methyl-6-(l-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazole in 1 30 ml of dimethylsulphoxide and the resultin~ mixture is stirred for 15 minutes at ambient temperature. Then 1.9 g (5.5 mMol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate are added and stirring is continued for a further 20 hours at ambient temperature. The mixture is then stirred into about 80 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (150 g silica gel; eluant: methylene chloride/ethanol =

2 ~ ~ O c~

98:2).
Yield: 1.4 g (50% of theory), Rf value: 0.47 (silica gel; methylene chloride~ethanol =
19:1) c) 4'-[(2-Ethyl-4-m`ethyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenYl-2-carboxYlic acid A solution of 1.4 g (2.4 mMol) of tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and 15 ml of trifluoroacetic acid in 30 ml of methylene chloride is stirred for 14 hours at ambient temperature, then concentrated by evaporation, the residue is mixed with about 30 ml of water and made alkaline with 2N
sodium hydroxide solution. After extracting twice with 30 ml of diethyl ether, the a~ueous phase is acidified with 20% citric acid. The crude product precipitated is suction filtered and purified by column chromatography (100 g silica gel; eluant: methylene chloride/ethanol =
96:4).
Yield: 850 mg (69% of theory~, Melting point: 246-248~C
C32H27FN402 (518.60~
Calculated: C 74.11 H 5.25 N 10.80 Found: 73.95 5.34 10.80 Mass spectrum: m/e = 518 Example 2 4'-[(2-n-Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2 carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 87% of theory, 2~49Q~ ?J 7 Melting point: 269-271C
C29H3lN304S (517-65) Calculated: C 67.2~ H 6.04 N 8.12 Found: 67.56 6.12 8.28 Rf value: 0.39 (silica gel; methylene chloride/ethanol =
9 : 1 ) Mass spectrum: m/e = 517 Exam~le 3 4'-[(2-Cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 50% of theory, Melting point: 245-248C
C32H26N402 (498-59) Calculated: C 77.09 H 5.26 N 11.24 Found: 76.88 5.37 11.30 Rf value: 0.63 (silica gel; methylene chloride/ethanol =
9 : 1 ) Mass spectrum: m/e = 498 Example 4 4'-[(2-Cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 53% of theory, 2 ~L ~ 2 1 Melting point: 310-312C
C32H30N402 (502.62) Calculated: C 76.47 H 6.02 N 11.15 Found: 76.23 5.97 10.85 Rf value: 0.17 (silica gel; methylene chloride/ethanol =
9 : 1 ) Mass spectrum: m/e = 502 Example 5 4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol 5-yl)-biphenyl - a) 4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl 616 mg (5.5 mMol) of potassium tert.butoxide are added to a solution of 1.55 g (5 mMol) of 2-ethyl 4-methyl-6-(l-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazole in 30 ml of dimethylsulphoxide and the mixture is stirred for 15 minutes at ambient temperature. Then 1.5 g (5.5 mMol) of 4'-bromomethyl-2-cyano-biphenyl are added and the resulting mixture is stirred for a further 20 hours at ambient temperature. Then the mixture is stirred into approximately 80 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography I (150 g of silica gel; eluant: methylene chloride/ethanol = 97:3).
Yield: 1.9 g (76~ of theory), Rf value: 0.43 (silica gel; methylene chloride/ethanol =
19 : 1 ) 2~3 ~2'~

b) 4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetr zol-5-yl)-biphenyl A solution of 1.9 g (3.8 mMol) of 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-~luoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl, 4.1 g (76 mMol) of ammonium chloride and 4.9 g (76 mMol) of sodium azide in 30 ml of dimethylformamide is heated to 140C for 15 hours, then a further 2.0 g of ammonium chloride and 2.4 ~ of sodium azide are added and the mixture is heated for another 4 hours to 140~C. Then the solution is stirred into about 80 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography tl50 g of silica gel; eluant: methylene chloride/ethanol = 19:1).
Yield: 1.25 g (61% of theory), Melting point: 267-269C
c32H27FN8 (542-60) Calculated: C 70.84 H 5.02 N 20.65 Found: 70.52 5.04 20.82 Rf value: 0.60 (silica gel; methylene chloride/ethanol =
9 : 1 ) Mass spectrum: m/e = 542 Example 6 4'-[(2-Ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl a) 4'-[(2-Ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl To a solution of 570 mg (1.86 mMol) of 2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazole in 20 ml of dimethylsulphoxide are added 224 mg (2.0 mMol) of potassium tert.butoxide and the mixture is stirred for 15 minutes at ambient temperature. Then 1.11 g 2 ~ 2 ~

