CA2093785A1 - Benzimidazoles - Google Patents

Benzimidazoles

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Publication number
CA2093785A1
CA2093785A1 CA002093785A CA2093785A CA2093785A1 CA 2093785 A1 CA2093785 A1 CA 2093785A1 CA 002093785 A CA002093785 A CA 002093785A CA 2093785 A CA2093785 A CA 2093785A CA 2093785 A1 CA2093785 A1 CA 2093785A1
Authority
CA
Canada
Prior art keywords
group
methyl
denotes
formula
benzimidazol
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
CA002093785A
Other languages
French (fr)
Inventor
Uwe Ries
Norbert Hauel
Berthold Narr
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 DE4212250A external-priority patent/DE4212250A1/en
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Publication of CA2093785A1 publication Critical patent/CA2093785A1/en
Abandoned legal-status Critical Current

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0033—Blends of pigments; Mixtured crystals; Solid solutions
    • C09B67/0046—Mixtures of two or more azo dyes
    • C09B67/0055—Mixtures of two or more disazo dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • 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
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D11/00—Inks
    • C09D11/30—Inkjet printing inks
    • C09D11/32—Inkjet printing inks characterised by colouring agents
    • C09D11/328—Inkjet printing inks characterised by colouring agents characterised by dyes

Abstract

Abstract Benzimidazoles The invention relates to benzimidazoles of formula I

Description

~37~

59340.559 Benzimidazoles The present invention relates to new benzimidazoles, processes for their preparation and pharmaceutical compositions containing them.

EP-A-468470 discloses benzimidazoles which are valuable angiotensin-antagonists.

It has been found that certain novel benzimidazoles have particularly valuable pharmacological properties as angiotensin-II-antagonists.

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

...~
(I) (wherein R1 denotes a hydrogen, fluorine, chlorine or bromine atom or a fluoromethyl, difluoromethyl, trifluoromethyl or alkyl group;

R2 denotes an imidazol-2-yl group optionally substituted in the l-position by the group Ra, wherein Ra denotes a phenyl or phenylalkyl group, in which the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the . . .

. , :.

. 2~1~37~

substituents may be identical or different, a C3 7-cycloalkyl group or a C16-alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertible in vivo into a carboxy group, by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or from position 2 by a hydroxy, alkoxy, amino, alkyIamino, dialkylamino, pyrrolidino, piperidino or morpholino group, a 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl group, an imidazolium-2-yl group substituted in the 1- and 3-positions by groups Rb, which groups may be identical or different, wherein ~ :

Rb denotes a phenylalkyl group in which the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different, or Rb denotes a C16-alkyl :~ group in which the alkyl moiety may additionally be~ substituted by a group metabolically convertible ln- vivo into a carboxy group, or by a trifluoromethyl, ~. car~oxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, an oxazol-2-yl or thiazol-2-yl group, whilst in the above mentioned imidazol-2-yl, imidazolium-2-yl, oxazol-2-yl or thiazol-2-yl moieties, the 4-, 5-positions may be substituted by a C15~alkyl group or by a phenyl group, wherein the substituents may be identical or different, or an n-propylene or n-- butylene bridge may be added via the 4-, 5-positions, an oxazolin-2-yl or imidazolin-2-yl group substituted in .
' ' '' ' ` ` ' '` - :.:

- ` 2~3~ -- 3 --the 4-position by the groups R9 and R1o and in the 5~
position by the group R8, wherein an imino group may additionally be substituted by Ra or by an R8CO-(R9CR1o)~
NRa-CO- group, wherein Ra is as hereinbefore defined, and R8, R9 and R10, which may be identical or different, denote hydrogen atoms, C1s-alkyl groups or phenyl groups;

R3 denotes a C1s-alkyl group, a C3s-cycloalkyl group, a C14-alkoxy or Cl4-alkylthio group; and R4 denotes a hydrogen atom or a group of formula .

_CH2 ~r ~ ~ \

wherein Rs denotes a group metabolic:ally convertabla in vivo into a carboxy group, or de:notes a carboxy, cyano, - 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, lH-tetrazolyl, l-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group;

whilst unless otherwise specified any alkyl or alkoxy group contains l to 3 carbon atoms, and the phrase "a group metabolically convertable in vivo into a carboxy group" as used herein denotes the esters thereof of formulae - CO - OR', - Co - O - (HCR") - O - CO - R"' and 2~37~

~, - CO - O - (HCR" ) -- O - CO - OR" ' wherein R' denotes a straight-chained or branched C16-alkyl group, a Cs7-cycloalkyl group, a 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 C16-alkyl group, a Cs7~cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group) ' and the 3-isomers, the 1-, 3-isomer mixtures and the salts thereof.

Examples of the definitions of groups R1, R2, R3 and Rs mentioned above are as follows:

R1 may denote a hydrogen, fluorine, chlorine or bromine atom or a fluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl or isopropyl group;

~ R2 may denote the 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl, 1-methyl-5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl, 1-ethyl-5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl, 1-n-propyl-5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl, 1-isopropyl-5,5-spiro-cyclopentano-dihydro-imidazol 4-on-2-yl, 4,5-dimethyl-oxazol-2-yl, 4-methyl-5-ethyl-oxazol-2-yl, 4-methyl-5-n-propyl-oxazol-2-yl, 4-methyl-5-n~
butyl-oxazol-2-yl, 4-methyl-5-n-pentyl-oxazol-2-yl, 4-methyl-5-phenyl-oxazol-2-yl, 4,5-diethyl-oxazol-2-yl, 4-ethyl-5-n-propyl-oxazol-2-yl, 4-ethyl-5-n-butyl-oxazol-2-yl, 4-ethyl-5-n-pentyl-oxazol-2-yl, 4-ethyl-5-phenyl-oxazol-2-yl, 4,5-di-n-propyl-oxazol-2-yl, 4-n-propyl-5-', : ~ ' , ,, : '' ' " ' .:
,, , .

~37~
.

n-butyl-oxazol-2-yl, 4-n-propyl-5-n-pentyl-oxazol-2-yl, 4-n-propyl-5-phenyl-oxazol-2-yl, 5-methyl-4-ethyl-oxazol-2-yl, 5-methyl-4-n-propyl-oxazol-2-yl, 4,5-diphenyl-oxazol-2-yl, 5,6,7,8-tetrahydro-benzoxazol-2-yl, 4,5-dimethyl-thiazol-2-yI, 4-methyl-5-ethyl-thiazol-2-yl, 4-methyl-5-n-propyl-~hiazol-2-yl, 4-methyl-5-phenyl-thiazol-2-yl, 4,5-diethyl-thiazol-2-yl, 4-ethyl-5-n-propyl-thiazol-2-yl, 4-ethyl-5-phenyl-thiazol-2-yl, 4,5-di-n-propyl-thiazol-2-yl, 4,5-di-n-isopropyl-thiazol-2-yl, 4-n-propyl-5-phenyl-thiazol-2-yl, 4,5-diphenyl-thiazol-2-yl, 5,6,7,8-tetrahydro-benz-thiazol-2-yl, 4-methyl-oxazolin-2-yl, 4-ethyl-oxazolin-2-yl, 4-n-propyl-oxazolin-2-yl, 4-isopropyl-oxazolin-2-yl, 4-n-butyl-oxazolin-2-yl, 4-isobutyl-oxazolin-2-yl, 4-benzyl-oxazolin-2-yl, 4-phenyl-oxazolin-2-yl, 4,4-dimethyl-oxazolin-2-yl, 4-methyl-5-phenyl-oxazolin-2-yl, 4,4-dimethyl-5-n-propyl-oxazolin-2-yl, 4,5-tetramethylene-oxazolin-2-yl, 4-methyl-imidazolin-2-yl, 4,5-dimethyl-imidazolin-2-yl, 4,5-tetramethylene-imidazolin-2-yl, 4-methyl-imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl, 1,4,5-trimethyl-imidazol-2-yl, 1-ethyl-4,5-dimethyl-imidazol-2-yl, 1-n-propyl-4,5-dimethyl-imidazol-2-yl, 1-isopropyl-4,5-dimethyl-imidaz~1-2-yl, 1-n-butyl-4,5 dimethyl-imidazol-2-yl, 1-isobutyl-4,5-dimethyl-imidazol-2-yl, 1-cyclopropyl-4,5-dimethyl-imidazol-2-yl, l-cyclobutyl-4,5-dimethyl-imidazol-2-yl, l-cyclopentyl-4,5-dimethyl-imidazol-2-yl, 1-cyclohexyl-4,5-dimethyl-imidazol-2-yl, 1-cycloheptyl-4,5-dimethyl-imidazol-2-yl, 1-benzyl-4,5-dimethyl-imidazol-2-yl, 1-(2-phenyl-ethyl)-4,5-dimethyl-imidazol-2-yl-, 1-carboxymethyl-4,5-dimethyl-imidazol-2-yl, 3-methoxycarbonylmethyl-4,5-dimethyl-imidazol-2-yl, 1-ethoxycarbonylmethyl-4,5-dimethyl-imidazol-2-yl, 1-n-propoxycarbonylmethyl-4,5-dimethyl-imidazol-2-yl, 1-isopropoxycarbonylmethyl-4,5-dimethyl-imidazol-2-yl, 1-aminocarbonylmethyl-4,S-dimethyl-imidazol-2-yl, 1-methylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl, 1-ethylam.inocarbonylmethyl-4,5-~37~

dimethyl-imidazol-2-yl, 1-n-propylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl, l-isopropylamino-carbonylmethyl-4,5-dimethyl-imidazol-2-yl, 1-dimethylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl, 1-diethylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl, l-di-n-propylaminocarbonylmethyl-4,5-dimethylimidazol-2-yl, l-diisopropylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl, 1-N-methyl-ethylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl, 1-(2-carboxy-ethyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-methoxycarbonyl-ethyl)-4,5-dimethy].-imidazol-2-yl, 1-(2-ethoxycarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-n-propoxycarbonyl-ethyl)-4,5~dimethyl-imidazol-2-yl, 1-(2-isopropoxycarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl, 1-~2-aminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-methylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-ethylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl, 1~(2-n-propylaminocarbonyl-ethyl)- 4,5-dimethyl-imidazol-2-yl, 1-(2-isopropylaminocarbonylethyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-dimethylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-diethylaminocarbonyl-ethyl)-4,5-climethyl-imidazol-2-yl, 1-(2-d1-n-propylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl, 1.-(2-diisopropylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-N-methyl-ethylamino-carbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl, 1~(3-carboxy-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-methoxycarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-ethoxycarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-n-propoxycarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-isopropoxycarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-aminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, l-(3-methylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-ethylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3~n-propylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-isopropylaminocarbonylpropyl)-4,5-dimethyl-imidazol-2-.

:.

