CA2087800A1 - Benzimidazoles, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents

Benzimidazoles, pharmaceutical compositions containing these compounds and processes for preparing them

Info

Publication number
CA2087800A1
CA2087800A1 CA002087800A CA2087800A CA2087800A1 CA 2087800 A1 CA2087800 A1 CA 2087800A1 CA 002087800 A CA002087800 A CA 002087800A CA 2087800 A CA2087800 A CA 2087800A CA 2087800 A1 CA2087800 A1 CA 2087800A1
Authority
CA
Canada
Prior art keywords
methyl
imidazol
group
formula
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002087800A
Other languages
French (fr)
Inventor
Norbert Hauel
Berthold Narr
Uwe Ries
Jacques Van Meel
Wolfgang Wienen
Michael Entzeroth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Dr Karl Thomae GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE4201554A external-priority patent/DE4201554A1/en
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Publication of CA2087800A1 publication Critical patent/CA2087800A1/en
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

ABSTRACT
Benzimidazoles The invention relates to benzimidazoles of formula I
(I) (wherein R1, R2, R3 and R4 are as defined in the claims) and the addition salts thereof, compounds which have valuable properties, in particular, as angiotensin-II
antagonists.

Description

~7~0 59063.556 Benzimidazoles The present invention relates to new benzimidazoles, processes for their preparation and pharmaceutical compositions containing them.
EP-A-392317 describes benzimidazoles which are valuable angiotensin antagonists.
It has now been found that certain new benzimidazoles are even more useful angiotensin antagonists, particularly angiotensin-II-antagonists.
Thus, according to one aspect the present invention provides compounds of formula I:

Rl R~- ~ ~ Rg R
2 ~ ~ ~

(I) (wherein R1 represents a C13-alkyl group, a hydrogen, fluorine, chlorine or bromine atom;

R2 represents an oxazol-4-yl or thiazol-4-yl group optionally substituted in the 2-position by a C16-alkyl group or by a phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a C16-alkyl group or by a phenyl group and substituted in the l-position by a C17-alkyl group optionally substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, , .

2~7~0 alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or l-oxido-thiomorpholinocarbonyl group, by a C2~,-alkyl group substituted in the 2-, 3- or ~-position by a hydroxy, alkoxy, alkoxyalkoxy, dialXylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, l-oxido-thiomorpholino or imidazol-l-yl group, by a C13-alkyl group substituted by a trifluoromethyl group, by a C37-cycloalkyl group or by a phenyl group itself optionally mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, by a C13-alkyl group substituted by two phenyl groups, or by a C37-cycloalkyl group;

where unless otherwise specified the above mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms;

R3 represents a C24-alkyl, C23-alkoxy, C23-alkylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy, cyano, lH-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group or a group convertable in vivo into a carboxy group);

and the salts thereof, particularly, for pharmaceutical use, the physiologically acceptable salts thereof with inorganic or organic acids or bases.

The term "a group convertable in vivo into a ' 2~7~0 carboxy group" may denote, for example, carboxyl esters such as those of formulae - CO OR', - CO - O - (HCR") - O - CO - R"' and - CO - O - (HCR") - O - CO - OR"' (wherein R' denotes a straight-chained or branched C16-alkyl group or C57-cycloalkyl, benzyll l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, ~, R" denotes a hydrogen atom or a methyl group, and R"' denotes a straight-chained or branched C16-alkyl group or a C57-cycloalkyl, phenyl, benzyl, l-phenylethyl, 2-phenylethyl or 3-phenylpropyl group).

The ~ollowing are examples of the definitions o~
groups R1 to R4 given hereinbe~ore:

R1 may represent a hydrogen, fluorine or chlorlne atom, a methyl, ethyl, n-propyl or isopropyl group;

R2 may represent an oxazol-4-yl, 2-methyl-oxazol-4-yl, 2-ethyl-oxazol-4-yl, 2-n-propyl-oxazol-4-yl, 2-isopropyl-oxazol-4-yl, 2-n-butyl-oxazol-4-yl, 2-isobutyl-oxazol-4-yl, 2-n-pentyl-oxazol-4-yl, 2-isoamyl-oxazol-4-yl, 2-n-hexyl-oxazol-4 yl, 2-phenyl-oxazol-4-yl, thiazol-4-yl, 2-methyl-thiazol-4-yl, 2-ethyl-thiazol-4-yl, 2-n-propyl-thiazol-4-yl, 2-isopropyl-thiazol-4-yl, 2-n-butyl-thiazol-4-yl, 2-isobutyl-thiazol-4-yl, 2-n-pentyl-thiazol-4-yl, 2-isoamyl-thiazol-4-yl, 2-n-hexyl-thiazol-4-yl, 2-phenyl-thiazol-4-yl, 1-methyl-imidazol-4-yl, 1-ethyl-imidazol-4-yl, 1-n-propyl-imidazol-4-yl, 1-isopropyl-imidazol-4-yl, 1-n-butyl-imidazol-4-yl, 1-isobutyl-imidazol-4-yl, 1-n-pentyl-imidazol-4-yl-, l-, 2087~0 - 4 - .
isoamyl-imidazol-4-yl, 1-n-hexyl-imidazol-4-yl, l-n-hexyl-2-methyl-imidazol-4-yl, l-(l-methyl-n-pentyl)-imidazol-4-yl, 1-(1-ethyl-n-butyl)-imidazol-4-yl, 1-(1-methyl-n-hexyl)-imidazol-4-yl, l-(l-ethyl-n pentyl)-imidazol-~-yl, l~ n-propyl-n-butyl)-imidazol-4-yl, 1-n-heptyl-imidazol-4-yl, 1-ethyl-2-methyl-imidazol-4-yl, l-n-propyl-2-methyl-imidazol-4-yl, 1-isopropyl-2~methyl-imidazol-4-yl, 1-n-butyl-2-methyl-imidazol-4-yl, 1-isobutyl-2-methyl-imidazol-4-yl, 1-n-pentyl-2-methyl-imidazol-4-yl, 1-isoamyl-2-methyl~imidazol-4-yl, l-n-hexyl-2-methyl-imidazol-4-yl, 1-n-heptyl-2-methyl-imidazol-4-yl, 1-cyclopropylmethyl-imidazol-4-yl, 1-cyclobutylmethyl-imidazol-4-yl, l-cyclopentylmethyl-imidazol-4-yl, 1-cyclohexylmethyl-imidazol-4-yl, 1-cycloheptylmethyl-imidazol-4-yl, 1-(2-cyclo-propylethyl~-imidazol-4-yl, 1-(2-cyclobukylethyl)-imidazol-4-yl, 1-(2-cyclopentylethyl)-imidazol-4-yl, 1-(2-cyclohexylethyl~-imidazol-4-yl, 1-(2-cycloheptyl~
ethyl)-imidazol-4-yl, 1-(3-cyalopropylpropyl)~imidazol-4-yl-, 1-(3-cyclobutylpropyl)-imidazol-4-yl, 1-(3-cyclopentylpropyl)-imidazol-4-yl, 1-(3-cyclohexyl-propyl)-imidazol-4-yl, 1-(3-cycloheptylpropyl)-imidazol-4-yl, 1-(2,2,2-trifluoroethyl)-imidazol-4-yl, 1-(3,3,3-~rifluoropropyl)-imidazol-4-yl, 1-benzyl-imidazol-4-yl, 1-(2-phenylethyl)-imidazol-4-yl, 1-(3-phenylpropyl)-imidazol-4-yl, 1-(4-fluorobenzyl)-imidazol-4-yl, 1-(4-chlorobenzyl)-imidazol-4-yl, l-(~-chlorobenzyl)-imidazol-4-yl, 1-(4-trifluoromethyl-benzyl)-imidazol-4-yl, 1-(3-methyl-benzyl)-imidazol-4-yl, 1-(4-methyl-benY.yl)-imidazol-4-yl, 1-(3-methoxy-benzyl)-imidazol-4-yl, 1-(4-methoxy-benzyl)-imidazol-4-yl, 1-(3,4-dimethoxy-benzyl)-imidazol-4-yl, 1-(3,5-dimethoxy-benzyl)-imidazol-4-yl, 1-cyclopropylmethyl-2-methyl-imidazol-4-yl, 1-cyclobutylmethyl-2-methyl-imidazol-4-yl, 1-cyclopentylmethyl-2-methyl-imidazol-4-yl, 1-cyclohexylmethyl-2-methyl-imidazol-4-yl, l-cyclo-heptylmethyl-2-methyl-imidazol-4-yl, 1-(2-, . .

2~78~0 cyclopropylethyl)-2-methyl-imidazol-4-yl, 1-(2-cyclobutylethyl)-2-methyl-imidazol-4-yl, 1-(2-cyclopentylethyl)-2-methyl-imidazol-4-yll 1-(2-cyclohexylethyl)-2-methyl-imidazol-4-yl, 1-(2-cyc~oheptylethyl)-2-methyl-imidazol-4-yl, 1-(3-cyclopropylpropyl)-2-methyl-imidazol-4-yl, 1-(3-cyclobutylpropyl~-2-methyl-imidazol-4-yl, 1-(3-cyclopentylpropyl)-2-methyl-imidazol-4-yl, 1-(3-cyclohexylpropyl)-2-methyl-imidazol~4-yl, 1-(3-cycloheptylpropyl)-2-methyl-imidazol-4-yl, 1-(2,2,2-trifluoroethyl)-2-methyl-imidazol-4-yl-, 1-(3,3,3-trifluoropropyl)-2-methyl-imidazol-4-yl-, 1-benzyl-2-methyl-imidazol-4-yl, 1-(2-phenylethyl)-2-methyl-imidazol-4-yl, 1-(3-phenylpropyl)-2-methyl-imidazol-4-yl, l-(4-fluorobenzyl)-2-methyl-imidazol-4-yl, 1-(4-chlorobenzyl)-2-methyl-imidazol-4-yl, 1-(3-chloro-benzyl)-2-methyl-imidazol-4-yl, 1-(4-trifluoromethyl-benzyl)-2-methyl-imidazol-4-yl, 1-(3-methyl-benzyl)-2-methyl-imidazol-4-yl, 1-(4-methyl-benzyl)-2-methyl-imidazol-4-yl, 1-(3-methoxy-benzyl)-2-methyl-imidazol-4-yl, 1-(4-methoxy-benzyl)-2-methyl-imidazol-4-yl, 1-(3,4-dimethoxy-benzyl)-2-methyl-imidazol-4-yl, 1 (3,5-dimethoxy-benzyl)-2-methyl-imidazol-4-yl, 1-carboxymethyl-imidazol-4-yl, 1-(2-carboxyethyl)-imidazol-4-yl, 1-~3-carboxypropyl)-imidazol-4-yl, 1-(4-carboxybutyl)-imidazol-4-yl, 1-(5-carboxypentyl)-imidazol-4-yl, 1-(6-carboxyhexyl)-imidazol-4-yl, 1-(7-carboxyheptyl)-imidazol-4-yl, l-methoxycarbonylmethyl-imidazol-4-yl, 1-(2-methoxycarbonylethyl)-imidazol-4-yl, 1-(3-methoxycarbonylpropyl)-imidazol-4-yl, 1-(4-methoxycarbonylbutyl)-imidaæol-4-yl, 1-(5-methoxycarbonylpentyl)-imidazol-4-yl, 1-(6-methoxycarbonylhexyl)-imidazol-4-yl, 1-(7-methoxy-carbonylheptyl)-imidazol-4-yl, l-ethoxycarbonylmethyl-imidazol-4-yl, 1-(2-ethoxycarbonylethyl)-imidazol-4-yl, 1-(3-ethoxycarbonylpropyl)-imidazol-4-yl, 1-(4-ethoxycarbonylbutyl)-imidazol-4-yl, 1-(5-ethoxycarbonyl-20~78~D