(2.0 mMol) of 4'-bromomethyl-2~(2-triphenylmethyl-tetrazol-5-yl)-bipheny'l are added and the mixture is stirred for a further 3 hours at ambient temperature.
Then the mixture is stirred into about 50 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (100 g silica gel; eluant: ethyl acetate/petroleum ether = 4:1).
Yield: 860 mg (59% of theory), R~ value: 0.56 (silica gel; ethyl acetate/petroleum ether = 4:1) b) 4'-[(2-Ethoxy-4-methyl-6-(1-methyl-benzimidazol~2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biPhenylA mixture of 830 mg (1.06 mMol) of 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl, 2.5 ml of lN sodium hydroxide solution and 20 ml of ethanol is stirred for 2 hours at 80C. The solution is then evaporated down, the residue is mixed with about 30 ml of water and made slightly acidic with glacial acetic acid. It is then extracted three times with about 20 ml of methylene chloride, the combined organic extracts are washed with 20 ml of water and concentrated by evaporation. The crude product thus obtained is purified by column chromatography (50 g silica gel; methylene chloride/ethanol = 97:3).
Yield: 430 mg (75~ of theory), Melting point: 194-197~C
C32H2sNs (540.60) Calculated: C 71.10 H 5.22 N 20.73 Found: 69.99 5.36 20.54 Mass spectrum: m/e = ~70 ~c~a~1~ 2 ~

Example 7 4'-[(2-Ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid-hydrate -Prepared analogously to Example 1 from tert.butyl 4'-[(2-ethoxy-4-methyl-6~(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 72% of theory, Melting point: 207-209C
C3~H26N403 x H20 (520.60) Calculated: C 71.52 H 5.42 N 10.76 Found: 71.22 5.37 10.76 Rf value: 0.36 (silica gel; methylene chloride/ethanol =
19 : 1 ) Example 8 Mixture of 4'-[(2 n-Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-l-yl)-methyl]-2-[1-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl and 4'-[(2-n Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-l-yl)-methyl]-2-[2-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl A solution of 400 mg (0.74 mMol) of 4'-[(2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, 0.16 ml (1.1 mMol) of chloromethyl pivalate and 194 mg (1.1 mMol) of potassium carbonate-dihydrate in 10 ml of dimethylformamide is stirred for 14 hours at ambient temperature, then stirred into about 50 ml of saturated sodium chloride solution and extracted three times with about 20 ml of methylene chloride. The combined or~anic extracts are washed with water and evaporated down. The crude product thus obtained is purified by column chromatography (50 ~ silica gel; eluant: methylene chloride/ethanol = 98:2).
Yield: 400 mg (82% of theory), Melting point: amorphous C3sH41N704S (655.80) Calculated: C 64.10 H 6.30 N 14.95 S 4.88 Found: 63.99 6.22 14.80 5.03 Rf value: 0.46 (silica gel; methylene chloride/ethanol =
19 : 1 ) ~=,~

Mixture of 4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-[1-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl and 4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-[2-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl Prepared analogously to Example 8 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl and chloromethylpivalate.
Yield: 75% of theory, Melting point: 203-205C
C38H42N8O2 (642.80) Calculated: C 71.00 H 6.59 N 17.43 Found: 70.85 6.63 17.43 Rf value: 0.43 (silica gel; methylene chloride/ethanol =
19 ~
Mass spectrum: m/e = 642 2rl Example 10 4'-[(2-n-Propyl-4-methyl-6 (5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-[l-(cyclohexyloxycarbonyloxy) ethyloxycarbonyl]-biphenyl -A solution of 504 mg (1.0 mMol) of 4l-[(2-n-propyl~4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, 600 mg of l-(cyclohexyloxycarbonyloxy)-ethyliodide and 350 mg of potassium carbonate in 25 ml of dimethylsulphoxide is stirred for 14 hours at ambient temperature, then stirred into about 70 ml of saturated sodium chloride solution and extracted three times with 30 ml of ethyl acetate. The combined organic extracts are washed with water and evaporated down. The crude product thus obtained is purified by column chromatography (100 g silica gel; eluant: methylene chloride/ethanol = 98:2).
Yield: 325 mg (48% of theory), Melting point: 162-164C
C41H46N4O5 (674.85) Calculated: C 72.97 H 6.87 N 8.30 Found: 72.63 6.77 8.17 Rf value: 0.52 (silica gel; methylene chloride/ethanol =
19 : 1 ) Mass spectrum: m/e = 674 Example 11 4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidaæol-1-yl)-methyl]-2-(pivaloyloxymethyloxycarbonyl)-biphenyl Prepared analogously to Example 8 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic 3 ~ ~