2~3~8~

yl, l-(3-dimethylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-diethylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-di-n-propylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-diisopropylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-N-methyl-ethylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl, 1-(2,2,2-trifluoroethyl)-4,5-dimethyl-imidazol-2-yl, l-(2-hydroxyethyl)-4,5-dimethyl-imidazol-2-yl, l-(3-hydroxypropyl)-4,5-dimethyl-imidazol-2-yl, l-(4-hydroxybutyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-methoxyethyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-methoxypropyl)-4,5-dimethyl-imidazol-2-yl, l-(4-methoxybutyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-ethoxyethyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-ethoxypropyl)-4,5-dimethyl-imidazol-2-yl, l~
ethoxybutyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-isopropoxyethyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-n-propoxypropyl)-4,5-dimethyl-imidazol-2-yl, 1-(4-isopropoxybutyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-pyrrolidinoethyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-pyrrolidinopropyl)-4,5-dimethyl-imidazol-2-yl, l-(4-pyrrolidinobutyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-piperidinoethyl)-4,5-dimethyl-imidazol-2~yl, 1-(3-piperidinopropyl)-4,5-dimethyl-imidazol-2-yl, 1-(4-piperidinobutyl)-4,5-dimethyl-imidaæol-2-yl, 1-(2-morpholinoethyl~-4,5-dimethyl-imidazol-2-yl, 1-(3-morpholinopropyl)-4,5-dimethyl-imidazol-2-yl, 1-(4-morpholinobutyl)-4,5-dimethyl-imidazol-2-yl, l-phenyl-4,5-dimethyl-imidazol-2-yl, 1-benzyl-4,5-dimethyl-imidazol-2-yl, 1-(1-phenylethyl)-4,5-dimethyl-imidazol-2-yl, l-(2-phenylethyl)-4,5-dimethyl-imidazol-2-yl, 1-(1-phenylpropyl)-4,5-dimethyl-imidazol-2-yl, 1-(2-phenylpropyl)-4,5-dimethyl-imidazol-2-yl, 1-(3-phenylpropyl)-4,5-dimethyl-imidazol-2-yl, 1-methyl-4,5-diethyl-imidazol-2-yl, 1,4,5-triethyl-imidazol-2-yl, 1-ethyl-4-isopropyl--5-methyl-imidazol-2-yl, l-ethyl-4-isobutyl-5-methyl-imidazol-2-yl, 1-n-propyl-4-isopropyl-2~37~

5-methyl-imidazol-2-yl, 1-n-propyl-4-isobutyl-5-methyl-imidazol-2-yl, 1,4-diisopropyl-5-methyl-imidazol-2-yl, 1-isopropyl-4-isobutyl-5-methyl-imidazol-2-yl, 1-(2-dimethylamino-ethyl)-4-isopropyl-5-methyl-imidazol-2-yl, 1-(2-dimethylamino-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl, 1-(3-dimethylamino-propyl)-4-isopropyl-5-methyl-imidazol-2-yl, 1-(3-dimethylamino-propyl)-4-isobutyl-S-methyl-imidazol-2-yl, 1,5-dimethyl-4-ethyl-imidazol-2-yl, 1,5-dimethyl-4-n-propyl imidazol-2-yl, 1,5-dimethyl-4-isopropyl-imidazol-2-yl, 1,5-dimethyl-4-isobutyl-imidazol-2-yl, 1,5-dimethyl-4-phenyl-imidazol-2-yl, 1-methyl-4,5-diphenyl-imidazol-2-yl, 1-ethyl-4,5-diphenyl-imidazol-2-yl, 1-n-propyl-4,5-diphenyl-imidazol-2-yl, 1-isopropyl-4,5-diphenyl-imidazol-2-yl, l-carboxymethyl-4,5-diphenyl-imidazol-2-yl, 1-methoxycarbonylmethyl-4,5-diphenyl-imidazol-2-yl, 1-ethoxycarbonylmethyl-4,5-diphenyl-imidazol-2-yl, 4,5-trimethylene-imidazol-2-yl, 1-methyl-4,5-trimethylene-imidazol-2-yl, 5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-methyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-ethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-n-propyl-5,6,7,8-tetrahydro-benzimidaæol-2-yl, 1-isopropyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-n-butyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-isobutyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-n-pentyl-5,6,7,8-tetrahydro-benzimidazol 2-yl, 1-n-hexyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-cyclopropyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-cyclobutyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-cyclopentyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-cyclohexyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-cycloheptyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-carboxymethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, l-methoxycarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-ethoxycarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, l-n-propoxycarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-isopropoxycarbonylmethyl-5,6,7,8-- .
- : .
.' ~ ~. ' ' - " .

2~3~

g tetrahydro-benzimidazol-2-yl, l-aminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-methylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-ethylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, l-n-propylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, l-isopropylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-dimethylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-diethylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, l-di-n-propylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-diisopropylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, l-N-methyl-ethylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-carboxy-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-methoxycarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-ethoxycarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, l-(2-n-propoxycarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-isopropoxycarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-:2-yl, 1-(2-aminocarbonyl-ethyl)~5,6,7,8-tetrahydro-benzimidazol-2-yl, l-(2-methylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-ethylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-n-propylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-t2-isopropylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-dimethylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-diethylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-di-n-propylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-diisopropylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-N-methyl-ethylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-carboxy-propyl)-5,6,7,8-2 ~

tetrahydro-benzimidazol-2-yl, 1-(3-methoxycarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-ethoxycarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-n-propoxycarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-isopropoxycarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-aminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-m~thylaminocarbonyl-propyl)-5,6,7,8-tetrahydro benzimidazol-2-yl, 1-(3-ethylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-n-propylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-.
benzimidazol-2-yl, 1-(3-isopropylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-dimethylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-diethylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-di-n-propylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-diisopropylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-N-methyl-ethylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-phenyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-benzyl-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(1-phenylethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-phenylethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(1-phenylpropyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2-phenylpropyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(3-phenylpropyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl, 1,3-dimethyl-5,6,7,8-tetrahydro-benzimidazolium-2-yl, 1,3-diethyl-5,6,7,8-tetrahydro-benzimidazolium-2-yl, 1,3-di-n-propyl-5,6,7,8-tetrahydro-benzimidazolium-2-yl or 1,3-dibenzyl-5,6,7,8-tetrahydro-benzimidazolium-2-yl group;

R3 may denote a methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, 1-methyl-n-propyl, tert.butyl, n-.: . . . :
- - ~ , ' ,' ' ' - .

. .

~3~

pentyl, 1 methyl-n-butyl, 2-methyl-n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio or isobutylthio group; and R5 may denote a carboxy, cyano, lH-tetrazolyl, 1-triphenylmethyl-tetrazolyl, 2-triphenylmethyl-tetrazolyl, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, tert.butyloxycarbonyl, n-pentyloxycarbonyl, isoamyloxycarbonyl, n-hexyloxycarbonyl, 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, 1-phenylpropionyIoxymethaxycarbonyl, 2-phenylpropionyloxymethoxycarbonyl, 3-phenylbutyryloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, 1-acetoxyethoxycarbonyl, l-propionyloxyethoxycarbonyl, l-n-butyryloxyethoxycarbonyl, 1-isobutyryloxyethoxycarbonyl, l-n-pentanoyloxyethoxycarbonyl, 1-isopentanoyloxy-ethoxycarbonyl, 1-pivaloyloxyethoxycarbonyl, 1-n-hexanoyloxyethoxycarbonyl, l-cyclopentanoyloxy-ethoxycarbonyl, l-cyclohexanoyloxyethoxycarbonyl, 1-phenylacetoxyethoxycarbonyl, 1-(1-phenylpropionyloxy)-ethoxycarbonyl, l-(2-phenylpropionyloxy)-ethoxycarbonyl, 1-(3-phenylbutyryloxy)-ethoxycarbonyl, 1-2~3~5 benzoyloxyethoxycarbonyl, methoxycarbonyloxy-methoxycarbonyl, ethoxycarbonyloxymethoxycarbonyl, n-propyloxycarbonyloxymethoxycarbonyl, isopropyloxycarbonyloxymethoxycarbonyl, n-butyloxycarbonyloxymethoxycarbonyl, isobutyloxycarbonyloxymethoxyearbonyl, tert.butyloxycarbonyloxymethoxycarbonyl, n- :
pentyloxyearbonyloxymethoxyearbonyl, isoamyloxycarbonyloxymethoxyearbonyl, n-hexyloxycarbonyloxymethoxyearbonyl, eyclopentyloxycarbonyloxymethoxycarbonyl, cyclohexyloxycarbonyloxymethoxycarbonyl, benzyloxycarbonyloxymethoxycarbonyl, 1-phenylethoxycarbonyloxymethoxyearbonyl, 2-phenylethoxycarbonyloxymethoxycarbonyl, 3-phenylpropyloxycarbonyloxymethoxycarbonyl, einnamyloxycarbonyloxymethoxycarbonyl, 1-(methoxycarbonyloxy)-ethoxycarbonyl, 1-(ethoxycarbonyloxy)-ethoxycarbonyl, l-(n-propyloxycarbonyloxy)-ethoxycarbonyl, 1-(isopropyloxycarbonyloxy)-ethoxyearbonyl, l-(n-butyloxyearbonyloxy)-ethoxyearbonyl, 1-(isobutyloxyearbonyloxy)-ethoxyearbonyl, 1-(tert.butyloxycarbonyloxy)-ethoxycarbonyl, l-(n-pentyloxycarbonyloxy)-ethoxycarbonyl, 1-(isoamyloxycarbonyloxy)-ethoxycarbonyl, 1-(n-hexyloxycarbonyloxy)-ethoxycarbonyl, 1-(cyclopentyloxy-carbonyloxy)-ethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)-ethoxycarbonyl, 1-(benzyloxycarbonyloxy)-ethoxycarbonyl, 1-(1-phenylethoxycarbonyloxy)-ethoxycarbonyl, 1-(2-phenylethoxycarbonyloxy)-ethoxycarbonyl, 1-(3-phenylpropyloxycarbonyloxy)-ethoxycarbonyl, 1-(cinnamyloxycarbonyloxy)-ethoxyearbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-.

. . . . .
.
'' , ' : '' .
' 2~37~

propylaminocarbonyl, diisopropylaminocarbonyl, N-methyl-ethylaminocarbonyl, N-ethyl-isopropylaminocarbonyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group.