pentyl)-imidazol-4-yl, 1-(6-ethoxycarbonylhexyl)-imidazol-4-yl, 1-(7-ethoxycarbonylheptyl)-imidazol-4-yl, 1-n-propoxycarbonylmethyl-imidazol-4-yl, 1-(2-n-propoxycarbonylethyl)-imidazol-4-yl, 1-(3-n-propoxycarbonylpropyl)-imidazol-4-yl, 1-(4-n-propoxy carbonylbutyl)-imidazol-4-yl, 1-(5-n-propoxycarbonyl-pentyl)-imidazol-4-yl, 1-(6-n-propoxycarbonylhexyl)-imidazol-4-yl, 1-(7-n-propoxycarbonylheptyl)-lmidazol-4-yl, l-isopropoxycarbonylmethyl-imidazol-4-yl, 1-(2-isopropoxycarbonylethyl)-imidazol~4-yl, 1-(3-isopropoxycarbonylpropyl)-imidazol-4-yl, 1-(4-isopropoxycarbonylbutyl)-imidazol-4-yl, 1-(5-isopropoxycarbonylpentyl)-imidazol-4-yl, 1-(6-isopropoxycarbonylhexyl)-imidazol-4-yl, 1-(7-isopropoxycarbonylheptyl)-imidazol-4-yl, 1-aminocarbonylmethyl-imidazol 4-yl, 1-(2~aminocarbonyl-ethyl)-imidazol-4-yl, 1-(3-aminocarbonylpropyl)-imidazol-4-yl, 1-(4-aminocarbonylbutyl)-imidaæol-4-yl, 1-(5-aminocarbonylpentyl)-imidazol-4-yl, 1-(6-aminocarbonylhexyl)-imidazol-4-yl, 1-(7-aminocarbonyl-heptyl)-imidazol-4-yl, l-methylaminocarbonylmethyl-imidazol-4-yl, 1-(2-methylaminocarbonyle~hyl)-imidazol-4-yl, 1-(3-methylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-methylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-methylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-methylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-methylaminocarbonylheptyl)-imidazol-4-yl, 1-ethylaminocarbonylmethyl-imidazol-4-yl, 1-(2-ethylamino-carbonylethyl)-imidazol-4-yl, 1-(3-ethylaminocarbonyl-propyl)-im.idazol-4-yl, 1-(4-ethylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-ethylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-ethylaminocarbonylhe~yl)-imidazol-4-yl, 1-(7-ethylaminocarbonylheptyl)-imidazol-4-yl, l-n propylaminocarbonylmethyl-imidazol-4-yl, 1-(2-n-propylaminocarbonylethyl)-imidazol-4-yl, 1-(3-n-propylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-n-propylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-n-;

:

2~878~

propylaminocarbonylpentyl)-imidazol-4-yl, 1 (6-n-propylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-n-propylaminocarbonylheptyl)-imidazol-4-yl, 1-isopropylaminocarbonylmethyl-imidazol-4-yl, 1-(2-isopropylaminocarbonylethyl)-imidazol-4-yl, 1-~3-isopropylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-isopropylaminocarbonylbutyl)~imidazol-4-yl, 1-(5-isopropylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-isopropylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-isopropylaminocarbonylheptyl)-imidazol-4-yl, 1-dimethylaminocarbonylmethyl-imidazol-4-yl, 1-(2-dimethylaminocarbonylethyl)-imidazol-4-yl, 1-(3-di-methylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-dimethylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-dimethylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-dimethylaminocarbonylhexyl) imidazol-4-yl, 1-(7-dimethylaminocarbonylheptyl)-imidazol-4-yl, 1-diethylaminocarbonylmethyl-imidazol-4-yl, 1-(2-diethylaminocarbonylethyl)-imidazol-4 yl, 1-t3-diethylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-diethylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-diethylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-diethylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-diethylaminocarbonylheptyl)-imidazol-4-yl, l-di-n-propylaminocarbonylmethyl imidazol-4-yl, 1-(2-di-n-propylaminocarbonylethyl)-imidazol-4-yl, 1-(3-di-n-propylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-di-n-propylaminocarbonylbutyl)-imidazo~-4-yl, 1-(5-di-n-propylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-di-n-propylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-di-n-propylaminocarbonylheptyl)-imidazol-4-yl, l-diiso- -propylaminocarbonylmethyl-imidazol-4-yl, 1-(2-diiso-propylaminocarbonylethyl)-imidazol-4-yl, 1-(3-diiso-propylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-diiso-propylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-diiso-propylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-diisopropylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-20~78~

diisopropylaminocarbonylheptyl)-imidazol-4-yl, 1-morpholinocarbonylmethyl-imidazol-4-yl, 1-(2-morpholinocarbonylethyl)-imidazol-4-yl, 1-(3-morpholinocarbonylpropyl)-imidazol-4-yl, 1-t4-morpholinocarbonylbutyl)-imidazol-4-yl, 1-(5-morpholinocarbonylpentyl)-imidazol-4-yl, 1-(6-morpholinocarbonylhexyl)-imidazol-4-yl, 1-(7-morpholinocarbonylheptyl)-imidazol-4-yl, 1-thiomorpholinocarbonylmethyl-imidazol-4-yl, 1-(2-thiomorpholinocarbonylethyl)-imidazol-4-yl, 1-(3-thiomorpholinocarbonylpropyl)-imidazol-4-yl, 1-(4-thiomorpholinocarbonylbutyl)-imidazol-4-yl, 1-(S-thiomorpholinocarbonylpentyl)-imidazol-~-yl, 1-(6-thiomorpholinocarbonylhexyl)-imidazol-4-yl, 1-(7-thiomorpholinocarbonylheptyl)-imidazol-4-yl, 1-oxi~othiomorpholinocarbonylmethyl-imidazol-4-yl, 1--(2-oxidothiomorpholinocarbonylethyl)-imidazol-4-yl, 1-(3 oxidothiomorpholinocarbonylpropyl)-imidazol-4-yl, 1-(4-oxidothiomorpholinocarbonylbutyl)-imidazol-4-yl, 1-(5-oxidothiomorpholinocarbonylpentyl)-imidazol-4-yl, 1-(6-oxidothiomorpholinocarbonylhexyl)-imidazol-4-yl, 1-~7-oxidothiomorpholinocarbonylheptyl)-imidazol-4-yl, 1-carboxymethyl-2-methyl-imidazol-4-yl, 1-(2-carboxyethyl)-2-methyl-imidazol-4-yl, 1-(3-carboxypropyl)-2-methyl-imidazol-4-yl, 1-(4-carboxybutyl)-2-methyl-imidazol-4-yl, 1-(5-carboxypentyl)-2-methyl-imidazol-4-yl, 1-(6-carboxyhexyl)-2-methyl-imidazol-4-yl, 1-(7-carboxyheptyl)-2-methyl-imidazol-4-yl, 1-methoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-methoxycarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-methoxycarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-methoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-methoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-methoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-methoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1-ethoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-2~87~0 ethoxycarbonylethyl)-2-methyl-imidazol-4~yl, 1 (3-ethoxycarbonylpropyl~-2-methyl-imidazol-4-yl, 1-(4-ethoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-ethoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-ethoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-ethoxycarbonylheptyl)-2-methyl-imidazol-4-yl, l-n-propoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-n~
propoxycarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-n-propoxycarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-n-propoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-n-propoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-n-propoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-n-propoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1-isopropoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-isopropoxycarbonylethyl)-2-me-thyl-imidazol-4-yl, 1--(3-isopropoxycarbonylpropyl)-2-methyl-imidazol~4-yl, 1-(4-isopropoxycarbonylbutyl)-2-methyl-imidazol-4~yl, 1-(5-isopropoxycarbonylpentyl)-2~methyl-imidazol-4-yl, 1-(6-isopropoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-isopropoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1-aminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-aminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-aminocarbonylpropyl)-2-me-thyl-imidazol-4-yl, 1-(4-aminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-aminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-aminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-aminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-methylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-methylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-methylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-methylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-methylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-methylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-methylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-ethylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-ethylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-ethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-- 2~78~0 ethylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-ethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-ethylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-ethylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, l-n-propylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-n-propylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-n-propylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-n-propylaminocarbonylbutyl)-2-methyl-~midazol-4-yl, 1-(5-n-propylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, l-(6-n-propylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-n-propylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-isopropylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-isopropylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-isopropylaminocarbonyl-propyl)-2-methyl-imidazol~4-yl, 1-(4-isopropylamino-carbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-isopropylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-isoprop~laminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-isopropylaminocarbonylheptyl)-2-methyl-imidaæol-4-yl, 1-dimethylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-~2-dimethylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-dimethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-dimethylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-~5-dimethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-dimethylaminocarbonyl-hexyl)-2-methyl-imidazol-4-yl, 1-(7-dimethylamino-carbonylheptyl)-2-methyl-imidazol-4-yl, 1-diethylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-diethylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-diethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-diethylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-diethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-diethylaminocarbonylhexyl)-2 methyl-imidazol-4-yl, 1-(7-diethylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, l-di-n-propylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-di-n-propylaminocarbonylethyl)-2-methyl-imidazol-4-yl, l-(3-di-n-propylaminocarbonylpropyl)-2-methyl-20~7~a imidazol-4-yl, 1-(4-di-n-propylaminocarbonylbutyl)-2-methyl-imidazol-4~yl, 1-(5-di-n-propylaminocarhonyl-pentyl)-2-methyl-imidazol-4-yl, 1-(6-di-n-propylamino-carbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-di-n-propylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-diisopropylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-diisopropylaminocarbonylethyl)-2--methyl-imidazol-4-yl, l-(3-diisopropylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-diisopropylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-diisopropylaminocarbonyl-pentyl)-2-methyl-imidazol-4-yl, 1 (6-diisopropylamino-carbonylhexyl~-2-methyl-imidazol-4-yl, 1-(7-diisopropyl-aminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-morpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-morpholinocarbonylethyl)-2-methyl-imidazol-4-yl, 1--(3-morpholinocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-morpholinocarbonylbutyl)-2-methyl-imidazol-4-yl, 1--(5-morpholinocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-morpholinocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-morpholinocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-thiomorpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-thiomorpholinocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-thiomorpholinocarbonylpropyl)-2-methyl-imidazol-4-yl, l-(4-thiomorpholinocarbonyl-butyl)-2-methyl-imidazol-4-yl, 1-(5-thiomorpholinocarbonylpentyl~-2-methyl-imidazol-4-yl, 1-(6-thiomorpholinocarbonyl-hexyl)-2-methyl-imidazol-4-yl, 1-(7-thiomorpholino-carbonylheptyl)-2-methyl-imidazol-4-yl, l-oxidothio-morpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-oxidothiomorpholinocarbonylethyl)-2-methyl-imidazol-4-yl, l-(3-oxidothiomorpholinocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-oxidothiomorpholinocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-oxidothiomorpholinocarbonyl-pentyl)-2-methyl-imidazol-4-yl, 1-(6-oxidothio-morpholinocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-oxidothiomorpholinocarbonylheptyl)-2-methyl-imidazol-4-yl, l-(2-hydroxyethyl)-imidazol-4-yl, 1-(3-20~7~0~