acid and chloromethylpi~alate in dimethylformamide.
Yield: 76% of theory, Melting point: 142-144C
C38H42N4O4 (618.79) Calculated: C 73.76 H 6.84 N 9.09 Found: 73.60 6.92 9.17 Rf value: 0.40 (silica gel; methylene chloride/ethanol =
19 : 1 ) Mass spectrum: m/e = 618 Example 12 4'-[(2-n-Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(pivaloyloxymethyloxy-carbonyl)-biphenyl Prepared analogously to Example 8 from 4'-[(2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and chloromethylpivalate in dimethylformamide.
Yield: 70% of theory, Melting point: Oil C3sH41N36S (631.80) Calculated: C 66.54 H 6.54 N 6.65 S 5.08 Found: 66.21 6.67 6.54 5.34 Rf value: 0.49 (silica gel; methylene chloride/ethanol =
19 : 1 ) Mass spectrum: m/e = 631 Example 13 4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-[1-(ethoxycarbonyloxymethyloxy)-carbonyl]-biphenyl Prepared analogously to Example 8 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid and 1-(ethoxycarbonyloxy)-methylchloride in dimethylformamide.
~ield: 38.5% of theory, Melting point: 123-125~C
C3lH40N405 (620.76) Calculated: C 71.59 H 6.50 N 9.03 Found: 71.57 6.58 9.03 Rf value: 0.33 (silica ~el; methylene chloride/ethanol =
19 : 1 ) Mass spectrum: m/e = 620 Example 14 4'-[(2-Ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl r Prepared analogously to Example 6 from 4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium hydroxide solution in ethanol.

Example 15 4'-[(2-Ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 6 from 4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-y~)-biphenyl and sodium hydroxide solution in ethanol.

2 '~

Example 16 4'-[(2-Ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 63% of theory, Melting point: 238-240C
Rf value: 0.62 (silica gel; methylene chloride/ethanol =
9:1) Example 17 4'-[(2-Ethyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(butanesultam-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 68~ of theory, Melting point: > 240C
C28H29N34S (503.60) Calculated: C 66.77 H 5.80 N 8.34 Found: 66.57 5.69 8.30 Rf value: 0.36 (silica gel; methylene chloride/ethanol =
9 : 1 ) 2 ~ ; 2~1 Example 18 4'-[(2-Ethyl-4-methyl-6-(3-chloro-5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl3-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4' [(2-ethyl-4-methyl-6-(chloro-5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 43% of theory, Melting point: 295-297C
C3lH29ClN402 (525-06) Calculated: C 70.91 H 5.57 N 10.67 Cl 6.75 Found: 70.81 5.54 10.55 6.83 Rf value: 0.36 (silica gel; methylene chloride/ethanol =
9 : 1 ) 2 ~ ~ ~ b ~

In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I, particularly those wherein R4 represents a tetrazolyl group substituted in the 1- or 2-position by an Ra~CO-O-CH2 group, or wherein R4 denotes a carboxy, lH-tetrazolyl, RaO-C0-, Rb-CO-O-(RCCH)-O-CO- or RbO-CO-O-(RCCH)-O-CO-group, may be used as the active substance:

Example I

Ampoules containing 50 mg of active substance per 5 ml Composition Active substance 50 mg KH2PO4 2 mg Na2HP04 x 2H20 50 mg NaCl 12 mg Water for injections ad 5 ml PreParation:

The buffer substances and isotonic substance are dissolved in some of the water. The active substance is added and, once it has been completely dissolved, water is added to make up the required volume.

Example II

I Ampoules containing 100 mg of active substance per 5 ml -Composition Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene-glycol block polymer 250 mg 2 ~

Water for injections ad 5 ml Preparation:

Methyl glucamine is dissolved in some of the water and the active substance is dissolved with stirring and heating. After the addition of solvents, water is added to make up the desired volume.

Example III

Tablets containing 50 mg of active substance Composition Active substance 50.0 mg Calcium phosphate 70.0 mg Lactose 40.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 1.5 mg 200.0 mg Preparation:

The active substance, CaHPO4, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50C in a circulating air dryer and screened again.
I!
After the lubricant has been added, the granules are compressed in a tablet making machine.