Pre~erred compounds according to the invention include thos of formula I wherein R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group or a C13-alkyl group;

R2 denotes an imidazol-2-yl group optionally substituted in the 1 position by the group Ra, wherein Ra denotes a phenyl group, a phenyl(C~3-alkyl) group, a Cs7-cycloalkyl group or a C15-alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertable ln vivo into a carboxy group, or by a trifluoromethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl or : dimethylaminocarbonyl group or from position 2 by a hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, pyrrolidino, piperidino or morpholino group, ' ~'.
a 5,5-spiro-cyclopentano-dihydro-imidazol-~-on-2-yl group, an imidazolium-2-yl group substituted i.n the 1- and 3-position by groups Rb, which may be identical or different, wherein Rb denotes a C13-alkyl or phenyl(C13-alkyl) group, an oxazol-2-yl or thiazol-2-yl group, whilst in the above-mentioned imidazol-2-yl, :

2~7~

imidazolium-2-yl, oxazol-2-yl or thiazol-2-yl moieties, the 4-, 5-positions may be substituted by a C14-alkyl group or by a phenyl group, wherein the substituents may be identical or different, or an n-butylene bridge may be added via the 4-, 5-positions, an oxazolin-2-yl or imidazolin-2-yl group substituted by the groups R8, R9 and R10, wherein an imino group may additionally be substituted by Rar wherein R8, R9, R10 and Ra each represent a hydrogen atom or a C14-alkyl group;
, R3 denotes a C2s-alkyl group, a C3s-cycloalkyl group, a C24-alXoxy or C24-alkylthio group; and R4 denotes a 4-biphenylylmethyl group subsituted in the 2'-position by the group Rs/ wherein Rs denotes a group metabolically convertable in vivo i.nto a carboxy group, or denotes a carboxy, cyano, lH-tetrazolyl, l-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group;

whilst the expression "a group metabolically convertable in vivo into a carboxy group" as used hereinbefore denotes, for example, the esters thereof of the formulae - CO - OR', - CO - O - (HCR") - O - CO - R"' and - CO - O - (HCR") - O - CO - OR"' wherein R' denotes a straight-chained or branched Cl4-alkyl group or a Cs7-cycloalkyl group, R" denotes a hydrogen atom or a methyl group, and R"' denotes a straight-chained or branched C14-alkyl group or a C57-cycloalkyl group;

' : . ' ' . .

. .

2~3~8~

and the 3-isomers, the 1-, 3-isomer mixtures and the salts thereof.

Particularly preferred compounds according to the invention include those of formula I above wherein R3 and R4 are as hereinbefore defined;

R2 is in the 6-position and has the meanings given above;
and .
R1 in the 4-position denotes a fluorine, chlorine or bromine atom, a trifluoromethyl group or a C13-alkyl group;

and the 3-isomers, the 1-, 3-isomer mixt-lres and the salts thereof.

More particularly preferred compounds according to the invention include those of formula I above wherein R2 in the 6-position denotes one of the imidazolyl groups mentioned above;

and the 3-isomers, the 1-, 3-isomer mixtures and salts thereof.

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

(a) 4'-[~2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid;

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

2~7~

(c) 4'-[[2-n-propyl-4-methyl-6-(1-methyl-5,6,7,8-te~rahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl;

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

(e) 4'-[[2-ethyl-4-methyl-6-(1-phenyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid;

(f) 4'-[[2-n-propyl-4-methyl-6-(1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid;

(g) 4'-[[2-ethyl-4-methyl-6-(1-ethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl;

~h) 4'-[[2-n-propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid;

(i) 4'-[[2-n-propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; and (k) 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-1,5-dimethyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid;

and the salts thereof.

Viwed from a further aspect, the invention provides a process for the preparation of compounds of the invention, said processing comprising at least one of .- '' ' :.

.. . . . .

2~37~

the following steps:

a) (to prepare compounds of formula I wherein R2 denotes an oxazol 2-yl, thiazol-2-yl or imidazol-2-yl group, in which an n-butylene bridge is added via the 4,5-positions and additionally the imino group in the imidazole ring may be substituted by a C16-alkyl group, by a phenyl(C13-alkyl~ group or by a phenyl group) reacting a compound of formula II

(II) (wherein R1, R3 and R4 are as hereinbefore defined and X denotes an oxygen or sulphur atom or an imino group optionally substituted by a C16-alkyl group, by a phenyl(C13-alkyl) group or by a phenyl group) with an ~-haloketone of formula III

(III) (wherein Z1 denotes a halogen atom such as a chlorine atom)i b) (to prepare compounds of formula I wherein R2 denotes one of the imidazol-2-yl groups mentioned hereinbefore optionally substituted in the l-position by the group Ra) reacting a compound of formula IV

2 ~

(IV) . .
(wherein - R1, R3 and R4 are as hereinbefore defined and R2' denotes one of the above-mentioned oxazol-2-yl groups) with an amine of formula V

: H2N - R6 ( V ) :
: (wherein R6 has the meanings given for Ra hereinbefore or denotes a hydrogen atom);

c) (to prepare benzimidazoles of formula I wherein R4 : denotes a group of the formula:

Rs CH2~--reacting a compound of~formula VI

(VI) ~37~

(wherein R1, R3 and R4 are as hereinbefore defined and R2" has the meanings given for R2 hereinbefore, with the exception of the imidazol-2-yl and imidazolin-2-yl groups unsubstituted in the l-position) with a biphenyl compound of formula VII

\
Z2-CH ~ \

(VII) (wherein Rs is as hereinbefore defined and Z2 denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group);

d) (to prepare a compound of formula I wherein Rs denotes a carboxy group) converting a compound of formula VIII

R2- ~ ~ R3 1HZ~ ~ :

(VIII) (wherein R1, R2 and R3 are as hereinbefore defined and Rsl denotes a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a compound of formula I by hydrolysis, thermolysis or hydrogenolysis;

2~3~

e) (to prepare compounds of formula I wherein R2 denotes a 5,5-spiro-cyclopentano-dihydro-imidazol-4~on-2-yl group) treating a benzimidazole of formula IX

(IX) (wherein `~
R1, R3 and R4 are as hereinbefore defined and R2"' denotes an imidazol-2-yl group in which an n-butylene group is attached via the 4,5-position) with a base in the presence of air and light;

f) (to prepare a compound of formula I wherein Rs denotes a lH-tetrazolyl group) cleaving a protective group from a compound of formula X

R2--~C ~R3 r (X) (wherein R1, R2 and R3 are as hereinbefore defined and R5" denotes a lH-tetrazolyl or 2H-tetrazolyl group protected in the l- or 2-position by a protecting group);

g) (to prepare a compound of formula I wherein Rs denotes a lH-tetrazolyl group) reacting a compound of formula XI

..

,. , ", : ' R2 ~ ~ R3 CN

CHz~

(XI) (wher~in R1, R2 and R3 are as hereinbefore defined) with hydrazoic acid or a salt thereofi h) (to prepare compounds of formula I wherein R2 denotes one of the above-mentioned imidazol-2-yl groups which may be substituted in the l-position by a phenylalkyl group twhilst the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different), or by a C16-alkyl group, whilst the alkyl group may additionally be substituted by a group metabo:lically convertable ln vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, or R2 denotes one of the imidazolium-2--yl groups mentioned hereinbefore) reacting a compound of formula XII

R2~ R3 -R

(XII) (wherein R1 and R3 are as hereinbefore defined, R2"" represents one of the imidazol-2-yl groups unsubstituted in the l position mentioned for R2 ~3~

hereinbefore and Rsll' denotes a carboxy group or a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, or a lH-tetrazolyl or 2H- -tetrazolyl group protected by a protecting group) with a compound of formula XIII

Z3 - R SXIII) (wherein R7 denotes a phenylalkyl group (whilst the phenyl nucleus may he mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or dif~erent), or a C16-alkyl group, whilst the alkyl group may additionally be substituted by a group metabolically convertable i vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, and Z3 denotes a nucleophilic leavig group such as a halogen atom, e.g. a chlorine, bromine or iodine atom) and subsequently, if necessary, cleaving any protecting group used;

i) (to prepare compounds of formula I wherein R2 represents one of the imidazol-2-yl groups mentioned hereinbefore substituted by the groups R8, R9 and R1o, but wherein R9 or Rlo must denote a hydrogen atom) reacting an aminoketone of formula XIV

R~ CO-C N~a'-CO ~

(XIV) , ... "

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

(wherein R1, R3, R4, R~, R9 and R1o are as hereinbefore defined, but R9 or R1o must denote a hydrogen atom, and Ral has the meanings given for Ra hereinbefore or denotes a hydrogen atom) with an ammonium salt of a lower aliphatic carboxylic acid;

j) (to prepare compounds of formula I wherein R2 denotes one of the oxazolin-2-yl or imidaæolin-2-yl groups mentioned hereinbefore) dehydrating a compound of formula XV

R~ CN'~R3 (xv) (wherein R1, R3, R4, R8, R9 and R10 are as hereinbefore defined and Y denotes a hydroxy or HNRa group wherein Ra is as hereinbefore defined~;

k) (to prepare compounds of formula I wherein R2 denotes one of the imidazolin-2-yl groups mentioned hereinbefore) reacting a compound of formula XVI

R2" " '--~ ~Ra (XVI) (wherein R1, R3 and R4 are as hereinbefore defined and - : : . . -. '. . .: . - . :
.: , .: . . .
. ~
.. . . .

:. ' , ' .. : ' ~
:

$

R2""' denotes one of the oxazolin-2-yl groups mentioned for R2 hereinbefore, substituted by groups R8, R9 and R10) with an amine of formula XVII

H2N-(R8cH)-(R9cR1o)-NH2 (XVII) (wherein R8, R9 and R1o are as hereinbefore defined);

l) (to prepare compounds of formula I wherein R2 denotes one of the oxazol-2-yl groups mentioned hereinbefore substituted by groups R8, R9 and R10) dehydrating an aminoketone of formula XVIII

; R3-C-C-NH-C ~ ~ R3 (XVIII) (wherein R1, R3, R4, R8, R9 and R1o are as hereinbefore defined, but ~9 or R10 must denote a hydrogen atom);

m) (to prepare compounds of formula I wherein R2 denotes one of the imidazol-2-yl groups mentioned hereinbefore, substituted by the groups R8, R9 and R10) dehydrogenating a compound of formula XIX

N~

(XIX) . : . .. . . : ~
- . - .. ~ . . -' ~ :.. . : .
.
:
- : ~
.
: .

.

2 ~

(wherein R1, R3 and R4 are as hereinbefore defined and R2""" denotes one of the imidazolin-2-yl groups mentioned for R2 hereinbefore, substituted by the groups R8, R9 and R~o~ but R9 or R10 must denote a hydrogen atom);

n) (to prepare compounds of formula I wherein R5 denotes a 2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl group) reacting an amidoxime of formula XX

; 2 { ~ (XX) N -OH
(wherein R1, R2 and R3 are as hereinbefore defined) optionally prepared in the reaction mixture, with a compound of formula XXI
Z4 - CO - OR (XXI) (wherein '- Z4 denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, and R11 denotes an alkyl, aryl or aralkyl group, preferably a lower alkyl group such as a methyl, ethyl, n-propyl or isopropyl group) and subsequently cyclisizing an acylated amidoxime thus obtained;

o) converting a compound of formula I thus obtained into a salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound; and . .: ., . : ~ . ,. ~ , : ' . , ~ ' .
., ,,, :

7 ~ ~

p) performing a process as defined in any one of steps (a) to (o) above on a corresponding protected compound and subsequently removing the protecting group used.