hydroxypropyl)-imidazol-4-yl, 1-(4-hydroxybutyl)-imidazol-4-yl, 1-(2-methoxyethyl)-imidazol-4-yl, 1-(3-methoxypropyl)-imidazol-4-yl, 1-~4-methoxybutyl)-imidazol-4-yl, 1-(2-ethoxyethyl)-imidazol-4-yl, 1-(3-ethoxypropyl)-imidazol-4-yl, 1-(4-ethoxybutyl)-imidazol-4-yl, 1-(2-n-propoxyethyl)-imidazol-4-yl, 1-(3-n-propoxypropyl)-imidazol-4-yl, 1-(4-n-propoxybutyl)-imidazol-4-yl, 1-~2-isopropoxyethyl)-imidazol-4-yl, 1-(3-isopropoxypropyl)-imidazol-4-yl, 1-(4-isopropoxy-butyl)-imidazol-4-yl, 1-(2-imidazol-1-yl-ethyl)-imidazol-4-yl, 1-(3-Imidazol-l-yl-propyl)-imidazol-4-yl, (4-imidazol-1-yl-butyl)-imidazol-4-yl, 1-(2,2-diphenyl-ethyl)-imidazol-4-yl, 1-(3,3-diphenyl-propyl)-imidazol-4-yl, 1-(4,4-diphenyl-butyl)-imidazol-4-yl, 1-(2-hydroxyethyl)-2-methyl-imidazol-4-yl, 1-~3-hydroxy-propyl)-2-methyl-imidazol-4-yl, 1-(4-hydroxybutyl)-2-methyl-imidazol-4-yl, 1-(2-methoxyethyl)-2-methyl-imidazol-4-yl, 1-(3-methoxypropyl)-2-methyl-imidazol-4-yl, l-(4-methoxybutyl)-2-methyl-imidazol-4-yl, 1-(2-ethoxyethyl)-2-methyl-imidazol-4-yl, 1-(3-ethoxypropyl)-2-methyl-imidazol-4-yl, 1-(4-ethoxybutyl)-2-methyl-imidazol-4-yl, 1-(2-n-propoxyethyl)-2-methyl-imidazol-4-yl, l-(3-n-propoxypropyl)-2-methyl-imidazol-4-yl, 1-(4-n-propoxybutyl)-2-methyl-imidazol-4-yl, 1-(2-isopropoxyethyl)-2-methyl-imidazol-4-yl, 1-(3-isopropoxypropyl)-2-methyl-imidazol-4-yl, 1-(4-isopropoxybutyl)-2-methyl-imidazol-4-yl, 1-(2-imidazol-l-yl-ethyl)-2-methyl-imidazol-4-yl, 1-~3-imidazol-1-yl-propyl)-2-methyl-imidazol-4-yl, 1-(4-imidazol-1-yl-butyl)-2-methyl-imidazol-4-yl, 1-(2,2-diphenyl-ethyl)-2-methyl-imidazol-4-yl, 1-(3,3-diphenyl-propyl)-2-methyl-imidazol-4-yl, 1-(4,4-diphenyl-butyl)-2-methyl-imidazol-4-yl, 1-[2-(2-methoxyethoxy)-ethyl]-imidazol-4-yl, 1-[3-(2-methoxyethoxy)-propyl]-imidazol-4-yl, 1-[4-(2-methoxyethoxy)-butyl]-imidazol-4-yl, 1-[2-(2-ethoxyethoxy)-ethyl]-imidazol-4-yl, 1-[3-(2-ethoxyethoxy)-propyl]-imidazol-4-yl, 1-[4-(2-20g7~0 ethoxyethoxy)-butyl]-imidazol-4-yl, 1-[2-(2-n-propoxyethoxy)-ethyl]-imidazol-4-yl, 1-[3-(2-n-propoxyethoxy)-propyl]-imidazol-4-yl, 1-[4-(2-n-propoxyethoxy)-butyl]-imidazol-4-yl, 1-[2-(2-isopropoxyethoxy)-ethyl]-imidazol-4-yl, 1-[3-(2-isopropoxyethoxy)-propyl]-imidazol 4-yl, 1-[4-(2-isopropoxyethoxy)-butyl]-imidazol-4-yl, 1-(2-~imethylaminoethyl)-imidazol-4-yl, 1-(2-diethylamino-ethyl)-imidazol-4-yl, 1-(2-di-n-propylamino-ethyl)-imidazol-4-yl, 1-(2-diisopropylaminoethyl)-imidazol-4-yl, 1-(3-dimethylaminopropyl)-imidazol-4-yl, 1-(3-diethylaminopropyl)-imidazol-4-yl, 1-(3-di-n-propylamino-propyl)-imidazol-4-yl, 1-(3-di-isopropylamino-propyl)-imidazol-4-yl, 1-(4-dimethylamino-butyl)-imidazol-4-yl, 1-(4-diethylamino-butyl)-imidazol-4-yl, 1-(4-di-n-propylamino-butyl)-imidazol-4-yl, 1-(4-diisopropylamino-butyl)-imidazol-4-yl, l-(2-morpholino-ethyl)-imidazol-4-yl, 1-(3-morpholino-propyl)-imidazol-4-yl, 1-(4-morpholino-butyl)-imidazol-4-yl, 1-(2-pyrrolidino-ethyl)-imidazol-4-yl, 1-(3-pyrrolidino-propyl)-imidazol-4-yl, 1-(4-pyrrolidino-butyl)-imidazol-4-yl, 1-(2-piperidino-ethyl)-imidazol-4-yl, 1-(3-piperidino-propyl)-imidazol-4-yl, 1-(4-piperidino-butyl) imidazol-4-yl, 1-~2-hexamethyleneimino-ethyl)-imidazol-4-yl, 1-(3-hexamethyleneimino-propyl)-imidazol-4-yl, 1-(4-hexamethyleneimino-butyl)-imidazol-4-yl, 1-(2-thiomorpholino-ethyl)-imidazol-4-yl, 1-(3-thio-morpholino-propyl)-imidazol-4-yl, 1-(4-thiomorpholino-butyl)-imidazol-4-yl, 1-[2-(1-oxido-thiomorpholino)-ethyl]-imidazol-4-yl, 1-[3-(1-oxido-thiomorpholino)-propyl]-imidazol-4-yl or 1-[4-(1-oxido-thiomorpholino)-butyl]-imidazol 4-yl group;

R3 may represent an ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, cyclopropyl, cyclobutyl, ethoxy, n-propoxy, isopropoxy, ethylthio, n-propylthio or isopropylthio group; and ~78~0 R4 may represent a hydroxycarbonyl, methoxycarbonyl, sthoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, tert.butyloxycarbonyl, n-pentyloxycarbonyl, isoamyloxycarbonyl, n-hexyloxy-carbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, l-phenylethyloxycarbonyl, 2-phenylethyloxycarbonyl, 3-phenylpropyloxycarbonyl, methoxymethoxycarbonyl, cinnamyloxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, n-pentanoyloxymethoxycarbonyl, isopentanoyloxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl, n-hexanoyloxymethoxycarbonyl, cyclopentanoyloxy-methoxycarbonyl, cyclohexanoyloxymethoxycarbonyl, phenylacetoxymethoxycarbonyl, 2-phenylpropionyloxy-methoxycarbonyl, 3-phenyl-propionyloxymethoxycarbonyl, 4-phenylbutyryloxymethoxycarbonyl, benzoyloxy-methoxycarbonyl, 1-acetoxyethoxycarbonyl, 1-propionyloxyeth~xycarbonyl, 1-n-butyryloxy-ethoxycarbonyl, l~isobutyryloxyethoxycarbonyl, l-n-pentanoyloxyethoxycarbonyl, l-isopentanGyloxy-ethoxycarbonyl, l-pivaloyloxyethoxycarbonyl, l-n-hexanoyloxyethoxycarbonyl, l-cyclopentanoyl-oxyethoxycarbonyl, 1-cyclohexanoyloxyethoxycarbonyl, 1-phenylacetoxyethoxycarbonyl, 1-(1-phenylpropionyloxy)-ethoxycarbonyl, 1-~2-phenylpropionyloxy)-ethoxycarbonyl, 1-(3-phenylbutyryloxy)-ethoxycarbonyl, 1-benzoyloxyethoxycarbonyl, methoxycarbonyloxymethoxy-carbonyl, ethoxycarbonyloxymethoxycarbonyl, n-propyloxycarbonyloxymethoxycarbonyl, isopropyloxy-carbonyloxymethoxycarbonyl, n-butyloxycarbonyloxy-methoxycarbonyl, isobutyloxycarbonyloxymethoxy-carbonyl, tert.butyloxycarbonyloxymethoxycarbonyl, n-pentyloxycarbonyloxymethoxycarbonyl, isoamyloxycarbonyl-oxymethoxycarbonyl, n-hexyloxycarbonyloxymethoxy-carbonyl, cyclopentyloxycarbonyloxymethoxycarbonyl, 2 0 ~ 0 cyclohexyloxycarbonyloxymethoxycarbonyl, benzyloxy-carbonyloxymethoxycarbonyl, l-phenylethoxycarbonyloxy-methoxycarbonyl, 2-phenylethoxycarbonyloxy-methoxycarbonyl, 3-phenylpropyloxycarbonyloxy-methoxycarbonyl, cinnamyloxycarbonyloxymethoxycarbonyl, l-(methoxycarbonyloxy)-ethoxycarbonyl, 1-.
(ethoxycarbonyloxy)-ethoxycarbonyl, l-(n-propyloxycarbonyloxy)-ethoxycarbonyl, 1-(isopropyloxycarbonyloxy)-ethoxycarbonyl, l-(n-butyloxycarbonyloxy)-ethoxycarbonyl, 1-(isobutyloxy-carbonyloxy)-ethoxycarbonyl, l-(tert.butyloxy-carbonyloxy)-ethoxycarbonyl, l-(n-pentyloxycarbonyloxy)-ethoxycarbonyl, 1-(isoamyloxycarbonyloxy)-ethoxycar~onyl, l-(n-hexyloxycarbonyloxy)-ethoxycarbonyl, l-(cyclopentyloxycarbonyloxy)-ethoxy-carbonyl, l-(cyclohexyloxycarbonyloxy)-ethoxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl, 1-(benzyloxycarbonyloxy)-ethoxycarbonyl, 1-(1-phanylethoxycarbonyloxy)-ethoxycarbonyl, 1-(2-phenylethoxycarbonyloxy)-ethoxycarbonyl, 1-(3-phenylpropyloxycarbonyloxy)-ethoxycarbonyl, 1-(cinnamyloxycarbonyloxy)-ethoxycarbonyl, cyano, lH-tetrazolyl, l-triphenylmethyl-tetrazolyl or 2-. triphenylmethyl-tetrazolyl group.
`:
Preferred compounds according to the invention include those of formula I wherein R1, R2, R3 and R4 are as hereinbefore defined with R2 in the 6-position of the benzimidazole ring, and the salts thereof.