Example IV

Coated tablets containing 50 mg of active substance 2 ~J ~
- ~7 -Composition Active substance 50.0 mg Lysine 25.0 mg Lactose 60.0 mg Corn starch 3~.0 mg Gelatin 10.0 mg Magnesium stearate 1.0 mq 180.0 ~g Preparation:

The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying, the granules are mixed with magnesium stearate and compressed to form tablet cores.

The cores thus produced are covered with a coating by known methods. A colouring may be added to the coating suspension or solution.

Example V

Coated tablets containing 100 mg of active substance Composition Active substance 100.0 mg Lysine 50.0 mg Lactose 86.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 2.8 mg Microcrystalline cellulose60.0 mg Magnesium stearate 1.2 mg 350.0 mg 2 ~

Preparation:

The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm screen and dried at 45C.
After drying, it is-s~reened again and the magnesium stearate is added. This mixture is compressed into cores.

The cores thus produced are covered with a coating by known methods. Colourings may be added to the coating suspension or solution.

Example VI
.~
Capsules containing 250 mg of active substance -Composition Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 mq 320.0 mg Preparation:

The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The final mixture is packed into size 1 hard gelatin capsules.

Example VII

Oral suspension containing 50 mg of active substance per 5 ml .

21 ~ ~ ~ 2 ~

Composition Active substance 50.0 mg Hydroxyethylcellulose 50~0 mg Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg Water ad 5.0 ml Preparation:

Distilled water is heated to 70C. Hydroxyethyl-cellulose is dissolved therein with stirring. By the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and active substance are added. The suspension is evacuated with stirring to remove any air. One dose of 50 mg is contained in 5.0 ml.

Example VIII

Suppositories containing 100 mg of active substance Com~position Active substance 100.0 mg Solid fat 1600.0 m~
1700.0 mg .
Preparation:

The hard fat is melted. At 40C the yround active substance is homogeneously dispersed in the melt. It is cooled to 38C and poured into slightly chilled suppository moulds.

Claims (17)

1. Compounds of formula I:

(I) (wherein R1 denotes a hydrogen, fluorine, chlorine or bromine atom or a C13-alkyl, C3-7-cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group;

R2 denotes a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene group in a homophthalimino group may be substituted by one or two C1-3-alkyl groups, or R2 denotes a 5-, 6- or 7-membered alkyleneimino group (optionally substituted by one or two C1-3-alkyl groups) in which a methylene group is replaced by a carbonyl or sulphonyl group, or R2 denotes a maleic acid imido group optionally mono-or disubstituted by a C1-3-alkyl group or by a phenyl group, wherein the substituents may be identical or different, or R2 denotes a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group optionally substituted in the 1-position by a C1-6-alkyl group or by a C3-5-cycloalkyl group or in the phenyl nucleus thereof by a fluorine atom or by a methyl or trifluoromethyl group, or R2 denotes an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, 3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-

2-yl, imidazo[1,2-b]-pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or a carbon attached pyrrolidine, piperidine or pyridine ring wherein a phenyl group may be condensed on to the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or R2 denotes an R7-NR6-CO-NR5- group wherein R5 denotes a hydrogen atom or a C1-5-alkyl, cyclohexyl or benzyl group, R6 denotes a hydrogen atom or a C1-6-alkyl, allyl, cyclohexyl, benzyl or phenyl group, R7 denotes a hydrogen atom or a C1-3-alkyl group, or R6 and R7 together with the nitrogen atom between them denote an unbranched cyclic C4-6-alkyleneimino group or a morpholino group, or R5 and R6 together denote a C2-3-alkylene group;

R3 denotes a C1-5-alkyl, C3-5-cycloalkyl, or C1-3-alkoxy group; and R4 denotes a tetrazolyl group substituted in the 1- or 2-position by an Ra-CO-O CHz- group, or an Rb-CO-O-(RcCH)-O-CO-, RaO-CO- or RbO-CO-O-(RcCH)-O-CO-group, wherein Ra denotes a straight-chained or branched C1-6-alkyl group or a C5-7-cycloalkyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, Rb denotes a straight-chained or branched C1-6-alkyl group or a C5-7-cycloalkyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group and Rc denotes a hydrogen atom or a methyl group, or if (i) R3 denotes an alkoxy group, R4 may also denote a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group or, if (ii) R2 is other than a 1-methyl-benzimidazol-2-yl group and R3 denotes a cyclopropyl group, R4 may also represent a carboxy group or, if (iii) R2 denotes a butanesultam-1-yl group, R4 may also denote a carboxy group or, if (iv) R2 denotes a 1-methyl-5-fluoro-benzimidazol-2-yl group and R3 denotes an ethyl group, R4 may also represent a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group) and the tautomers and the salts thereof.