The reaction of step (a) is preferably carried out in the presence of a suitable solvent such as dimethylformamide, diethyleneglycoldimethylether, triethyleneglycoldimethyl-ether or sulpholane, optionally in the presence of a base such as potassium carbonate, pyridine, triethylamine, N-ethyl-diisopropylamine or N-ethyl-dicyclohexylamine, at temperatures between 0 and 250C.

If X in formula II denotes an oxygen or sulphur atom, the reaction is preferably carried out in a sol~ent having a boiling point above 150C or in a melt at temperatures between 150 and 250C, pre~erably at temperatures between 175 and 225C.

If X in formula II denotes an optionally alkyl-substituted imino group the reaction is preferably carried out in the presence of a corresponding amine as solvent, e.g. in the presence of liquid ammonia, methylamine, ethylamine, n-propylamine or isopropylamine, at temperatures between 0 and 100C, preferably at temperatures between 20 and 75C.

The reaction of step (b) is expediently carried out in an excess of the amine used and preferably in the presence of a corresponding formamide of formula HCONHR6 as solvent, optionally in a pressurised vessel at elevated temperatures, e.g. at temperatures between 100 and 250C, preferably at temperatures between 175 and 225C.

During the reaction of step (b), any substituted carboxy group present in the group R4 is simultaneously converted - . . : ~ - .

,- : ~

2~37g~

into a carboxy group or any substituted tetrazolyl group present is converted into a lH-tetrazol-5-yl group.

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

The reaction of step (c) preferably produces a mixture of the 1- and 3-isomers which may subsequently, if desired, be resolved into the corresponding 1- and 3-isomers, preferably by chromatography using a carrier such as silica gel or aluminium oxide.

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

The hydrolysis of step (d) is conveniently carried out in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid, optionally in the presence of a reaction accelerator such as hexadecyl-tributyl-phosphonium bromide, in a suitable .. . . .
.
.
.. . .
.
.. . .
, , .
.

3 ~

solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between -10C and 120C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

If Rsl in a compound of formula VIII represents a cyano or aminocarbonyl group, these groups may also be converted into a carboxy group with a nitrite, e.g.
sodium nitrite, in the presence of an acid such as sulphuric acid, which may also be simultaneously used as solvent, at temperatures between 0 and 50C.
~ .

If Rsl in a compound of formula VIII represents, for example, a tert.-butyloxycarbonyl group, the tert. butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as trifluoroacetic acid, p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40C and 100 C .

If Rsl in a compound of formulà VIII 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, and under a hydrogen pressure of l to 5 bar. During hydrogenolysis, other groups may be reduced at the same time, e.g. a nitro group to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to the -: .
.
: . ' 2~3~

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 by a hydrogen atom.

The reaction of step (e) is conveniently carried out in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxan2, at temperatures between -10C and 120C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

During the reaction of step (e~, any ester group present in the group R4 is simultaneously converted into a carboxy group.

Suitable protecting groups for use in step (f) include, for example, the triphenylmethyl, tributyl tin or triphenyl tin groups.

The cleaving of a protective group used in step (f) is preferably carried out in the presence of a hydrohalic acid, 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 reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and 150~C, preferably at temperatures between 120 and 140~C.

The reaction of step (g) is preferably carried out in a solvent such as benzene, toluene or dimethylformamide, :. . . .

.: . . . . .

.

- : .:

3 ~ ~ ~

at temperatures between 80 and 150C, preferably at 125C. Conveniently, 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 a tetrazolide salt obtained in the reaction mixture during the reaction with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which is also preferably produced in the reaction mi~ture by reacting aluminium chloride or tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently libsrated by acidification with a dilute acid such as 2N hydrochloric acid or 2N sulphuric acid.

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

If the reaction of step (h) is carried out in the presence of an excess of the compound of formula XIII
used, a corresponding imidazolium-2-yl compound of formula I is obtained at the same time.

The subsequent cleaving of a protecting group is preferably carried out by hydrolysis, thermolysis or hydrogenolysis.

The hydrolytic cleaving of a protecting group used is preferably carried out in the presence of an acid such - :
.' .: ' ' . '~

~3~

as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid, optionally in the presence of a reaction accelerator such as hexadecyl-tributyl-phosphonium bromide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, ~ater/isopropanol or water/dioxane at temperatures between -10C and 120C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

The thermolytic cleaving of a protecting group such as the tert.butyloxycarbonyl group is preferably effected in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40C and 100C.

The hydrogenolytic cleaving of a protecting group such as the benzyloxycarbony] group is effected in the presence of a hydrogenation catalyst sUch as ~- palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50~C, e.g. at ambient temperature, and a hydrogen pressure of 1 to 5 bar.

The reaction of step (i) is conveniently carried out with an ammonium salt of a lower aliphatic carboxylic acid such as ammonium acetate or ammonium propionate, preferably in the presence of a solvent such as glacial acetic acid or propionic acid at elevated temperatures, but preferably at the boiling temperature of the reaction mixture, e.g. at temperatures between 100 and - ,: ' . :- . : -: ........................... : . : .

, 2~3~

150C.

The dehydration of step (j) is conveniently carried out in the presence of a dehydrating agent such as phosphorusoxychloride, sulphuric acid, polyphosphoric acid or thionyl chloride, tha latter preferably being used as solvent at the same time, at elevated temperatures, e.g. at the boiling temperature of the dehydrating agent used, e.g. at temperatures between 105 and 150C.

The reaction of step (k) is conveniently carried out in a solvent such as toluene, dimethylformamide or dimethylsulphoxide, but preferably in an excess of the amine of formula XVII used, at elevated temperatures, e.g. at temperatures between 100 and 150C. However, the reaction is preferably carried out without a solvent.

The dehydration of step (1) is conveniently carried out in the presence of a dehydrating agent such as phosphorusoxychloride, phosphoric: acid or sulphuric acid, which is preferably used as solvent at the same time, at elevated temperatures, e.g. at the boiling temperature of the dehydrating agent used, e.g. at -temperatures between 105 and 150C. During the reaction with phosphorus-oxychloride any tert.butylester present can simultaneously be cleaved.

The dehydrogenation of step (m) is conveniently carried out in the presence of a dehydrogenating agent such as palladium/charcoal, barium manganate or selenium dioxide, in a suitable solvent such as toluene or methylene chloride at elevated temperatures, e.g. at the boiling temperature of the solvent used, e.g. at temperatures between 110 and 150C.

~37~

The reaction of step (n) is conveniently carried out in a solvent such as methylene chloride, chloroform, tetrahydrofuran, dioxane or acetonitrile preferably in the presence of an inorganic base, such as sodium or potassium carbonate, or an organic base such as triethylamine or pyridine whilst the latter two may simultaneously also be used as solvent at temperatures between 0 and 20C.

The subsequent cyclization of a thus obtained acylated amidoxime is conveniently carried out in an organic solvent such as benzene, toluene, xylene, tetrahydrofuran or dioxane at elevated temperatures, e.g. at temperatures between 50 and 100C, preferably at the boiling temperature of the solvent used.

The necessary starting amidoxime is conveniently prepared by reaction of a corresponding nitrile of formula XI with hydroxylamine in the presence of a solvent such as methanol, ethanol, methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or dioxane in the presence of a suitable base such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, sodium methoxide, sodium ethoxide or sodium hydride at temperatures between 50 and 100C.

In the reactions described hereinbefore, any reactive groups present such as hydroxy, amino or alkylamino groups may be protected during the reaction by conventional protecting groups which may be cleaved after the reaction.

Examples of suitable protecting groups for a hydroxy group include trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, benzyl and tetrahydropyranyl groups and suitable protecting groups for an amino, alkylamino or imino group include acetyl, benzoyl, ethoxycarbonyl ' .. . . .

2~7~5 - 3~ -and benzyl groups.

The optional subsequent eleaving of a proteeting group used is preferably earried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presenee of an aeid sueh as hydroehlorie aeid or sulphurie aeid or in the presenee of an alkali metal base sueh as sodium hydroxide or potassium hydroxide, at temperatures between o and 100C, preferably at the boiling temperature of the reaetion mixture. However, a benzyl group is preferably split off by hydrogenolysis, e~g.
with hydrogen in the presence of a eatalyst sueh as palladium/eharcoal in a solvent sueh as methanol, ethanol, ethyl acetate or glaeial aeetie aeid, optionally with the addition of an aeid sueh as hydroehlorie aeid at temperatures between O and 50C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

An isomer mixture of a eompound of formula I thus obtained may, if desired, be separated, preferably by ehromatography using a earrier sueh~as siliea gel or aluminium oxide.
.. .
The eompounds of formula I obtained may be converted into the acid addition salts thereof, more particularly for pharmaeeutieal use into the physiologically aeeeptable salts thereof with inorganie or organie aeids. Suitable acids for this purpose include, for example, hydrochloric acid, hydrobromic aeid, sulphuric aeid, phosphoric acid, fumarie aeid, suecinic acid, lactie acid, citric acid, tartaric acid and maleic acid.

Furthermore, the new eompounds of formula I thus obtained, if they contain a carboxy or lH-tetrazolyl group, may if desired subsequently be converted into the 2~r~

~ 35 -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, cyclo~exylamine, ethanolamine, diethanolamine and triethanolamine.

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

Thus, for example, compounds of formulae II, IV, VI, VIII, IX, X, XI and XII may be obtained by acylation of a corresponding o-phenylenediamine and subsequent cyclisation or by acylation of a corresponding o-amino-nitro compound, subsequent reduction of the nitro group and cyclisation, whilst an NH-benzimidazole can optionally be converted by alkylation with a corresponding biphenyl derivative into a compound which is correspondingly substituted in the l-position, with optional subsequent cleaving of any protecting group used.

The conversions of oxazol-2-yl compounds of formula IV
into imidazol-2-yl compounds substituted in the 1-position, as described in this application, may be carried out analogously to the synthesis of lH-imidazole described in Angew. Chem. 71: 761 (1959) (conversion of oxazoles into lH~imidazoles using formamide/ammonia).

The oxazoles of formulae IV, VI, VIII, X and XI may be prepared by acylation of a corresponding ~-aminoketone with a corresponding carboxylic acid chloride or carboxylic acid anhydride followed by cyclisation analogously to J. Chem. Soc. 95: 2167 (1909) and Synthesis 1970, 6~8, using as condensation agents strong acids such as sulphuric acid, phosphoric acid, ' ~ '; , ' ' ..
,'., , 2~3~

hydrofluoric acid or POC13.

A starting compound of formula XV is conveniently obtained by acylation of a corresponding ~-amino-alcohol and a compound of formula XVI is obtained by cyclisation of a compound of formula XV thus obtained.