Particularly preferred compounds according to the invention include those of formula I wherein R1 represents a hydrogen or chlorine atom or a methyl group;

2~'~78~0 R2 represents an oxazol-4-yl or thiazol-4-yl group optionally substituted in the 2-position by a methyl or phenyl group or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the l-position by a C17-alkyl group optionally substituted in the 1-, 2-, 3-, 4-, 5-, 6- or 7-position by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or l-oxido-thiomorpholino-carbonyl group, by a C2,4-alkyl group substituted in the 2-, 3- or 4-position by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-l-yl group, or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, 2~phenylethyl, 4-fluorobenæyl, 3-chlorobenzyl, 4-methylbenzyl, ~ trifluoromethylbenzyl, 3,5-dimethoxybenzyl or 2,2-diphenylethyl group;

K3 represents a C24-alkyl, C23~alkoxy, C23-alkylthio cyclopropyl or cyclobutyl group; and R4 represents a carboxy or lH-tetrazolyl group or a group convertable in vivo into a carboxy group;

especially those compounds wherein R2 is in the 6-positlon;

and the salts thereof.

- .:

. .

2~7~V

; More particularly preferred compounds of formula I include those wherein Rl represents a hydrogen atom or a methyl group;
, R2 represents an oxazol-4-yl or thiazol-4-yl group optionally substituted in the 2-position by a methyl or phenyl group or an imidazol-4-yl group optionally substituted in the 2-pasition by a methyl group and substituted in the 1-position by a C17-alkyI group which may be substituted in the 1-, 2-, 3-, 4-, 5-, 6- or 7-position by a carboxy, methoxycarbonyl, dimethylaminocarbonyl or morpholinocarbonyl group, ~ .
by a C24-alkyl group substituted in the 2-, 3- or 4-: position by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-l-yl group, , or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl or 4-fluoro-benzyl group;

R3 represents a C24-alkyl, ethoxy~ ethylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy or lH-tetrazolyl group;

particularly those compounds of formula I above wherein R2 is in the 6-position;

and the salts thereof.

~ : .

- , :~ ., .' ~ ' ,' ' '' . ' .

2~1~78~

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

(a) 4'-~(2-n-propyl-4-methyl-6-~1-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl~-biphenyl-2-carboxylic acid;

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

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

(d) 4'-[(2-ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid;

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

(f) 4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-- imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid; and (g) 4'-[(2-n-propyl-4-methyl-6-(1-(3-dimethylamino-propyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]
biphenyl-2-carboxylic acid;

and the salts thereof.

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

::

`::

2087~

a) cyclising a compound of formula II

~, X;

(II) (wherein one of the groups X1 and Y1 represents a group of ~ormula ~; --NR6--~H2~

and the other group X1 or Yl represents a group of ~ormula , 1 ,~ ~ Z2 Rs represents a hydrogen atom or an R3CO group, R1, R2, R3 and R4 are as hereinbefore defined, Z1 and Z2t which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by C16-alkyl groups or Z1 and Zz together represent an oxygen or sulphur atom, an imino group optionally substituted by a C13-alkyl group, or an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms) or an N-oxide thereof and optionally subsequently reducing a cyclized N-oxide thus ~ obtained;

:

. ~ .

2~7~1D0 b) reacting a benzimidazole of formula III

R2 ~ ~ R~

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

R

Z3--CH~ ~ ~

(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 sulphonylaxy 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

~:;
- ~ .
, ~ ' ' , .

~ ~ . . . .

2~878~

R

~ V) (wherein R1, R2 and R3 are as hereinbefore defined, 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 csr hydrogenolysis;

d) (to prepare a compound of formula I wherein R4 represents a lH-tetrazolyl group) cleaving a protec:ting group from a compound of formula VI
R

R2~ R~, 4 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 R4 represents a lH-tetrazolyl group) reacting a compound of formula VII

, 2~8780~

R~ 3 CN
CH~ ~ O } /~

(VII~
twherein R1, R2 and R3 are as hereinbefore defined) with hydrazoic acid or a salt thereof:

f) converting a compound of formula I wherein R4 denotes a carboxy group, by esterification into a corresponding compound of formula I wherein R4 denotes a group convertable in vivo into a carboxy group;

q) converting a compound of formula I wherein R2 denotes an imidazol-4-yl qroup subst.ituted in the 1- ~osition by a C24-alkyl group itself substituted in the 2-, 3- or ~-position by an alkoxy or alkoxyalkoxy group, by ether splitting into a corresponding compound of formula I
wherein Rz denotes an imidazol-4-yl group substituted in the l-position by a C24-alkyl group substituted in the 2-, 3- or 4-position by a hydroxy group;

h) separating the l-isomer from a 1-, 3-isomer mixture of a compound of formula I by isomer separation;
.
i) converting a compound of formula I into a salt thereof, more particularly into a physiologically -:.
acceptable addition 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 j) performing a process as defined in any one of steps (a) to ti) above on a corresponding protected compound ' ., "; ' , .
~ . ' 20~3~0 and subsequently removing the protecting groups used.

The cyclisation of step (a~ is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, ben~ene, chlorobenzene, toluene, xylene, glycol, glycolmono-methylether, 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 O
and 250C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphuryl-chloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid or acetic anhydride, or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide. However, ~he cyclisation may also be carried out without a solvent and/or condensing agent.
It i5 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 resulting N-oxide is then converted by reduction into a corresponding compound of formula I.
The subsequent reduction of the N-oxide of formula I obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney 20~78~0 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 terk.-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 between ambient temperature and 50C.
In the reaction of step tb~, a mixture of the 1-and 3- isomers is preferably obtained from which subsequently the l-isomer is isolated 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 optionally substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines and anhydrides, and nitrile and tetrazolyl groups may be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. tert.butylesters, may be co~verted by thermolysis into a carboxy group and esters with aralkanols, e.g. benzylesters, may be converted by hydrogenolysis into a carboxy group.
The hydrolysis of step (c) is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium 2~878~0 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 a trifluoroacetoxy group.
If R4' in a compound of formula V represents a cyano or aminocarbonyl group, such a group may also be converted into a carboxy group with a nitrite r e.g.
sodium nitrite, in the presence of an acid such as sulphuric acid, which may simultaneously also be used as solvent, at temperatures between 0 and 50C.
If R4' in a compound of formula V represents ~or example a tert.-butyloxycarbony]. group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, henzene, toluene, tetrahydrofuran or dioxana and preferably in the presence of a catalytic amount o~ an acid such as p-toluenesulphonic acid, sulphuri.c acid, phosphoric acid or polyphosphoric acid, conveniently at temperatures between 40C and 100C, preferably at the boiling temperature of the solvent used.
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 208~

nitro group may be reduced to the amino group, a benzyloxy group to the hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.
Suitable protecting groups for use in step (d) incl~lde, for example, triphenylmethyl/ tributyl tin and triphenyl tin groups.
The cleaving of a protecting group used is preferably carried out in the presence of a hydrohalic -~ acid, more preferably in the presence of hydrochloric `-acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia, in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, at temperatures between 0 and 100C, but preferably at ambient temperature or, if the react:ion is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between lO0 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 conversion in step ~f) of a carboxyl group into : `

20~78~

a group which is metabolically convertable in vivo into a carboxy group is expediently carried out by esterifiGation with a corresponding alcohol or with a corresponding reactive acyl derivative, conveniently in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide or in an excess of an acylating agent as solvent, optionally in the presence of an acid activating or dehydrating agent such as thionyl chloride, 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 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.
The subsequent ether splitting is conveniently carried out hydrolytically in an aqueous solvent, e.g.
in water, isopropanol/water, tetrahydrofuran/water or dioxane~water, in the presence of an acid such as hydriodic acid or hydrobromic acid, but preferably under the effect of a Lewis acid such as boron trifluoride, boron tribromide, boron trichloride, dimethyl borobromide or aluminium trichloride in a suitable solvent such as dichloromethane or chloroform, or with the aid of bromotrimethylsilane, iodotrimethylsilane or chlorotrimethylsilane/sodium iodide in a suitable ; solvent such as acetonitrile, dichloromethane or chloro~orm, at temperatures between 0 and 100C, preferably at 20C, with subsequent aqueous working up.
In the reactions described above, any reactive groups present such as hydroxy, amino or alkylamino groups may be protected during the reaction by means of con~entional protecting groups which are split off again after the reaction.
Examples of suitable protecting groups for a hydroxy group include trimethylsilyl, acetyl, benzoyl, ~:' ~ .

- 2~ -methyl, ethyl, tert.butyl, benzyl and tetrahydropyranyl groups and suitable protecting groups for an amino, alkylamino or imino group may include acetyl, benzoyl, ethoxycarbonyl and benzyl groups.
The optional subsequent cleaving of a protecting group is preerably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrouran/water or dioxane/water, in the presence of an acid such hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures between O and lOO~C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is pre~erably 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 h~drochloric acid, at temperatures between O and 50C, but preferably at ambien~ 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.
The compounds of formula I obtained may, if desired, be converted into the acid addition salts thereof, more particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Suitable acids for this purpose includ~ hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
Furthermore, the new compounds of formula I thus obtained, if they contain a carboxy or lH-tetrazolyl group, may if desired subse~uently be converted into the - , 2n~78~0 addition 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.
Some of the compounds of formulae II to VII used as starting materials are known from the literature.
Otherwise those compounds may be obtained by methods known from the literature.
Thus, for example, a compound of formula I~ may be obtained by alkylation of a corresponding o-amino-acylamino compound with a compound of formula IV. The o-amino-acylamino compound re~uired for this may be obtained by reduction of a corresponding o-nitro-acylamino compound which in turn may be obtained by nikration of a corresponding acylamino-acetophenone, subsequent conversion of the resulting corresponding o-nitro-acylamino-acetophenone into the corresponding ~-bromo-acetophenone, subsequent cyclisation of the ~-bromo-acetophenone with a corresponding acid amide and subsequent reduction of the nitro group. Before the reduction of the nitro group an oxazol~4-yl compound thus obtained may be converted into the corresponding imidazol-4-yl compound by means of a corresponding amine, preferably with ammonia, under pressure, or an imidazol-~-yl compound unsubstituted in the l-position obtained in this way may be con~erted 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 and VII 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 .