2. Compounds of formula I as claimed in claim 1, wherein R1 denotes a hydrogen atom or in the 4-position a chlorine atom, a C1-3-alkyl group or a trifluoromethyl group;

R2 denotes a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group, or R2 denotes a 5-, 6- or 7-membered alkyleneimino group in which a methylene group is replaced by a carbonyl or sulphonyl group, or R2 denotes a maleic acid imido group optionally mono-or disubstituted by a methyl or phenyl group, wherein the substituents may be identical or different, or R2 denotes a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group optionally substituted in the 1-position thereof by a C1-6-alkyl group or by a cycloalkyl group or in the phenyl nucleus thereof by a fluorine atom or a methyl or trifluoromethyl group, or R2 denotes an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, 3-chloro-5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or R2 denotes an R7-NR6-CO-NR5- group wherein R5 denotes a hydrogen atom or C15-alkyl, cyclohexyl or benzyl group, R6 denotes a hydrogen atom or a C1-6-alkyl, allyl, cyclohexyl, benzyl or phenyl group, R7 denotes a hydrogen atom or a C1-3-alkyl group, or R6 and R7 together with the nitrogen atom between them denote a straight-chained C4-6-alkyleneimino group or a morpholino group, or R5 and R6 together denote a C2-3-alkylene group;

R3 denotes a C1-5-alkyl, C3-5-cycloalkyl, or C2-3-alkoxy group; and R4 denotes a tetrazolyl group substituted in the 1- or 2-position by an Ra-CO-O-CH2- group, or an Rb-CO-O-(RcCH)-O-CO-, RaO-CO- or RbO-CO-O-(RcCH)-O-CO-group, wherein Ra denotes a straight-chained or branched C1-6-alkyl group or a C5-7-cycloalkyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, Rb denotes a straight-chained or branched C1-6-alkyl group or a C5-7-cycloalkyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group and Rc denotes a hydrogen atom or a methyl group, or, if (i) R3 denotes an alkoxy group, R4 may also denote a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group or, if (ii) R2 is other than a 1-methyl-benzimidazol-2-yl group and R3 denotes a cyclopropyl group, R4 may also represent a carboxy group or, if (iii) R2 denotes a butanesultam-1-yl group, R4 may also denote a carboxy group or, if (iv) R2 denotes a 1-methyl-5-fluoro-benzimidazol-2-yl group and R3 denotes an ethyl group, R4 may also represent a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group, and the tautomers and the salts thereof.

3. Compounds of formula I as claimed in claim 1 or claim 2 wherein R1 denotes a hydrogen atom or in the 4-position a methyl group;

R2 denotes an imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, 3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, 1-methyl-benzimidazol-2-yl, 1-methyl-5-fluoro-benzimidazol-2-yl or butanesultam-1-yl group;

R3 denotes a C24-alkyl group, a cyclopropyl group or a C2-3-alkoxy group; and R4 denotes a tetrazolyl group substituted in the 1- or 2-position by an Ra-CO-O-CH2- group, or an Rb-CO-O-(RcCH)-O-CO-, RaO-CO- or RbO-CO-O-(RcCH)-O-CO-group, wherein Ra denotes a straight-chained or branched C1-6-alkyl group or a C5-7-cycloalkyl, benzyl,1l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, Rb denotes a straight-chained or branched C1-6-alkyl group or a C5-7-cycloalkyl, phenyl, benzyl, 1-phenylethyl, 2 phenylethyl or 3-phenylpropyl group and Rc denotes a hydrogen atom or a methyl group;

and the tautomers and the salts thereof.

4. Compounds of formula I as claimed in claim 1 being:

4'-[(2-cyclopropyl-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

4'-[(2-ethoxy-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

4'-[(2-ethoxy-4-methyl-6-(4,5,6,7-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl;

4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl;

4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5 yl)-biphenyl;

4'-[(2-ethyl-4-mathyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl) benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl;

4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol 1-yl)-methyl]-biphenyl-2-carboxylic acid; or 4'-[(2-n-propyl 4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

and the tautomers and the salts thereof.

5. Compounds of formula I as claimed in claim 1 being:

(a) 4' [(2-ethyl-4-methyl-6-(1 methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

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

(c) 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

(d) 4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid; or (e) 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl;

and the tautomers and the salts thereof.