The acylated ~-aminoketones mentioned above can also be converted directly into the corresponding substituted imidazoles by treatment with ammonium acetate in glacial acetic acid analogously to Chem. Ber. 106: 2~15 (1973).

.~ .
Starting compounds of formulae XIV and XVIII may be obtained by acylating a corresponding ~-amino-acetone with a corresponding activated benzimidazole carboxylic acid, to obtain thé desired ~-amino-acetone from the corresponding ~-amino acids according to Dakin/West (see Chem. Soc. Rev. 17: 91 (19g8)).

A starting compound of formula XIX may be obtained by acylating a corresponding ~-amino-alcohol with a corresponding activated benzimidazole carboxylic acid, the resulting compound subsequent.ly being cyclised and then reacted with a corresponding ethylenediamine.
.... .
The compounds of formula I and the physiologically acceptable salts thereof have valuable pharmacological properties. They are angiotensin-antagonists, particularly angiotensin~ antagonists.

Those compounds of formula I wherein Rs denotes a group metabolically convertable in vivo into a carboxy group, or denotes a carboxy or lH-tetrazolyl group, have particularly valuable pharmacological properties, since they are angiotensin-antagonists, more particularly angiotensin-II-antagonists. The other compounds of formula I wherein R4 denotes a hydrogen atom or Rs .

~3~J~

denotes a cyano, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group are valuable intermediates for preparing the compounds mentioned above.

By way of example, the following compounds:

= 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid;

B = 4'-[[2-n-propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl~2-carboxylic acid;

C = 4'-[[2-n-propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]- .
methyl]-2-(lH-tetrazol-5-yl)biphenyl;

D = 4'-~[2-n-propyl-4-methyl-6-(1-benzyl-5,6,7,8-tetrahydrobenzimidaæol-2-yl)--lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid;

E = 4'-[~2-ethyl-4-methyl-6-(1-phenyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)--lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-hydrate;

F = 4'-[[2-n-propyl-4-methyl-6-(1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-semihydrate;

G = 4'-[[2-ethyl-4-methyl-6-(1-ethyl-5,6,7,8-tetrahydrobenzlmidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrate;

H = 4'-[[2-n-propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-.

,, . - . : .

' .

, carboxylic acid-di-trifluoroacetate;

I = 4'-[[2-n-propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl~2-carboxylic acid-hydrate; and K = 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-1,5-dimethyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid x 1.2S water were tested for their biological effects as follows:

.
Descri~tion of method: Angiotensin II-receptor bonding The tissue (rats lung) is homogenised in Tris-buffer (50 mMol Tris, 150 mMol NaCl, 5 mMol EVTA, pH 7.40) and centrifuged twice for 20 minutes at 20,000 x g. The finished pellets are resuspended in incubating buffer (50 mMol Tris, 5 mMol MgCl2, 0.2~ BSA, pH 7.40) 1:75, based on the moist weight of the tissue. Each 0.1 ml of homogenate is incubated for 60 minutes at 37C with 50 pM [125I]-angiotensin II (NEN, Dreieich, FRG) with increasing concentrations of the test substance in a total volume. of 0.25 ml. Incubation is 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 MgCl2, 0.1% BSA, pH 7.40). The bound radioactivity is measured using a gamma-counter. The corresponding ICso value is obtained from the dose-activity curve.

In the test described, substances A to K show the following ICso values:

2~3~$~

Substance IC50 [nM]
_ .-A 12.0 B 3.8 C 2.6 D 6.0 E 46.0 F 38.0 G 1.6 H 37.0 I 3.2 K 19.5 Moreover, when the above-mentioned compounds were administered in a dose of 30 mg/kg i.v. no toxic side effects, e.g. no negative inotropic effects and no disorders in heart rhythm, were observed. The compounds are therefore well tolerated.

In view of their pharmacological properties, the new compounds and the physiologically acceptable salts thereof are suitable for the treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.

The new compounds and the physiologically acceptable salts thereof are also suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after .~ - -.: . . . .

: . , . : . .
.. . ..
. ~ ., ~ , ' ~ . ' - 2~3~

vascular operatlons, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetylcholine and dopamine in the brain, the new angiotensin-antagonists are also suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's disease, Parkinson syndrome, bulimia and disorders of cognitive function.

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.

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

In particular, the 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, for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, in particular for treating pulmonary diseases, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy.

~3'~

More particularly, the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture o~ a therapeutic agent for alleviating central nervous system disorders.

Viewed from a yet still further aspect the invention provides a method of treatment of the human or non-human animal body to combat hypertension and cardiac insufficiency, for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, in particular to combat pulmonary diseases, arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.

More particularly, the invention provides a method of treatment of the human or non-human animal body to alleviate central nervous system disorders, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
. .
The dosage required to achieve these effects in adults is appropriately, when administered intravenously, 0.5 to 100 mg, preferably 1 to 70 mg, and, when administered orally, 0.1 to 200 mg, preferably 1 to 100 mg, 1 to 3 times a day. For this purpose, the compounds of formula I prepared according to the invention, optionally in conjunction with other active substances, such as hypotensives, ~CE inhibitors, diuretics and/or calcium antagonists, may be incorporated together with one or - .
. ~ ~ . .. .
. ~ . . .

2 ~
- 42 ~
more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water~ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, 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.

Additional active substances which may be included in the combinations mentioned above include, for example, bendroflumethiazide, chlorothiazide, hydrochloro-thiazide, spironolactone, benzothiazide, cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosine, atenolol, propranolol, (di)hydralazine-hydrochloride, diltiazem, felodipin, nicardipin, nifedipin, nisoldipin, nitrendipin, captopril, enalapril, lisinopril, cilazapril, quinapril, fosinopril and ramipril. The dosage for these active substances is appropriately 1/5 of the lowest recommended dose up to 1/1 of the normally recommended dose, i.e., 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, ~ to 60 mg of felodipine, 5 to 60 mg of nifedipin or 5 to 60 mg of nitrendipin.

The following non-limîting Examples are provided to illustrate the invention. All percentages and ratios are by weight, other than eluant or solvent ratios which are by volume.

~37$~

Example 1 Methyl 4'-[[2-n-propyl-4~methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2 carboxylate a) Methyl 4'-[(2-n-propyl-4-methyl-6-amidino-lH-benzimidazol-1-yl)-methyll-biphenyl-2-carboxylate Hydrogen chloride gas is piped into a solution of 6.2 g (14.6 mMol) of methyl 4'-[[2-n-propyl-4-methyl-6-cyano-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate in 750 ml of absolute methanol for 3 hours at ambient temperature and the mixture is stirred for a further 2 hours at ambient ternperature. After removal of the solvent the mixture is evaporated down in vacuo, the residue is taken up twice with 50 ml of methanol and 50 ml of ether and evaporated down once more. Then the residue is dissolved in 750 ml of absolute methanol and mixed with 30 g of ammonium carbonate. After 12 hours at ambient temperature, 50 g of silica gel (parti~le size: 0.06-0.3 mm) are added. Ater filtration and evaporation of the filtrate the residue is chromatographed on silica gel (particle size 0.032-0.063 mm) using as eluant mixtures of methylene chloride and methanol of increasing polarity (9:1, 4:1, 3:1 and 1:1). The uniform fractions are combined and evaporated down.
Yield: 4.3 g (57% of theory), Foam, Rf value: 0.14 (silica gel; methylene chloride/ethanol = 9:1) b) Methyl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyll-bi~henvl-2-carboxylate 0.5 g (1.0 mMol) of methyl 4'-[(2-n-propyl-4-methyl-6-amidino-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate, 0.13 g (1.0 mMol) of 2-chloro-cyclohexanone and 10 ml of liquid ammonia are heated to 60C in a bomb . , - . ~ . ' ' , - . .

~ $ ~ $ 3 for 15 hours. After cooling and evaporation of the ammonia the residue is dissolved in methanol/methylene chloride (2:1) and chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluant mixtures of methylene chloride and ethanol of increasing polarity (19:1 and 9:1). The uniform fractions are combined and evaporated down.
Yield: 0.1 g (19% of theory), Foam, R~ value: 0.50 (silica gel; methylene chlGride/ethanol = 9:1) Example 2 4'-[[2-n-Propyl-4-methyl-6-(s,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 0.1 g (0.2 mMol) of methyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and 10 mg (0.02 mMol) of hexade~yl-tributylphosphonium bromide are taken up in lO ml of (48%) hydrobromic acid and heated to llO~C for 15 minutes. After cooling, 20 ml of ether are poured over and the mixture is diluted with lO ml of water.
After extraction the organic phase is separated off.
The aqueous phase is adjusted to pH 7 with ammonia, the precipitate thus formed is suction filtered, washed with water and taken up in methylene chloride/ethanol (4:1).
The solvent is evaporated off, the residue is triturated with ether and dried. The crude product is chromatographed on silica gel ~particle size:
0.032-0.063 mm), using as eluant methylene chloride/ethanol (9:1). The uniform fractions are combined and evaporated down. The residue is triturated with ether and dried.
Yield: 64 mg (64% of theory), Melting point: 231-235C (decomp.) C32H32N402 (504-64) ~3,~

Mass spectrum: (M + H)~ = 505 Example 3 4'-[[2-n-Propyl-4-methyl-6-(5,5-spiro-cyclopentano)-dihydroimidazol-4-on-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-semihydrate 0.05 g (0.1 mMol) of methyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate are dissolved in 4 ml of ethanol, mixed with 2 ml of 1 N sodium hydroxide solution and stirred for 4 days at ambient temperature.
After the addition of 4 ml of water the pH is adjusted to 6 using glacial acetic acid, the precipitate formed is suction filtered, washed with water and dried over potassium hydroxide. The crude product is chromatographed on silica gel (particle size:
0.032-0.063 mm), using as eluant methylene chloride/ethanol/glacial acetic acid (50:1:0.1 and 30:1:0.1). The uniform fractions are combined and evaporated down. The residue is triturated with ether and dried.
Yield: 30 mg (59% of theory), Melting point: 310-311C (decomp.) C32H32N4O3 (520.64) Mass spectrum: (M + H)+ = 521 Examp]e 4 Tert.butyl 4'-[[2-n-propyl-4-methyl-6 (5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate . . _ . _ .
a) 2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzoxazol-2-yl~-lH-benzimidazole 2.17 g (10 mMol) of 2-n-propyl-4-methyl-6-aminocarbonyl-lH-benzimidazole and 10.25 g (77 mMol) of 2-chloro-- ~ .' ' ' ' .
.
' ,. . .