2~7~0 physiologically acceptable salts thereof have valuable pharmacological properties. They are angiotensin-antagonists, in particular, angiotensin-II antagonists.
The compounds of formula I wherein R4 represents a group convertable in vivo into a carboxy group, a carboxy or lH-tetrazolyl group have, in particular, useful pharmacological properties since they are angiotensin-antagonists, particularly angiotensin-II-antagonists. The other compounds of formula I are valuable as intermediate products for preparing the compounds mentioned above.
By way of example, the ~ollowing compounds:

A = 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl~-biphenyl-2-carboxylic acid;

B = 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl~-methyl]-2-(lH-tetrazol-5-yl)-biphenyl;

c - 4 ' - E ( 2-n-propyl 4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxyli~
acid;

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

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

F = 4'- E t 2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid; and ~ ' 2~78~0 G = 4'-[(2-n-propyl-4-methyl 6~ 3-dimethylamino-propyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid-dihydrochloride-pentahydrate were investigated for their biological activities as follows:

Description of method: an~iotensin-II-receptor bondinq The tissue (rat's lung) is homogenised in tris bu~fer (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 ~inished pellet is resuspended in incubation buffer (50 mMol Tris, 5 mMol MgC12, 0. 2% BSA, pH 7.40) 1:75, based on the moist weight of the tissue.
Each Q.l ml of homogenate is incubated for 60 minutes at 37C with 50 pM t125~]-angiotensin-II (NEN, Dreieich, ~RG) and increasing concentrations of the test substance in a total volume of 0.25 ml. The incubation i~ ended by rapid filtration through glass fibre filter mats.
The filters are each washed with 4 ml of ice cold buffer (25 mMol Tris, 2.5 mMol MgC12, ~ BSA, pH 7.40). The bound radioactivity is measured in a gamma-counter. The corresponding IC50 value is determined ~rom the dosage-activity curve.
Substances A to G show the following IC50 values in the test described:
_ Substance ICso [nM]
A 1.2 B 1.5 F 3.4 G 1.3 208781)0 ~ n view of their pharmacological properties, namely a hypotensive effect with a diureticJsaluretic component, the new compounds and the physiologically acceptable addition salts thereof are suitable for the treatment of hypertension and cardiac insu~ficiency and also for treating chronic renal insufficiency, ischaemic peripheral circulatory disorders (e.g. Raynaud's syndrome) and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and retinopathy, 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 re-stenosis after angioplasty, for preventing thickening of the ~ascular walls aPter vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout.
Bec~use of the effect of angiotensin on the releasa of acetylcholine and dopamine in the brain, the new an~iotensin antagonists are also suitable for alleviating central nervous system disorders, e.g.
depression, Alzheimer's disease, Parkinson's syndrome, 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 at least one physiologically acceptable carrier or excipient.
Viewe~ from a still further aspect the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension and cardiac insufficiency and also for 20878~0 ~ 33 -treating chronic renal insufficiency, ischaemic peripheral circulatory disorders (e.g. Raynaud's syndrome) and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treatin~ diabetic nephropathy and retinopathy, glaucoma, gastrointestinal diseases and bladder diseases.
In particular, the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of pulmonary diseasesl for preventing arterial re-sterosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout.
More particularly, the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for alleviating central nervous system disorders.
Viewed from a yet still further aspect the present invention provides a method of treatment of the human or non-human animal body to combat hypertension and cardiac insufficiency and also for treating chronic renal insufficiency, ischaemic peripheral circulatory disorders and cerebovascular circulatory disorders, myocardial ischaemia ~angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and retinopathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
In particular, the present invention provides a method of treatment of the human or non-human animal .

208~8~0 body to combat pulmonary diseases, for preventing arterial re-sterosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
More particulary, the present invention provides a method of treatment o~ the human or non-human animal body to combat central nervous system disorders, said method comprising administering to said body a compound of formula I or a physiologically acceptahle 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 inaorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, micro-crystalline cellulose, magnesium stearate, polyvinyl-pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, waterjsorbitol, 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, 20~7~0 cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosin, atenolol, propranolol, ~di)hydralazine-hydrochloride, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, nitrendipine, captopril, enalàpril, 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 or 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. All percentages and ratios given are by weight, other than eluant or solvent ratios which are by volume.

-, :

.
.

2087~0 Example 1 4'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-ben7imidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid a) 3-Methyl 4-but~ylamino-5-nitro-acetophenone 32.6 g (148 mMol) of 3-methyl-4-butyrylamino-acetophenone are added in batches to 300 ml of fuming nitric acid, with stirring, at -15C and stirred for a further 30 minutes at -15C. The reaction mixture is then poured onto 3 litres of ice with stirring, the crude product precipitated is suction filtered, washed with 400 ml of water, dried and purified by recrystallisation from ethanol/diethylether ~1:1).
Yield: 23.~ g (61.0% of theory), Rf value: 0.32 (~ilica gel; methylene chloride~
R~ value: 0.48 ~silica gel; methylene chloride~methanol =
50:1) b) 3-MethYl-4-butyrvlamino-5-nitro-~-bromoaceto~-enone At ambient temperatura, with stirring, a solution of 16.0 g (200 mMol) of bromine in 140 ml of dioxane is slowly added dropwise to a solution of 23.8 g (90 mMol) of 3-methyl-4-butyrylamino-5-nitro-acetophenone in 900 ml of dichloromethane so that the reaction mixture is constantly completely decolorised. It is then stirred for a further two hours, then the reaction mixture is evaporated to dryness in vacuo, the residue thus obtained is triturated with about 20 ml of dichloromethane/diethylether (1:1), suction filtered and then dried. 23 g (74% of theory) of 3-methyl-4-butyrylamino-5-nitro-~-bromoacetophenone are thus obtained, containing about 10% of starting material.
The product is further reacted without any more purification.
Rf value: 0.69 (silica gel; methylene chloride/methanol =
50:1) ~: :

:` `
,, Rf value~ 0.84 (silica gel; methylene chloride/methanol =
g : 1 ) c) 2-Butyx~lamino-3-nitro-5-(imidazol-4-yl) toluene A solution of 6.8 g (20 mMol) of 3-methyl-4-butyrylamino-5-nitro-~bromoacetophenone in 20 ml of formamide is heated to 140C for 2 hours. The cooled solution is then poured into about 50 ml of 1 N ammonia and stirred for about 15 minutes. The crude product precipitated is suction filtered, washed with about 50 ml of water and dried. In this way, 4.4 g (75% of theory) of the product are obtained, which is further reacted without any more purification.
Rf value: 0.29 (silica gel; methylene chloride/methanol =
9 1) d) 2-Butyrylamino-3 nitro-5~ methyl-imidazol-4-yl)-toluenQ _ _ 1.3 g (9.5 mMol) of methyl iodide are added dropwise at ambient temperature to a solution of 2.5 g (8~7 mMol) of Z-butyrylamino-3-nitro-5-(imida 2 ol-4-yl)-toluene and 5.2 g (30 mMol) of potassium carbonate dihydrate in 30 ml of dimethylsulphoxide at ambient temperature and ~hen stirred for 2 hours. The reaction mixture is then stirred into about 150 ml of water and then extracted four times with 25 ml of ethyl acetate. The organic extracts are washed with about 30 ml of water, dried and concentrated by evaporation. The crude product thus obtained is purified by column chromatography (300 g silica gel, eluant: methylene chloride/methanol = 30:1).
Yield: 640 mg (24% of theory), Rf value: 0.54 (silica gel; methylene chloride/methanol -9:1) e) 2-Butyrylamino-3-amino-5-(1-methyl-imidazol-4-yl)-toluene 640 mg (2.1 mMol) of 2-butyrylamino-3-nitro-5-(1-methyl-2~7~0 imidazol-4-yl)-toluene are hydrogenated at ambient temperature under a hydrogen pressure of 5 bar in 30 ml of methanol after the addition of about 200 mg of 20%
palladium/charcoal. After all the water has bean absorbed the catalyst is filtered off and the filtrate is evaporated down. The crude product thus obtained is further reacted without any more purification.
Yield: 600 mg (100% o theory), Rf value~ 0.23 tsilica gel; methylene chloride/methanol =
9 : 1 ) f) 2-n-Propyl-4-methyl-6-(1-methyl-imida~ol-4-yl)-benzimidazole 600 mg (2.1 mMol) of 2-butyrylamino-3-amino-5~ methyl-imidazol-4-yl)-toluene are refluxed in 10 ml of glacial acetic acid for one hour. Then the mixture is e~aporated to dryness ln vacuo, the residue is mixed with about 15 ml of water, made alkaline with ammonia and extracted four times with about 10 ml of ethyl acetate. The or~anic extracts are washed with about 15 ml of water, dried and finally evaporated down. The crude produc~ thus obtained is further reacted without any more purification.
Yield: 420 mg (79% of theory), R~ value: 0.37 (silica gel; methylene chloride/methanol -9:1) g~ Tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate 280 mg (0.8 mMol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate are added to a solution of 200 mg (0.79 mMol) of 2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole and 90 mg (0.8 mMol) of potassium tert.butoxide in 5 ml of dimethylsulphoxide and the mixture is stirred for 90 minutes at ambient ,~

2l1~78VO

temperature, then stirred into about 40 ml of water, extracted four times with about 10 ml of ethyl acetate, then the organic extracts are washed with lo ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel; eluant;
dichloromethane/methanol = 30:1).
Yield: 230 mg (56% of theory), Rf value: 0.61 (silica gel; methylene chloride/methanol =
9 : 1 ) h) 4'-[(2-n-Propyl-4-methyl-6-~1-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl1-biphenyl-~-carboxylic acid A solution of 230 mg (0.44 mMol) of tert.butyl 4'-[(2-n-propyl-4-methyl~6-(1-methyl-imidazol-4~yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and 2 ml of tri~luoroacetic acid in 10 ml of dichloromethane is stirred overnight at ambient temperature and then evaporated to dryness. The residue is dissolved in about 5 ml of dilute sodium hydroxide solution, the solution is neutralised with acetic acid, the precipitate ~ormed is suction filtered, washed with water and ~ried.
Yield: 120 mg ~59% of theory), Melting point: 293-295C
R~ value: 0.39 ~silica gel; methylene chloride~methanol =
9:1) 4'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrate a) 4'-[(2-n-Propyl-4-methyl-6-(1-methylimidazol-4-yl)-benzimidazol-l-Yl)-methvll-2-cYano-biphenyl : .

2~87g~0 218 mg (0.8 mMol) of 4'-bromomethyl-2-cyano-biphenyl are added to a solution of 200 mg (0.79 mMol) of 2-n-propyl-4-methyl-6~ methyl-imidazol-4-yl~-benzimidazole and 90 mg (0.8 mMol) of potassium tert.butoxide in 6 ml of dimethylsulphoxide and the mixture is stirred for 14 hours at ambient temperature. Then it is stirred into about 40 ml of water, extracted four times with about 10 ml of ethyl acetate, the oryanic extracts are washed with about 10 ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel; eluant:
dichloromethane/ethanol = 50:1).
Yield: 240 mg (67% of theory), Rf value: 0.38 (silica gel; methylene chloride/ethanol =
19 : 1 ) '~
b) 4' [(2-n-Propyl-~-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetraæol-5 yl)-biphenvl-hvdrate A solution of 222 mg (0.5 mMol) of 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl, 660 mg (10 mMol) of sodium azide and 540 mg (10 mMol) of ammonium chloride in 12 ml of pure dimethylformamide is heated to 140C for 18 hours. The solution is then evaporated substantially to dryness and the product is isolated by column chromatography (60 g of silica gel, eluant:
dichloromethane with 10% ethanol). The product thus obtained is taken up in about 10 ml of dilute ammonia solution and the solution is then adjusted to pH 6 with acetic acid. A greasy residue is formed which becomes crystalline after the addition of a little ethyl acetate and several hours' stirring. The crystalline product is suction filtered, washed with about 5 ml of water and dried.
Yield: 61.0 mg (24.0% of theory), ~`
:~ `

2087~6~

Melting point: 255-257C
C29H28N~ x H20 (506.62) Calculated: C 68.75 H 5.97 N 22.12 Found: 68.90 5.97 22.03 Rf value: 0.24 ~silica gel; methylene chloride/methanol =
9 : 1 ~

Example 3 4'-[(2-n-Propyl-4-methyl-6-~1-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid _ _ _ Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-tl-isopropyl-imidazol~4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 84.0% o~ theory, Melting po~nt: 285-286C
Rf value: 0.55 (silica gel; methylene chloride/methanol =
9 : 1 ) Example 4 , 41-[(2-n~Propyl-4-methyl-6-(l-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid .
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 74.0% of theory, Melting point: 258-259C
C34H3gN402 (534-71) Rf value: 0.48 (silica gel; methylene chloride/methanol =
9 : 1 ) Mass spectrum: m/e = 534 .
.~ ' .