6. A compound as claimed in any one of claims 1 to 5 being a physiologically acceptable salt of a compound of formula I as claimed in any one of claims 1 to 5.

7. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients.

8. Process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps:

a) cyclising a compound of formula II

(II) (wherein R1 and R2 are as defined in any one of claims 1 to 5, one of the groups X1 or Y1 represents a group of formula and the other group X1 or Y1 represents a group of the formula wherein R3 and R4 are as defined in any one of claims 1 to 5, R7 represents a hydrogen atom or an R3CO- group, wherein R3 is defined as hereinbefore, Z1 and Z2, which may be identical or different, represent amino, hydroxy or mercapto groups optionally substituted by C1-6-alkyl groups or Z1 and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C1-3-alkyl group, or a C2-3-alkylenedioxy or C2-3-alkylenedithio group) optionally formed in the reaction mixture or a hydroxylamine equivalent thereof and if required reducing an N-oxide thus obtained;

b) reacting a benzimidazole of formula III

(III) (wherein R1, R2 and R3 are as defined in any one of claims 1 to 5) with a biphenyl compound of formula IV

(IV) (wherein R4 is as defined in any one of claims 1 to 5 and Z3 represents a nucleophilic leaving group);

c) (to prepare a compound of formula I wherein R4 represents a carboxy group) converting a compound of formula V

(V) (wherein R1, R2 and R3 are as defined in any one of claims 1 to 5 and R4' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis;

d) (to prepare a compound of formula I wherein R4 represents a 1H-tetrazolyl group) cleaving a protecting group from a compound of formula VI

(VI) (wherein R1, R2 and R3 are as defined in any one of claims 1 to 5 and R4" represents a 1H-tetrazolyl group protected in the 1-or 3-position by a protecting group);

e) (to prepare a compound of formula I wherein R4 represents a 1H-tetrazolyl group) reacting a compound of formula VII

(VII) (wherein R1, R2 and R3 are as defined in any one of claims 1 to 5) with hydrazoic acid or a salt thereof;

f) (to prepare a compound of formula I wherein R4 denotes a tetrazolyl group substituted in the 1- or 2-position by an Ra-CO-O-CH2- group or R4 denotes an RaO-CO-, Rb-CO-O-(RcCH)-O-CO- or RbO-CO-O-(RcCH)-O-CO- group) reacting a compound of formula VIII

(VIII) (wherein R1, R2 and R3 are as defined in any one of claims 1 to 5 and R4"' denotes a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group) with a compound of formula IX

Z4 - Y2 (IX) (wherein Y2 denotes an Ra-CO-O-CH2-, Rb-CO-O-(RcCH)-, RbO-CO-O-(RcCH)- or Ra- group, wherein Ra, Rb and Rc are as defined in any one of claims 1 to 5 and Z4 denotes a nucleophilic leaving group or, if Y denotes an Ra- group, Z4 may denote a hydroxy group);

g) resolving a 1-, 3 isomer mixture of a compound of formula I thus obtained into the 1- and 3-isomers thereof;

h) converting a compound of formula I thus obtained into a salt thereof, more particularly, for pharmaceutical use, into a physiologically acceptable salt thereof with an inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound;
and i) performing a process as defined in any one of steps (a) to (h) above on a corresponding protected compound and subsequently removing the protecting group used.

9. Use of a compoound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable sapt thereof for the manufacture of a therapeutic agent having an angiotensin-antagonistic activity.

10. Use of a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension and cardiac insufficiency and for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.

11. Use of a compound as claimed in claim 10 for treating pulmonary diseases, for preventing arterial re-stenosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, arteriosclerosis and diabetic angiopathy.

12. Use of a compound as claimed in claim 10 for the treatment of depression, Alzheimer's disease, Parkinson's syndrome, bulimia and disorders of cognitive functions.

13. A method of treatment of the human or non-human animal body for the treatment of hypertension and cardiac insufficiency and for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.

14. A method of treatment as claimed in claim 13 for treating pulmonary diseases, for preventing arterial re-stenosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, arteriosclerosis and diabetic angiopathy.

15. A method of treatment as claimed in claim 13 for the treatment of depression, Alzheimer's disease, Parkinson's syndrome, bulimia and disorders of cognitive functions.

16. A compound of formula I as claimed in claim 1 or a pharmaceutical composition thereof substantially as herein disclosed in any one of the Examples.

17. Each and every novel compound, composition, process, use and method as herein disclosed.