~37~
~ 46 -cyclohexanone are heated to 190C for one hour. After cooling to ambient temperature the reaction mixture is triturated with ether and suction filtered. The residue is taken up in water and mixed with concentrated ammonia. Then it is extracted with methylene chloride, the organic phase is washed with water, dried over magnesium sulphate and evaporated down~ The residue is chromatographed on silica gel (particle size:
0.032 0.063 mm) using as eluant mixtures of methylene chloride and ethanol of increasing polarity (50:1, 25:1 and 20:1). The uniform fractions are combined and evaporated down.
Yield: 1.9 g (64% of theory), Foam, Rf value: 0.20 (silica gel; ethyl acetate) b) Tert.butyl 4i-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-1-yl]-methvl]-biphen~1-2-carboxylate 3.3 g (11 mMol) of 2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazole are dissolved in 15 ml of dimethylformamide and at 5-10C
1.5 g (13.2 mMol) of potassium tert.butoxide are added in batches. After 15 minutes at 5C 4.6 g (13.2 mMol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate are added. After a further 45 minutes at 5C the reaction mixture is stirred into 200 ml of water. The precipitate formed is suction filtered, washed with water and taken up in 200 ml of ethyl acetate. The solution is washed with water and with saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The residue is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant methylene chloride/ethanol (50:1). The uniform fractions are combined and evaporated down.
Yield: 4.8 g (78% of theory), Foam, Rf value: 0.23 (silica gel; methylene chloride~ethanol = 49:1) 2~3785 _xample 5 4'-[[2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate 2.0 g (3.56 mMol) of tert.butyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate, 16 ml (40 mMol) of formamide and 40 ml of ammonia (liquid) are heated to 200C in the bomb for 14 hours. After cooling, the reaction mixture is diluted with wàter, the precipitate thus formed is suction filtered. The filtrate is adjusted to pH 6 with glacial acetic acid, the precipitate formed is removed by centrifuging and washed with water. The residue is taken up in 50 ml of 2 N hydrochloric acid. By the addition of concentrated ammonia the pH is adjusted to 6 and the precipitate thus formed is suction filtered, washed with water and dried.
Yield: 1.3 g (72% of theory), Melting point: from 235C (decomp.) Example 6 4'-[[2-n-Propyl-4-methyl-6-(1,3-dimethyl-5,6,7,8-tetrahydrobenzimidazolium iodide-2-ylj-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 0.85 g (1.7 mMol) of 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid are dissolved in 9 ml of dimethylsulphoxide, mixed with 420 mg (3.7 mMol) of potassium tert.butoxide at 5C and stirred for 10 minutes. After the addition of 570 mg (4.0 mMol) of methyliodide the reaction mixture is heated to 70C for 25 minutes. After cooling, it is poured onto ice, the precipitate formed is suction filtered and washed with water. The residue is taken up in 50 ml of ethanol, 2~378~

combined with 12 ml of 1 N sodium hydroxide solution and stirred for 5 days at ambient temperature. The solvent is evapor~ted off ln vacuo, the residue is mixed with ice and acidified with aqueous citric acid (5%). The preci,pitate thus formed is suction filtered, washed with water and dried.
Yield: 470 mg (42% of theory), Melting point: 240-242C (decomp.) C34H37N4O2I (660.61) Calculated: C 61.82 H 5.65 N 8.48 Found: 61.69 5.88 8.72 ~ .
Example 7 4'-[[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-hydrate Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-methylformamide/methylamine.
Yield: 27% of theory, Melting point: 183-186C
C33H34N4o2 x H20 (536.68) Calculated: C 73.85 H 6.76 ~ 10.44 Found: 74.22 6.97 10.48 Example 8 4'-[[2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl-semihydrate a) 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-1-yl]-methYll-2-(l-triphenylmethyl-tetrazol-5-vl)biphen Prepared analogously to Example 4b from 2-n-propyl-4-2~37~

methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazole and 4'-bromomethyl-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl.
Oil, Rf value: 0.67 (silica gel; ethyl acetate) b) 4'-[[2-n-propyl-4-methyl-6-t5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl~-2-(lH-tetrazol-5-vl)biphenyl-semihydrate Prepared analogously to Example 5 from 2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and formamide/ammonia.
Yield: 70% of theory, Melting point: from 230C (decomp.) C32H3zN8 x 0 5 H2O (537.68) Calculated: C 71.48 H 6.19 N 20.84 Found: 71.43 6.46 21.20 Example 9 4'-[[2-n-Propyl-4~methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl-semihydrate Prepared analogously to Example 5 from 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and N-methyl-formamide/methylamine.
Yield: 63% of theory, ~elting point: from 240C (decomp.) C33H34N8 x 0-5 H2O (551.71) Calculated: C 71.84 H 6.40 N 20.31 Found: 71.63 6.45 20.64 - 5~ -Example lo 4'-[[2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid -1.2 g (24 mMol) of tert.butyl 2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate are dissolved in 25 ml of methylene chloride, mixed with 8.5 ml of trifluoroacetic acid and stirred for 3 hours at ambient temperature. Then the solvent is evaporated off in vacuo, the residue is mixed with ice and made alkaline with conc. ammonia. After one hour the pH is adjusted to 5 by the addition of citric acid. The precipitate thus formed is suction filtered, washed with water and dried. The crude product is purified on silica gel (particle size: 0.032-0.063 nm) using ethyl acetate as eluant. The uniform fractions are combined and evaporated down.
Yield: 33% of theory, Melting point: 229-232C (decomp.) C32H31N303 (505.62) Mass spectrum: M~ = 505 Example 11 4'-[t2-Ethyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydro-benzimidazol-2-yl) lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrate a) 2~ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-Yl)-lH-benzimidazole Prepared analogously to Example 4a from 2-ethyl-4-methyl-6-aminocarbonyl-lH-benzimidazole and 2-chloro-cyclohexanone.
Yield: 60% of theory, , .
- .

~: ,: ' ' ' - ' ' ' : ' . ' ' 2 ~

Oil, Rf value: 0.17 (silica gel; ethyl acetate) b) 4'-[[2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-benzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl Prepared analogously to Example 4b from 2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazole and 4'-bromomethyl-2-(1-triphenylme~hyl~
tetrazol-5-yl)-biphenyl.
Yield: 63~ of theory, Oil, Rf value: 0.69 (silica gel; ethyl acetate) c) 4'-[[2-Ethyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methvl-2-flH-tetrazol-5-Yl)-biphenyl-hydrate Prepared analogously to Example 5 from 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl-2-(~-triphenylmethyl-tetrazol-5-yl)-biphenyl and N-methyl-formamide/me~hylamine.
Yield: 51% of theory, Melting point: from 180C ~decomp.) C32H32N8 x H2O (546.69) Calculated x H2O: C 70.31 H 6.27 N 20.50 Found: 70.07 6.55 20.60 - Mass spectrum: M+ = 528 Example 12 4'-[t2-Ethyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-hydrate a) tert.butyl 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methYll-biphenyl-2-carboxylate Prepared analogously to Example 4b from 2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazole and tert.butyl 4'-bromomethyl-biphenyl-2-''; ' . ' -' ' - ~:
- ,, : .
', ... :, ~ ' . .
:
~, ., . . . .. ~. .. . .. ~ -'~

_25~93 ~8 carboxylate.
Yield: 77% of theory, Melting point: 160-162C

~) 4'-[[2-ethyl-4-methyl 6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyll-bi~henyl-2-carboxylic acid-hydrate Prspared analogously to Example 5 from tert.butyl 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-methylformamide/methylamine.
Yield: 34% of theory, Melting point: 292-300C tdecomp.) C32H32N4O2 x H2O (522.66) Calculated x H2O: C 73.54 H 6.56 N 10.72 Found: 73.3~ 6.76 10.67 - Mass spectrum: M+ = 504 ExamPle 13 4'-[[2-Ethyl-4-methyl-6-(1-phenyl-5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid-hydrat:e Prepared analogously to Example 5 from tert.butyl 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxaæol-2-yl)-lH-benzimidazol-l-yl]-methyl3-biphenyl-2-carboxylate and N-formyl-anilide/aniline.
Yleld: 13% of theory, Melting point: 255-257~C (decomp.) C37H34N4O2 x H2O (584.73) Calculated x H2O: C 76.00 H 6.20 N 9.58 Found: 76.36 6.18 9.59 Mass spectrum: M' = 566 :, : . ............... . . ~ ,. . . .
,. : , -, . .
. . : . : , , ,: : , . .

~xample 14 4'-[[2-n-Propyl-4-methyl-6-(1-phenyl-5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl3-biphenyl-2-carboxylic acid-semihydrate Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4 methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-formyl-anilide/aniline.
Yield: 23% of theory, Melting point: 258-260C (decomp.) C38H36N4O2 x 1/2 H2O (589.
Calculated x 1/2 H2O: C 77.39 H 6.32 N 9.50 Found: 77.03 6.30 9.39 Mass spectrum: Mt = 580 Example 15 4' [[2-n-Propyl 4-methyl-6-(1-benzyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl 6 (5,6,7,8--tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-benzyl-formamidejbenzylamine.
Yield: 54% of theory, Melting point: 256-258C (decomp.) C39H38N4O2 (594.77) Calculated: C 78~76 H 6.44 N 9.42 Found: 78.50 6.49 9~35 Mass spectrum: M~ = 594 '; . , , '. . . ..
-~, . :

.: , .
, . : -2~3~37~

Example 16 4'-[[2-n-Propyl-4-methyl-6-(1-ethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl~-methyl]-biphenyl-2-carboxylic a~id-sesquihydrate Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-ethyl-formamide/ethylamine.
Yield: 17% of theory, Melting point: from 228C (decomp.) `` C34H36N4O2 x 1-5 H2O (559 7 ) Calc. x 1.5 H2O: C 72.96 H 7.02 N 10.01 Found: 73.04 6.90 9.77 Mass spectrum: M+ = 532 Example 17 4'-[[2~Ethyl-4-methyl-6-(1-isopropyl-5,6,7,8-tetrahydrobenzimldazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.hutyl 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-isopropyl-formamide/isopropylamine.
Yield: 2% of theory, Melting point: 197C
C34H36N4O2 (532.69) Mass spectrum: M+ = 532 ''. . ' ' . . : ,' .' : :' :
., . . :

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

7 8 ~

Example 18 4'-[[2-n-Propyl-4~methyl-6-(1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carbbxylic acid Prepared analogously to Example 5 ~rom tert.butyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl~-lH-benzimidazol-l-yl]-methyl~-biphenyl-2-carboxylate and i 5 obutylaminejwater.
Yield: 5% of theory, C36H40N4O2 (560.75) Mass spectrum: ~M+H)+ = 561 Example 19 4'-[[2-n-Propyl-4-methyl-6-(1,3-dibenzyl-5,6,7,8-tetrahydrobenzimidazolium acetate-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-semihydrate Prepared analogously to Example 6 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8--tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and benzylbromide/sodium hydroxide solution/glacial acetic acid.
Yield: 76% of theory, Melting point: sintering from 80C
C46H44N4O2 x CH3COOH x 1/2 H2O (753-95) Calc. x CH3COOH x 1/2 H2O: C 76.47 H 6.55 N 7.43 Found: 76.46 6.65 7.76 Mass spectrum: M+ = 684 .