2~g~

Example 5 4'-[(2-n-Propyl-4-methyl-6-(l-cyclopentylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example l from tert.butyl 4'-[(2-n-propyl-4-mekhyl-6-(l-cyclopentylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-bipheny:L-2-carboxylate and trifluoroacetic acid in methylene chloride.

Example 6 4'-[(2-n-Propyl~4-methyl-6-(1-cyclohexylmethyl-imidazol~
4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid _ Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(l-cyclohexylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.

Exam~le 7 4'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 44.0% of theory, Melting point: 226-227C
C35H32N402 (540.68) Rf value: 0.51 (silica gel; methyiene chloride/methanol =
9 : 1 ) 7~

Mass spectrum: m/e = 540 Example 8 4'-[(2-n-Propyl-4-methyl-6-(1-(4-fluorobenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 ~rom tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(4-fluorobenzyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.

The following compounds may be obtained analogously to Example 8:

4'-[(2-n-propyl-4-methyl-6-(1-(3-chlorobenzyl)-imidazol-4-yl)-benzimidazol-l~yl)-methyl]-biphenyl-2-carboxylic acid 4'-~(2-n-propyl-4-methyl-6-(1-(3,5-dimethoxybenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid 4'-~(2-n-propyl-4-methyl-6~ (4-methylbenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propyl-4-methyl-6-(1-(4-trifluoromethyl-benzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl~-biphenyl-2-carboxylic acid ; ' , ~ .

2~87~0~

Example 9 4'-[(2-n-Propyl-4-methyl-6-(1-(2-phenylethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6~ (2-phenylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.

Exam ~e lO

4'-[(2-n-Propyl-4-methyl-6-(1-(2,2,2-trifluoroethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl~-biphenyl-2-carboxylic acid Prepared analogously to Example l from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(2,2,2-trifluoroethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and tri~luoroacetic acid in methylene chloride.

Example 11 4'-[(2-n-Propyl-4-methyl-6-(1-(3,3,3-trifluoroprop~l)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-~(2-n-propyl-4-methyl-6-(1-(3,3,3-trifluoropropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.

~ . . .
;~

2~7~

Example 12 4'-[(2-n-Propyl-4-methyl-6~ aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert~butyl 4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol 4-yl)-banzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.

Example 13 4'-[(2-n-Propyl-4-methyl-6~ cyclobutylmethyl~imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 ~rom tert.butyl 4'-~(2-n-propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.

Example 14 4' [(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid -Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-~1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl~-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 59.0% of theory, Melting point: 279-280C
C32H32N40z (504-64) Calculated: C 76.16 H 6.39 N 11.10 208~8~

~ound: 76.41 6.37 11.20 Rf value: 0.44 (silica gel; methylene chloride/methanol =
9 : 1 ) Mass spectrum: m/e = 504 ExamPle 15 4'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)~
benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl .
Prepared analogously to Example 2 from 4'-[~2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl~-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 18.0% of theory, Melting point: amorphous C3~H32N8 (516.66) Rf value: 0.2~ (silica gel; methylene chloride/methanol =
9:1) Mass spectrum: m/e = 516 Exam~le 16 . .

4'-[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidaæol 4-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl a) 4'-[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biPhenyl To a solution of 300 mg (1.0 mMol) of 2-n-propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-~-yl)-benzimidazole and 110 mg (1.0 mMol) potassium tert.butoxide in 20 ml of dimethylsulphoxide are added 560 mg (1.0 mMol) of ~'-bromomethyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and the mixture , ' 2~7~0 - ~7 is stirred for 16 hours at ambient temperature, then stirred into about 120 ml of water and extracted four times with 15 ml of ethyl acetate. The organic extracts are washed with about 30 ml of water, dried and then evaporated to dryness. The crude product thus obtained is purified by column chromatography (:L00 g silica gel, eluant: methylene chloride/methanol = 30:1).
Yield: 460 mg ~60 % of theory), Rf value: 0.78 (silica gel; methylene chloride/methanol =
9 ~

b) 4'-L(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol~4-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-vl)-biphenvl A mixture of 460 mg (0.6 mMol) of 4'-~(2-n-propyl-4-methyl-6~ cyclopropylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl~-2-(2-triphenylmethyl-tetraæol-5-yl)~biphenyl and 10 ml of saturated methanolic hydrochloric acid is stirred Eor one hour at ambient temperature. The mixtura is then evaporated to dryness, the residue is dissolved in dilute ammonia solution and washed with ether. The aqueous phase is adjusted to pH 5 to 6 with acetic acid and subsequently the solid precipitate is suction filtered. The crude product thus obtained is purified by column chromatography (100 g silica gel, eluant: methylene chloride/methanol = 15:1) Yield: 130 mg (41% of theory), Melting point: amorphous C32H32N8 (528-67) Rf value: 0.32 (silica gel; methylene chloride/methanol =
9 : 1 ) Mass spectrum: m/e = 528 20~8~0 Example 17 4'-[(2-n-Propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl) bip~enyl Prepar~d analogously to Example 16 from ~'-[(2-n-propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]~2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium azide in dimethylformamide.

Exam~e 18 4'-t(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)~methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[~2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 67.0~ of theory, Melting point: 241-243C
C29H27N303 (465.56) Calculated: C 74.82 H 5.85 N 9.03 Found: 74.65 5.98 8.85 Rf value: 0.27 (silica gel; methylene chloride~ethanol =
19 : 1 ) Exam~le 19 4'-t(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-l-yl)-methylJ-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 from 4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-78~0 ~,9 methyl]-2-(2-triphenylmethyl-tetrazol-s-yl)-biphenyl and sodium azide in dimethylformamide.

Example O

4i-[(2-n-Propyl-4-methyl-6-(2~phenyl-oxazol-4-yl)-benzimidaæol-l-yl)-methyl]-biphenyl-2 carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87.0~ of theory, Melting point: 281-283C
C34H2sN303 (527-63) Calculated: C 77.40 H 5.54 N 7.96 Found: 77.09 5.71 7.76 Rf value: 0.18 (silica gel; methylene chloride~ethanol =
19 : 1 ) Example 21 4'-[(2-n-Propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 from 4'-[(2-n-propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium azide in dimethylformamide.

2~73~0 ExamPle 22 4'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl .. . .... _ . _ _ . _ .. . _ _ . . .
Prepared analogously to Example 16 from 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphe,nylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 45~0~ of theory, Melting point: 168-170C
C3$H32Ng (564.70) Rf value: 0.37 (silica gel; methylene chloride/methanol =
9 1) Mass spectrum: m/e = 564 Example 23 -4'-[(2-n-Propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 from 4'-[(2-n-Propyl-4-methyl-6-(l~n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl~-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 61.0% of theory, Melting point: 126-128C
C34H38N8 (558.74) Rf value: 0.31 (silica gel; methylene chloride/methanol =
9 : 1 ) Mass spectrum: m/e = 558 Example 24 4'-~(2-Ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 from 4'-[(2-ethoxy-6-2~781D0 (l-isopropyl-imidazol-4-yl)-benzimidazol-l~yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 69.0% of theory, Melting point: 175-178C
C2~H28N8O (504.61) Calculated: C 69.03 H 5.59 N 22.21 Found: 68.85 5.58 21.97 R~ value: 0.27 (silica gel; methylene chloride/ethanol =
9 : 1 ) Mass spectrum: m/e = 504 ~ .
Exam~le 25 ~ (2-Ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-C(2-ethoxy-6~(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)~methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 38.0% of theory, Melting point: 220-223C
c2~28N403 (480-58) Calculated: C 72.48 H 5.87 N 11.66 Found: 72.36 6.05 11.41 R~ value: 0.26 (silica gel; methylene chloride/methanol =
9:1) Mass spectrum: m/e = 480 Example 26 4~-[(2-Ethoxy-5~ isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 from 4'-~(2-ethoxy-5-(l-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-' - .

2~7~

2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 44.0% of theory, Melting point: amorphous C29H28N8 (504.61) Rf value: 0.24 (silica gel; methylene chloride/ethanol =
9 : 1 ) Mass spectrum: m/e = 504 xample 27 ,.
4'-[(2-n-Propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carbcxylic acid -Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4~methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylata and tri~luoroacetic acid in methylene chloride.
Yield: 79.0% of theory, Melting point: from 190C (decomp.) C35H38N4O2 (546.71) Rf value: 0.36 (silica gel; methylene chloride~methanol =
9:1) Mass spectrum: m/e = 546 Exam~le 28 4'-[(2-n-Propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 Erom 4'-[(2-n-propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 27.0% of theory, - -, ~ .

2~7~00 Melting point: 198-201C
C35H38N~ (570~75) Rf value: 0.48 (silica gel; methylene chloride/methanol =
9 : 1 ) Mass spectrum: m/e = 570 ~mEL~

4'-[(2-n-Propyl-4-methyl-6-(1-~1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl~-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 28.0% of theory, Melting point: 236-238C
C35H40N402 (548.73) Rf value: 0.61 (silica gel; methylene chloride/methanol =
9 : 1 ) Mass spectrum: m/e = 548 Example 30 4'-[~2-~thoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-ethoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-henzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 52.0~ of theory, ' - : ' ~0~78~0 Melting point: 172-173C
C3l~30N4O3 (506-61) Calculated: C 73.50 H 5.97 N 11.06 Found: 73.36 5,94 11.30 Rf value: 0.52 (silica gel; methylene chloride/methanol =
9 : 1 ) Mass spectrum: m/e = 506 Example 31 4'-[(2-Ethoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 from 4'-~2-ethoxy-4-methyl-6~ cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl tetrazol 5-yl)-biphenyl.
Yield: 42.0% o~ theory, Melting point: amorphous C31H30N8 (53~.64) Rf value: 0.50 (silica gel; methylene chloride/methanol =
9:1) . Mass spectrum: m/e = 530 Exam~le 32 4'-[(2-n-Propyl-4-methyl-6-(1-(l~n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 from 4'-[(2-n-propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 12.0% of theory, , 2 ~ 0 Melting point: from 150C (sintering) C35H40N~ (572,76) Rf value: 0.34 (silica gel; methylene chloride/methanol =
9 : 1 ) Mass spectrum: m/e = 572 Example 33 4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid hydrate a) tert. Butyl ~ (2-n-propyl 4-methyl-6-(2-methyl-~oxazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl--2-carboxylate _ _ A solution of 2.8 g (11 mMol) of 2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl~-benzimidazole and 1.7 g (15 mMol) of potassium tert.butoxide in 60 ml of dimethyl-sulphoxide is stirred for 15 minutes at ambient temperature. Then 5.2 g (15 mMol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate are added and the mixture is stirred for a further 14 hours at ambient temperature. Then the solution is stirred into about 150 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (400 g of silica gel; eluant:
methylene chloride with l to 2% ethanol).
Yield: 3.5 g (61.4% of theory), Melting point: amorphous Rf value: 0.90 (silica gel; methylene chloride/ethanol =
4:1) 20~78~0 b) 4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid hydrate A mixture of 1.5 g (3 mMol) of tert.butyl 4'-~(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate, 10 ml of 40~ N-methylamine solution and 15 ml of N-methylformamide is heated for 10 hours to 200C in an autoclave. ~fter cooling, the contents of the autoclave are stirred with about 40 ml of water, this suspension is adjusted to pH
6.5 with glacial acetic acid, then the crude product precipitated is suction filtered and dissolved in lN
sodium hydroxide solution. This solution is washed successively with 25 ml of acetic acid and diethylether, th~n adjusted to pH 6 with 20~ citric acid. The product precipitated is suction filtered, washed with about 30 ml of water and dried, then triturated with diethylether and dried in a high vacuum.
Yield: 950 mg (68% of theory), Melting point: 239-240C
C30H30N4O2 x H2O (496.62) Calculated: C 72.55 H 6.49 N 11.28 Found: 72.62 6.62 11.54 Rf value: 0.70 (silica gel; methylene chloride/ethanol =
4:1) Example 34 4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrate a) 4'-[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenYl 2~7~