': ' ' ' ' .

2~378~

Exampl Q20 4'-[[2-n-Propyl-4-methyl-6-(1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid-semihydrate Prepared analogously to Example 6 from 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol 1-yl]-methyl]-biphenyl-2 carboxylic acid and ethyl bromoacetate/sodium hydroxide solution.
Yield~ 34% of theory, Melting point: 239-242C
C34H34N4O4 x 1/2 H2O (571.69) Calc. x 1/2 H2O: C 71.43 H 6.17 N 9.80 Found: 71.39 6.19 9.81 Mass spectrum: M+ = 562 Example 21 4'-[[2-Cyclopropyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic ac:id-semihydrate Prepared analogously to Example '~ from tert.butyl 4'-[[2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl~-biphenyl-2-carboxylate and N-methyl-formamide/methylamine.
Yield: 50% of theory, Melting point: 285-289C
C33H32N4O2 x l/2 H2O (525.66) Calculated: C 75.40 ~ 6.33 N 10.66 Found: 75.24 6.44 10.42 Mass spectrum: M = 516 The following compounds may be obtained analogously to the preceding Examples:

., .
.. , ~ . - .

, . : .

: :
.

2~3~

(1) 4'-[[2-cyclopropyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol~5-yl)biphenyl (2~ 4'-[[2 ethoxy-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid (3) 41-[[2-ethoxy-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl (4) 4'-[[2-ethyl-4-methyl-6-(1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yljbiphenyl (5) 4'-[[2-n-propyl-4-methyl-6-(1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid (6) 4'-[[2-n-propyl-4-methyl-6-(1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl~biphenyl (7) 4'-[[2-ethyl-4-methyl-6-(1-i~obutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl3-biphenyl-2-carboxylic acid (8) 4'-[[2-ethyl-4-methyl-6-(1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl (9) 4'-[[2-n-propyl-4-methyl-6-(1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl (10) 4'-[[2-n-propyl-4-methyl 6-(1-carboxymethyl-.
, . ~ - : . : , 2~378~

5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl (11) 4'-[[2-n-propyl-4-meth~l-6-(1-methyl-4,5-trimethylene-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid (12) 4'-[[2-n-propyl-4-methyl-6-tl-methyl-4,5-trimethylene-imidazol-2-yl)-lH-benzimidazol-1-yl~-methyl]-2-(lH-tetrazol-5-yl~biphenyl Example 22 4'-[[2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-I-yl]-methyl]-2-(l-triphenylmethyl-tetrazol-5-yl)-biphenyl and hydrochloric acid in methanol.
Yield: 15~ o~ theory, Melting point: 140-142C (decomp.) H29N70 (515.63) Mass spectrum: (M+H)~ = 516 ', Example 23 4'-[[2-Ethyl-4-methyl-6-(l-ethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrate Prepared analo~ously to ~xample 5 from 4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(l-triphenylmethyl-te~razo~-5-yl)-biphenyl and N-ethyl-formamide/ethylamine.

, , :: . .

.

.. . .
.

2~37~

Yield: 25% of theory, Melting point: from 180C (decomp.) C33H34N8 x H20 (560.72) Calculated: C 70.68 H 6.47 N 19.99 Found: 70.46 6.44 19.56 Mass spectrum: M+ = 542 Example 24 4'-[[2-n-Propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid di-trifluoroacetate -Prepared analogously to Example 10 from tert.butyl 4'-[C2-n-propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 60% of theory, Melting point: 158-159C
C3~H31N303 x 2 CF3C00~l (709.64) Calculated: C 57.55 H 4.6g N 5.92 Found: 57.76 4.72 6.02 Mass spectrum: M+ = 481 Example 25 4:-[[2-n-Propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid-hydrate a) Tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(l-benzoyl-ethyl)-methylaminocarbonyl]-lH-benzimidazol-l-yl]-methyll-bi~henyl-2-carboxylate To a solution of 1.0 g (2.0 mMol) of tert.butyl 4'-[[2-n-propyl-4-methyl-6-chlorocarbonyl-lH-benzimidazol-l-yl]-methyl]-biphenyl-carboxylate in 20 ml of methylene chloride are added 20 ml of toluene and 0.44 g .
, .

%~7~

(2.2 mMol) of 2-methylamino-propiophenone. The reaction mixture is heated to 85C and 10 ml of pyridine are added dropwise within 4 hours. Then the reaction mixture ls evaporated down, the residue is mixed with ice water and extracted twice with methylene chloride.
The combined organic phases are dried over magnesium sulphate and evaporated down. The crude product is chromatographed on silica gel (particle size:
0.032-0.063 mm) using as eluant methylene chloride to start with and later methylene chloride/ethanolfammonia (50:1:0.25 and 25:1:0.01). The uniform fractions are combined and evaporated down.
Yield: 1.0 g (79% of theory), Foam, Rf value: 0.50 (silica gel; methylene chloride/ethanol = 9:1) b) Tert.butyl 4'-[[2-n-propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyll-biphenyl-2-carboxylate A solution of 1.0 g (1.5 mMol) of tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(1-benzoyl-ethyl)-methylaminocarbonyl]-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and 15 g of ammonium acetate in 80 ml of glacial acetic acid is refluxed for 2.5 hours.
Then the reaction mixture is evaporated down to half, the residue is mixed with ice water and extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate and evaporated down. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant methylene chloride with increasing amounts of ethanol (3%, 10% and 20%). The uniform fractions are combined and evaporated down.
Yield: 0.68 g ~74% of theory), Foam, Rf value: 0.40 (silica gel; methylene chloride/ethanol = 19:1) . . .

2~3~

c) 4'-[[2-n-Propyl-4-methyl-6-~1,5-dimethyl-4-phenyl-imidazol-2-yl)-lH-benzimidazol~1-yl]-methyl]-bi~henyl-2-carbox~ c acid-hydrate Prepared analogously to Example 10 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl~-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: ~rom 152C (decomp.
C36H33N402 x H20 (572.72) Calculated: C 75.50 H 6.34 N 9.78 Found: 75.95 6.48 9.92 Mass spectrum: M' = 554 Example 26 4'-~[2-n-Propyl-4-methyl-6-(1-methyl-4,5-diphenyl-imidazol-2-yl)-lH-benzimidazol-1 yl]-methyl]-biphenyl-2-carboxylic acid-sesquihydrate a) Tert.butyl 4'-[[2-n-propyl-4-methyl-6-(1-methyl-4,5-diphenyl-imidaæol-2-yl)-lH-benzimidazol-l-yl]-methvl1-biphenvl-2-carboxYlat:e Prepared analogously to Example ~Sb from tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(l-berlzoyl-benzyl)-methylaminocarbonyl3-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and ammonium acetate in glacial acetic acid.
Yield: 27% of theory, Oil, Rf value: 0.40 (silica gel; methylene chloride/ethanol = 19:1) b) 4'-[[2-n-Propyl-4-methyl-6-(1-methyl-4,5-diphenyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-sesquihvdrate Prepared analogGusly to Example 10 from tert.butyl 4'~
[[2-n-propyl-4-methyl-6-(1-methyl-4,5-diphenyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-2~3r~

carboxylate and trifluoroacetic acid.
Yield: 60% of theory, Melting point: 325-328C (decomp.) C41H36N402 x 1-5 ~2 (643.79) Calculated: C 76.49 H 6.11 N 8.70 Found: 76.53 6.1S 8.75 Mass spectrum: M+ = 616 Example 27 4'-[[2-n-Propyl-4~methyl-6-(5-methyl-4-isopropyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid-dihydrate-acetate a) Tert.butyl 4'-[[2-n-propyl-4-methyl-6-(5-methyl-4-isopropyl-imidazol~2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenYl-2-carboxylate Prepared analogously to Example 25b from tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(l-acetyl-2-methyl-n-propyl)-methylaminocarbonyl]-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate an~ ammonium acetate in glacial acetic acid.
Yield: 45% of theory, oil, Rf value: 0.10 (silica ~el; ethyl acetate/
petroleum ether = 2:1) : -`
b) 4'-[[2-n-Propyl-4-methyl-6-(S-methyl-4-isopropyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-dihYdrate-acetate Prepared analogously to Example 10 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(5-methyl-4-isopropyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 75~ of theory, Melting point: from 155C (decomp.) C32H34N402 x CH3COOH x 2 H20 (602.74) Calculated: C 67.75 H 7.02N 9.30 Found: 67.69 7.02 9.53 .' , . ~ - , -: , :
.

2~78~

Mass spectrum: M+ = 506 Example 28 4'-[[2-n-Propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-di-trifluoroacetate a) Tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-methyl imidazolin-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate A mixture of 0.43 g (Q.8 mMol) of tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and 0.67 ml (5.8 mMol) of 1,2-diaminopropane is heated to 120C for 48 hours. The yellow solid obtained after cooling to ambient temperatur~ is stirred with water for 1 hour, suction filtered and dried. The crude product is chromatographed on silica gel (particle size:
0.032~0.063 mm) using as eluant methylene chloride/ethanol/ammonia (50:1:0.05, 20:1:0.02 and 7:1:0.07). The uniform fractions are combined and evaporated down.
Yield: 0.26 g (62% of theory), Foam, Rf value: 0.20 (silica gel; methylene chloride/ethanol = 9:1 + ammonia) b) 4'-[[2-n-PropyI-4-methyl-6-(4-methyl-imidazolin-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-di-trifluoroacetate Prepared analogously to Example 10 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 72% of theory, Melting point: 115-118C (decomp., sinters from lOOaC) C29H30N402 x 2 CF3COOH (694.63) Calculated: C 57.06 H 4.64 N 8.07 , 2~3'~

Found: 57.02 5.02 8.13 Mass spectrum: M+ = 466 ~xam~le 29 4'-[[2-n-~ropyl-4-methyl-6 (4-isopropyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 3.9 g (6.7 mMol) of tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(l-acetyl-2-methyl-n-propyl)-aminocarbonyl]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate are dissolved in 50 ml of phosphorusoxychloride and stirred for 2.5 hours at 105 D C. Then the phosphorusoxychloride is removed, the residue is decomposed with water at 80~C
and, after cooling, mixed with conc. ammonia. The pH is adjusted to 5 by the addition of glacial acetic acid, the precipitate thus Eormed is suction filtered, washed with water, taken up in methylene chloride/methanol (9:1) and dried over magnesium sulphate. The crude product is chromatographed on silica gel (particle size:
0.032-0.063 mm) using as eluant petroleum ether/ethyl acetate/glacial acetic acid (1:1:0.002) and methylene chloride/ethanol/glacial acetic acid (20:1:0.002). The uniform fractions are combined, evaporated down, triturated with ether and suction filtered.
Yield- 2.4 g (71% of theory), Melting point. 222-223OC
C32H33N303 (507.64) Calculated: C 75.71 H 6.55 N 8.28 Found: 75.61 6.59 8.36 Mass spectrum: M+ = 507 : . ' ' . ' ' . ' , , 2~3'~8~

Example 30 4'~[[2-n-Propyl-4-methyl 6 (4-isopropyl-1,5-dimethyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl~-biphenyl-2-carboxylic acid x 1.25 water Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-methyl-formamide/methylamine.
Yield: 38~ of theory, Melting point: from 150~C (decomp.) C33H36N402 x 1-25 H2O (543.2 ) Calculated: C 72.97 H 7.14 N10.32 Found- 72.95 7.02 9.94 Mass spectrum: M~ = 520 Example 31 4'-[[2-n-Propyl-4-methyl-6-(1-ethyl-4-isopropyl-5-methyl-imidazol-2-yl)-lH-benzimiclazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-ethyl-formamide/ethylamine.