A solution of 2.8 g (11 mMol) of 2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazole and 1.7 g (15 mMol) of potassium tert.butoxide in 60 ml of dimethylsulphoxide is stirred for 15 minutes at ambient temperature. Then 6.0 g of (11 mMol) o~ 4'-bromomethyl-2-~2-triphenylmethyl-tetrazol-5-yl)-biphenyl are added and the mixture is stirred for a further 3 hours at ambient temperature. Then the solution is stirred into about 150 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (500 g of silica gel;
eluant: petroleum ether/ethyl acetate = 1:1) Yield: 3.6 g (45% o~ theory) b) 4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetra201-5-yl)-biphenyl-hYdrate A mixture of 3.6 g (4,9 mMol) of 4'~(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl, 20 ml of 40% N-methylamine solution and 30 ml of N-methylformamide is heated to 200C for 10 hours in an autoclave. After cooling, the contants of the autoclave are stirred with about 50 ml of water, this suspension is adjusted to pH 6.5 with 20% citric acid, then the crude product precipitated is suction filtered and purified by column chromatography (200 g silica gel;
eluant: methylene chloride with 5 to 20% ethanol).
Yield: 1.0 g (41% of theory), Melting point: from 195C sintering C30H30N8 x H20 (520.6) Calculated: C 69.21 H 6.19 N 21.52 Found: 68.99 6.26 21.37 Mass spectrum: m/e = 502 , .

208780~

Example 35 4'-[(2-Ethyl-4-methyl-6-~1-t2-methoxyethyl)-imidazol-4-yl)-banzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-ethyl-~-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chlorid~.
Yield: 49% of theory, Melting point: 165-167C
C30H30N4O3 (494.60) Calculated: C 72.85 H 6.11 N 11.33 Found: 72.62 6.27 11.35 Mass spectrum: m/e = 494 Example 36 4'-[(2-Cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid " Prepared analogously to Example 1 from tert. butyl 4'-[(2-cyclopropyl-4-methyl-6~ 2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 78% of theory, Melting point: 179-181C
C31H30N4O3 (506.61) Calculated: C 73.50 H 5.g7 N 11.06 Found: 73.37 6.02 11.02 Mass spectrum: m/e = 506 ' ~

~0~78~0 Example 37 4'-[(2~n-Propyl-4~methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert. butyl 4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 26% of theory, Melting point: 190-192C
C30H29N503 (507.60) Rf value: 0.44 (silica gel; methylene chloride/methanol =
8:2) Example 38 4'-C(2-n-Propyl-4-methyl-6-(l-ethoxycarbonylmethyl-imidazol-4-yl)-henzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid -Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4 methyl-6-(1-ethoxycarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 18% of theory, Melting point: 223-224C
C32H32N404 (536.63) Rf value: 0.69 (silica gel; methylene chloride/methanol =
8:2) Mass spectrum: m/e = 536 2087~0 6~ -Example 39 4'-[(2-Cyclapropyl-4-methyl-6-(1-(2-hydroxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid A solution of 500 mg (1.0 mMol) of 4'-[(2-cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl] biphenyl-2-carboxylic acid and 1.5 g (6.0 mMol) of boron tribromide in 50 ml of methylene chl~ride is stirred for 16 hours at ambient temperature, then mixed with about 30 ml of water and stirred vigorously for another 10 minutes. This mixture is evaporated to dryness and the residue is refluxed in about 40 ml of ethanol for 10 minutes. The mixture is evaporated to dryness once more, the residue is dissolved in about 30 ml of 2N ammonia solution and this solution is adjusted to pH 5-6 with ~N acetic acid. The crude product precipitated is suction filtered and purified by column chromatography (80 g silica gel;
eluant: methylene chloride/methanol = 4:1).
Yield: 150 mg (30% of theory), Melting point: 220-222C
C30H28N4O3 (492.58) Rf value: 0.20 (silica gel; methylene chloride/methanol =
9:1) Mass spectrum: m/e = 492 Exam~le 40 4'-[(2-n-Propyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert. butyl 4'-20~7~1D0 [(2-n-propyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)~benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 54% of theory, Melting point: 259-261~C
C34H37Ns3 (563-70) Calculated: C 72.44 H 6.62 N 12.42 Found: 72.68 6.65 12.53 Mass spectrum: m/e = 563 Example 41 4 ' - L ( 2-n-Propyl-4-methyl-6-(1-(2-methoxyethoxy-2-ethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-hiphenyl-2-carboxylic acid Prepared analogously to Example 1 from te,rt.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(2-methoxyethoxy-2-ethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 49% of theory, Melting point: 192-194C
C33H36N404 (552.67) Calculated: C 71.72 H 6.57 N 10.14 Found: 71.52 6.36 10.25 Rf value: 0.36 (silica gel; dichloromethane/methanol =
9 : 1 ) Mass spectrum: m/e = 552 20~78~

Example 42 4'-[(2-n-Propyl-4-methyl-6-(}-(3-dimethylaminopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid dihydroch-oride-pentahydrate -Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(3-dimethylaminopropyl)-imidazol-4-yl) benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 12% of theory, Melting point: from 128~C (decomp.) C33H37NsO2 x 2 HCl x 5 H20 (535 70) Rf value: 0.20 (silica gel; dichloromethane/methanol =
9 : 1 ) Mass spectrum: m/e = 535 Example 43 4'-[(2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-l-yl)-methyll-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 32% of theory, Melting point: 248-250C
Cz9H27N32S (481.62) Calculated: C 72.32 H 5.65 N 8.72 Found: 72.21 5.83 8.67 R~ value: 0.26 (silica gel; dichloromethane/methanol =
9 : 1 ) ~78~

Mass spectrum: m/e = 481 Example 44 4'-[~2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-dihydrochloride Prepared analogously to Example 16 from 4'-[(2-n-propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-1-yl)-methyl]-2-~2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 91% of theory, Melting point: from 219C (decomp.) C29Hz9C12N7s (578.58) Calculated: C 60.20 H 5.05 N 16.95 Cl 12.25 Found: 59.96 5.19 16.63 12.42 Rf value: 0.32 (silica ~el; dichloromethane/methanol =
9 : 1 ) Mass spectrum: m/e = 505 Example 45 4'-[(2-Ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 27 % of theory, Melting point: 201-202C
C33H35NsO3 (549.65) Calculated: C 72.11 H 6.42 N 12.74 20~7~00 Found: 72.00 6.48 12.62 Rf value: 0.36 (silica gel; methylene chloride/methanol =
9 : 1 ) mass spectrum: m/e = 549 Example 46 4'-[(2-Ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrate r Prepared analogously to Example 16 from 4'-[(2-ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimida~ol-l-yl)-methyl~-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 14 % of theory, Melting point: above 180C (decomp.) C33H35N9o x H2O (573.68) Calculated: C 66.98 H 6.30 N 21.31 Found: 66.87 6.36 21.22 Rf value: 0.31 (silica gel; methylene chloride/methanol =
9 : 1 ) mass sp ctrum: mJe _ 573 Example 47 4'-[(2-Ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-E ( 2-ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 66 % of theory, 20~780~

Melting point: above 185C (decomp.) C30H2sNs3 (507.59) Calculated: C 70.99 H 5.76 N 13.80 Found: 70.73 5.72 13.66 mass spectrum: m/e = 507 Example 48 4'-[t2-Ethyl-4-methyl-6-tl-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl~-biphenyl Prepared analogously to Example 16 Erom 4'-~(2-ethyl-4-methyl-6-~1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-l-yl?-methyl]~2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 42 ~ of theory, Melting point: above 191C (decomp.) C30H29N90 (531.63) Calculated: C 67.78 H 5.50 N 23.71 Found: 67.7g 5.4Q 23.66 Rf value: 0.20 (silica gel; methylene chloride~methanol =
8:2) mass spectrum: m/e = 531 Example 49 4'-[(2-Ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid -Prepared analogously to Example 1 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.

.
~ . ' : .
' , 20~78~

Yield: 60 % of theory, Melting point: 215-217C
C33H35N5O2 (533.67) Calculated: C 74.27 H 6.61 N 13.12 Found: 74.03 6.~5 13.11 Rf value: 0.30 tsilica gel; methylene chloride/methanol =
8:2) mass spectrum: m/e = 533 Example 50 4'-[(2-Ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl~-benzimidazol-1-yl)-methyl~-2-(lH-tetrazol-5-yl)-biphenyl __ __ Prepared analogously to Example 16 from 4'-[(2-ethyl-4-methyl-6~ (2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl~
tetrazol-5-yl)-biphenyl.
Yield: 38 % of theory, Melting point: above 128C (sintering) C33H3sN9 (551.71) Calculated: C 71.84 H 6.39 N 22.85 Found: 71.63 6.20 22.49 Rf value: 0.23 (silica gel; methylene chloride/methanol =
8:2~

Example 51 4'-[(2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid-dihydrochloride -Prepared analogously to Example 1 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-20~7~00 4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 32 ~ of theory, Melting point: 255-257C (decomp.) C33H37Ns2 x 2 HCl (608.60) Rf value: 0.24 (silica gel; methylene chloride/methanol =
9:1) mass spectrum: m/e = 535 Example 52 4'-[(2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 from 4'-[(2-ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol~l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 51 % o_ theory, Melting point: 191-193C
C33H37N9 (559.70) Calculated: C 70.81 H 6.66 N 22.52 Found: 70.59 6.66 22.58 Rf value: 0.30 (silica gel; methylene chloride/methanol =
8:2) Example 53 4'-[(2-Ethyl-4-methyl-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate 20~78~0 - 6~ -and trifluoroacetic acid in methylene chloride.
Yield: 19 % of theory r Melting point: amorphous C3sH39N502 (561.73) Cal~ulated: C 74.84 H 7.00 N 12.47 Found: 7~.61 6.92 12.31 Rf value: 0.34 (silica gel; methylene chloride/methanol =
8:2) Example 54 4~ [(2-Ethyl-4-mQthyl-6-~1-t3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyll-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 16 from 4'-[(2-ethyl-4-methyl-6~ (3-N-piperidinopropyl~-imidazol-4-yl)-~ben2imidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 71 ~ of theory, Melting point: above 140C (decomp.) C3sH39N9 (585.76) Calculated: C 71.77 H 6.71 N 21.52 Found: 71.58 6.68 21.44 Rf value: 0.22 (silica gel; methylene chloride/methanol =
8:2) 2~7300 In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I including the physiologically acceptable salts thereof, particularly those wherein ~4 represents a carboxy or lH-tetrazolyl group, may be used as the active substance:

Example I

Ampoules containing 50 mg of active substance per 5 ml Active substance 50 mg KH2P04 2 mg Na2HP04 x 2HzO 50 mg NaCl 12 mg Water for injections ad 5 ml PreParation:

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

Ampoules containing 100 mg of active substance per 5 ml Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene-glycol block polymer 250 mg Water for injections ad 5 ml , .

~87800 Preparakion:

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.

ExamE~Le III

Tablets containing 50 mg of active substance _ Active substance 50.0 mg Calcium phosphate 70.0 mg Lactose 4C.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 1 5 mq 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.

After the lubricant has been added, the granules are compressed in a tablet making machine.

Example IV

Coated tablets containing 50 mg of active substance Active substance 50.0 mg Lysine 25.0 mg Lactose 60.0 mg :~ ' 20~7~

Corn starch 34.0 mg Gelatin 10.0 mg Magnesium stearate 1.0 mq 180.0 mg 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.

Exa_ple V

Coated tablets containing 100 mg of active substance 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 mq 350.0 mg Preparation:

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

20~78~

The cores thus producad 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 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 ma~nesium 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 .
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 .

, , 2~87~

Preparation:

Distilled water is heated to 70~C. 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 substarlce Active sub~tance 100.0 mg Solid fat 1600.0 m~
1700.0 mg Th~ hard fat is melted. At 40C the ground 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 represents a C1-3-alkyl group, a hydrogen, fluorine, chlorine or bromine atom;

R2 represents an oxazol-4-yl or thiazol-4-yl group optionally substituted in the 2-position by a C1-6-alkyl group or by a phenyl group, or an imidazol-4-yl group optionally substituted in the
2-position by a C1-6-alkyl group or by a phenyl group and substituted in the 1-position by a C1-7-alkyl group optionally substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido-thiomorpholinocarbonyl group, by a C2-4-alkyl group substituted in the 2-, 3- or 4-position by a hydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholino or imidazol-1-yl group, by a C1-3-alkyl group substituted by a trifluoromethyl group, by a C3-7-cycloalkyl group or by a phenyl group itself optionally mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, by a C1-3-alkyl group substituted by two phenyl groups, or by a C3-7-cycloalkyl group, where unless otherwise specified the above-mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms;

R3 represents a C2-4-alkyl, C2-3-alkoxy, C2-3-alkylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group or a group convertable in vivo into a carboxy group) and the salts thereof.

2. Compounds of formula I as claimed in claim 1, wherein R2 is in the 6-position of the benzimidazole ring;

and the salts thereof.
3. Compounds of formula I as claimed in claim 1 or claim 2, wherein R1 represents a hydrogen or chlorine atom or a methyl group;

R2 represents an oxazol-4-yl or thiazol-4-yl group optionally substituted in the 2-position by a methyl or phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the 1-position by a C1-7-alkyl group optionally substituted in the 1-, 2-, 3-, 4-, 5-, 6- or 7-position by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido-thiomorpholino-carbonyl group, by a C2-4-alkyl group substituted in the 2-, 3- or
4-position by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-1-yl group, or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, 2-phenylethyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-methylbenzyl, 4-trifluoromethylbenzyl, 3,5-dimethoxybenzyl or 2,2-diphenylethyl group;

R3 represents a C2-4-alkyl, C2-3-alkoxy, C2-3-alkylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy or 1H-tetrazolyl group or a group convertable in vivo into a carboxy group;
and the salts thereof.

4. Compounds of formula I as claimed in any one of claims 1 to 3, wherein R4 denotes a carboxy group or a group of formula - CO - OR', - CO - O - (HCR") - O - CO - R"' or - CO - O - (HCR") - O - CO - OR"' (wherein R' 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, R" denotes a hydrogen atom or a methyl group, and R"' 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 the salts thereof.
5. Compounds of formula I as claimed in any one of claims 1 to 4, wherein R1 represents a hydrogen atom or a methyl group;

R2 represents an oxazol-4-yl or thiazol-4-yl group optionally substituted in the 2-position by a methyl or phenyl group or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the 1-position by a C1-7-alkyl group optionally substituted in the 1-, 2-, 3-, 4-, 5-, 6- or 7-position by a carboxy, methoxycarbonyl, dimethylaminocarbonyl or morpholino-carbonyl group, by a C2-4-alkyl group substituted in the 2-, 3- or 4-position by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-1-yl group;

or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl or 4-fluoro-benzyl group;

R3 represents a C2-4-alkyl group, an ethoxy, ethylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy or 1H-tetrazolyl group;
and the salts thereof.
6. Compounds of formula I as claimed in any one of claims 1 to 5 being:

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

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

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

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

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

(f) 4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid; or (g) 4'-[(2-n-propyl-4-methyl-6-(1-(3-dimethyl-aminopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid;

or a salt thereof.
7. A compound as claimed in any one of claims 1 to 6 being a physiologically acceptable addition salt of a compound of formula I as claimed in any one of claims 1 to 6.
8. A pharmaceutical composition containing a compound of formula I as claimed in any one of claims 1 to 6 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients.
9. A 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 one of the groups X1 and Y1 represents a group of formula and the other group X1 or Y1 represents a group of the formula R5 represents a hydrogen atom or an R3CO- group, R1, R2, R3 and R4 are as defined in any one of claims 1 to 6, Z1 and Z2, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by 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 an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms) or an N-oxide thereof and optionally subsequently reducing a cyclized 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 6) with a biphenyl compound of formula IV
(IV) (wherein R4 is as defined in any one of claims 1 to 6 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 6 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 6 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 6) with hydrazoic acid or a salt thereof;

f) converting a compound of formula I wherein R4 denotes a carboxy group by esterification into a corresponding compound of formula I wherein R4 denotes a group convertable in vivo into a carboxy group;

g) converting a compound of formula I wherein R2 denotes an imidazol-4-yl group substituted in the 1- position by a C2-4-alkyl group substituted in the 2-, 3- or 4-position by an alkoxy or alkoxyalkoxy group, by ether splitting into a corresponding compound of formula I
wherein R2 denotes an imidazol-4-yl group substituted in the 1-position by a C2-4-alkyl group substituted in the 2-, 3- or 4-position by a hydroxy group;
h) separating the 1-isomer from a 1-, 3-isomer mixture of a compound of formula I by isomer separation;
i) converting a compound of formula I into a salt thereof, more particularly into a physiologically acceptable addition 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 j) performing a process as defined in any one of steps (a) to (i) above on a corresponding protected compound and subsequently removing the protecting groups used.
10. Use of a compound of formula I as claimed in any one of claims 1 to 6 or physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension and cardiac insufficiency and also for treating chronic renal insufficiency, ischaemic peripheral circulatory disorders and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and retinopathy, glaucoma, gastrointestinal diseases and bladder diseases.
11. Use of a compound as claimed in claim 10 for treating pulmonary diseases, for preventing arterial re-sterosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout.
12. Use of a compound as calimed in claim 10 for alleviating central nervous system disorders.
13. A method of treatment of the human or non-human animal body to combat hypertension and cardiac insufficiency and also for treating chronic renal insufficiency, ischaemic peripheral circulatory disorders and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and retinopathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 6 or a physiologically acceptable salt thereof.
14. A method of treatment as claimed in claim 13 to combat pulmonary diseases, for preventing arterial re-sterosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout.
15. A method of treatment as claimed in claim 13 for alleviating central nervous system disorders.
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.
CA002087800A 1992-01-22 1993-01-21 Benzimidazoles, pharmaceutical compositions containing these compounds and processes for preparing them Abandoned CA2087800A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DEP4201554.5 1992-01-22
DE4201554A DE4201554A1 (en) 1992-01-22 1992-01-22 New benzimidazol-1-yl-methyl-bi:phenyl derivs.
DE4219782A DE4219782A1 (en) 1992-01-22 1992-06-17 New benzimidazol-1-yl-methyl-bi:phenyl derivs.
DEP4219782.1 1992-06-17
DE4225756A DE4225756A1 (en) 1992-01-22 1992-08-04 Benzimidazoles, medicaments containing these compounds and process for their preparation
DEP4225756.5 1992-08-04

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US10166215B2 (en) 2013-06-21 2019-01-01 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10363257B2 (en) 2013-06-21 2019-07-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US10500209B2 (en) 2013-07-31 2019-12-10 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors

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CA2115985A1 (en) * 1993-02-25 1994-08-26 Kohei Nishikawa Vascular hypertrophy suppressor
WO2011002425A2 (en) 2009-07-02 2011-01-06 Bilgig Mahmut Pharmaceutical composition increasing solubility and stability
WO2011002423A2 (en) 2009-07-02 2011-01-06 Mahmut Bilgic Solubility enhancing pharmaceutical composition
EP2377521A1 (en) 2010-03-26 2011-10-19 Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi Pharmaceutical formulations of telmisartan and diuretic combination

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DE3928177A1 (en) * 1989-04-08 1991-02-28 Thomae Gmbh Dr K BENZIMIDAZOLE, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
EP0400835A1 (en) * 1989-05-15 1990-12-05 Merck & Co. Inc. Substituted benzimidazoles as angiotensin II antagonists
RU1836357C (en) * 1990-07-23 1993-08-23 Др.Карл Томэ ГмбХ Benzimidazole derivatives, their isomers, mixtures of isomers, hydrates or their physiologically bearable salts possessing properties antagonistic to angiotenzine
SI9210098B (en) 1991-02-06 2000-06-30 Dr. Karl Thomae Benzimidazoles, drugs with this compounds, and process for their preparation

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US10166215B2 (en) 2013-06-21 2019-01-01 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US10226451B2 (en) 2013-06-21 2019-03-12 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US10363257B2 (en) 2013-06-21 2019-07-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US10772892B2 (en) 2013-06-21 2020-09-15 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US11026926B2 (en) 2013-06-21 2021-06-08 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US11446306B2 (en) 2013-06-21 2022-09-20 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US10500209B2 (en) 2013-07-31 2019-12-10 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains

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ATE141270T1 (en) 1996-08-15
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ES2093286T3 (en) 1996-12-16
HUT63626A (en) 1993-09-28
AU3196293A (en) 1993-07-29
PL297472A1 (en) 1994-01-24
MX9300306A (en) 1993-07-01
NZ245741A (en) 1995-07-26
PL172782B1 (en) 1997-11-28
NO930205L (en) 1993-07-23
FI930236A (en) 1993-07-23
HU217816B (en) 2000-04-28
IL104485A0 (en) 1993-05-13
SK279409B6 (en) 1998-11-04
NO930205D0 (en) 1993-01-21
NO303689B1 (en) 1998-08-17
AU660209B2 (en) 1995-06-15
IL104485A (en) 1999-10-28
DK0552765T3 (en) 1997-01-13
EP0552765A1 (en) 1993-07-28
HU9300168D0 (en) 1993-04-28
GR3021303T3 (en) 1997-01-31
SK394492A3 (en) 1998-11-04
EP0552765B1 (en) 1996-08-14
CZ394492A3 (en) 1993-11-17
DE59303388D1 (en) 1996-09-19
DE4225756A1 (en) 1994-03-10

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