Example 32 4'-[[2-n-Propyl-4-methyl-6-(1-isopropyl-4-isopropyl-5-methyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-isopropyl-formamide/isopropylamine.

2~37~

Exam~le 33 4'-[[2-n-Propyl-4-methyl-6~ cyclohexyl-4-isopropyl-5-methyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-cyclohexyl-formamide/cyclohexylamine.
Yield: 10% of theory, C38H44N402 (588.80) Rf value: 0.24 (silica gel; methylene chloride/ethanol/acetic acid = 9:1:0.01) Mass spectrum: (M+H)' = 589 Example 34 4'-[[2-n-Propyl-4-methyl-6-[1-(2-dimethylamino-ethyl)-4-isopropyl-5-methyl-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-semihydrate -Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)~lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and M-(2-dimethylamino-ethyl)-formamide/2-dimethylamino-ethylamine.
Yield: 48% of theory, Melting point: 192-195C (decomp.) C36H43Ns02 x 0-5 HzO (586.79) Calculated: C 73.69 H 7.56 N 11.93 Found: 73.53 7.55 11.94 Mass spectrum: M~ = 577 . .
: ~

-, ~ . .

~3~

Example 35 4'-[[2-n-Propyl-4-methyl-6-(1,5-dimethyl-4-isobutyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl 6-(4-isobutyl-5-methyl-oxazol-2-yl) lH-benzimidazol-1-yl~-methyl]-biphenyl-2-carboxylate and N-methyl-formamide/methylamine.
Yield: 64% of theory, Melting point 155-157C (decomp.) C34H3sN4O2 x 0-7S H20 (548.22) Calculated: C 74.49 H 7.28 N 10.22 Found: 74.45 7.29 10.35 Mass spectrum: M~ = 534 Example 36 4'-[[2-n-Propyl-4-methyl-6-(1-ethyl-4-isobutyl-5-methyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid x 0.25 water Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-ethyl-formamide/ethylamine.
Yield: 62% of theory, Melting point: 239-241C
~33H3sN33 x 0.25 H2O (526.17) Calc. x 0.25 H20: C 75.33 H 6.80 N 7.99 Found: 75.35 6.75 7.96 Mass spectrum: M~ = 527 Example 37 4'-[[2-n Propyl-4-methyl-6-(1-tert.butyl-4-isobutyl-5-methyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]~
biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N~tert.butyl-formamide/tert.butylamine.

Example 38 4'-[[2-n-Propyl-4-methyl-6-(1-benzyl-4-isobutyl-5-methyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-benzyl-formamide/benzylamine.

Example 39 4'-[[2-n-Propyl-4-methyl-6-~1-(2-morpholino-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl)--lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic ac:id Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-S-methyl-oxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-(2-morpholino-ethyl)-formamide/2-morpholino-ethylamine.
Yield: 30% of theory, Melting point: 201-203C (decomp.) C3sH47N503 (633.85) Calculated: C73.90 H 7.47 N 11.05 Found: 73.657.45 11.07 .
'::: ' : '.- ' ' ' , ' :

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

Mass spectrum: M~ = 633 Example 40 4'-[[2-n-Propyl-4-methyl-6-[1-(2-methoxy-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-hydrate Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-(2-methoxy-ethyl)-formamide/2-methoxy-ethylamine.
Yield: 29% of theory, Melting point: 135-137C (decomp., sintering from 110 C) C36H42N4O3 x HzO (596.78) Calculated: C 72.46 H 7.43 N 9.39 Found: 72.50 7.45 9.77 Mass spectrum: M~ = 578 Example. 41 4'-[[2-n-Propyl-4-methyl-6-[1-(2-hydroxy-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl]~lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-E [ 2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-(2-hydroxy-ethyl)-formamide/2-hydroxy-ethylamine.

Example 42 4'-[[2-n-Propyl-4-methyl-6-[1-(3-dimethylamino-propyl)-4-isobutyl-5-methyl-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-~3~

[[2~n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-(3-dimethylamino-propyl)-formamide/3-dimethylamino-propylamine.

Example 43 4'-[[2-n-Propyl-4-methyl-6-~1-carboxymethyl-4-isobutyl-5-methyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl 2-carboxylic acid Prepared analogousl.y to Example 5 from tert.butyl 4'-[~2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-formylglycineethylester/glycineethylesterc Examele 44 4'-[[2-n-Propyl-4-methyl-6-(1-aminocarbonylmethyl-4-i.sobutyl-5-methyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-formyl-glycinamide/glycinamide.

Example 45 4'-[[2-n-Propyl-4-methyl-6-[1-(2-carboxy-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and ethyl 3-formylamino-propionate/ethyl 3-aminopropionate.

'. ' ' ' : :
- : . . . ' : . :

.

:

2~3~

The following may be obtained analogously:

4'-~[2-n-propyl-4-methyl-6-(1,5~dimethyl-4-isobutyl-imidazol-2-yl)-lH-benzimidazol-l-yl~-methyl]-(lH-tetrazol-5-yl)biphenyl 4'-[[2-n-propyl-4-methyl-6-(1-n-propyl-4-isobutyl-5-methyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-(lH-tetrazol-5-yl)biphenyl 4'-[[2-n-propyl-4-methyl-6-[1-(2-dimethylamino-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-(lH-tetrazol-5-yl)biphenyl Example 46 Methyl 4'-[[2-n-propyl-4-methyl-6-(4-methyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate -A solution of 0.35 g (0.7 mMol) of methyl 4'-[[2-n-propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate in 10 ml of toluene is mixed with 0.16 g palladium (10% on activated charcoal) under nitrogen and the mixture is refluxed for 66 hours. Then the toluene is evaporated off, the residue is taken up in methylene chloride, filtered and evaporated down. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant methylene chloride to start with, later followed by methylene chloride/ethanol/
ammonia (50:1:0.05, 20:1:0.02, 10:1:0.01 and 5:1:0.005).
The uniform fractions are combined and evaporated down.
Yield: 0.30 g (9~ of theory), Mass spectrum: M+ = 478 2 ~

~Example 47 4'-[[2-n-Propyl-4-methyl-6-(1,4,5-trimethyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl 2-carboxylic acid 0.25 x H20 Prepared analogously to Example 5 from t* .butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-methyl-formamide/methylamine.
Yield: 61~ of theory, Melting point: 217-219C (decomp.) C31H32N402 x 0-25 HzO (497.13) Calculated: C 74.90 H 6.59 N 11.27 Found: 74.84 6.58 11.26 Mass spectrum: M' = 492 Example 48 4'-[[2-n-Propyl-4-methyl-6-(1-ethyl-4,5-dimethyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert~butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-ethylformamide/ethylamine.

Example 49 4'-[[2-n-Propyl-4-methyl-6-(1-methyl-4,5-diethyl-imidazol~2-yl)-lH-benzimidazol-l-yl]-methyl3-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 5 from 4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and N-methyl-formamide/methylamine.

.

.: ,-: , , - :

.
'" ~
,. ' ~' , , 2~37~

Example 50 4'-[[2-n-Propyl-4-methyl-6-(l-ethyl-4,5-dimethyl-imidazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 5 from 4'-[[2-n-propyl-4-methyl-6- (4,5-dimethyl-oxazol-2-yl)-lH-benzimidazol-1-yl~-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and N-ethyl-formamide/ethylamine.

Example 51 .
4'-[[2-n-Propyl-4-methyl-6-(1-isopropyl-4,5-dimethyl-imidazol-2-yl)-lH-benzimidazol-1-yl~-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-isopropyl-formamide/isopropylamine.

Example 52 4'-[[2-n-Propyl-4-methyl-6-[1-(2-dimethylamino-ethyl)-4,5-dimethyl-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Exampl.e 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-(2-dimethylamino-ethyl)formamide/2-dimethylamino-ethylamine.

~37~

Example 53 4'-[[2 n-Propyl-4-methyl-6-[1-(2-morpholino-ethyl)-4,5-dimethyl-imidazol-2-yl]-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dime~hyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-(2-morpholino-ethyl)-formamide/2-morpholino-ethylamine.

Example 54 4'-[[2-n-Propyl-4-methyl-6-[1-(2-morpholino-ethyl)-4,5-diethyl-imidazol-2-yl]-lH-benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 5 from 4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl~-lH-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl tetrazol-5-yl)-biphenyl and N-(2-morpholino-ethyl)-formamide/2-morpholino-ethylamine.

Exam~le 55 4'-[[2-n-Propyl-4-methyl-6-[1-(2--methoxy-ethyl)-4,5-dimethyl-imidazol-2-yl]-lH-benzim.idazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-(2-methoxy-ethyl)-~ormamide/2-methoxy-ethylamine.

2~3~

Example 56 4'-[[2-n-Propyl-4-methyl-6-[1-(2-methoxy-ethyl)-4,5-dimethyl-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl -Prepared analogously to Example 5 from 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-lH-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and N-(2-methoxy-ethyl)-formamide/2-methoxy-ethylamine.

Example 57 , 4'-[[2-n-Propyl-4-methyl-6-[l-(2-carboxy-ethyl)-4,5-dimethyl-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-2-biphenyl-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2~n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]~biphenyl-2-carboxylate and ethyl N-formyl-3-aminopropionate~ethyl 3-aminopropionate.

E mple 58 4'-[[2-n-Propyl-4-methyl-6-(1-methyl-4,5-diethyl-imidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid x 0.25 H20 Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol 2-yl)-lH-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-methyl-formamide/methylamine.
Yield: 65% of theory, Melting point: 247-249C (decomp.) C33H36N4O2 x 0.25 HzO (525.18) Calculated: C 75.47 H 7.01 N 10.67 Found: 75.43 7.11 10.6 2~7~

Mass spectrum: M = 520 Example 59 4'-[[2-n-Propyl-4-methyI-6~ methyl-imidazolin-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared by heating tert.butyl 4'-[[2-n-propyl-4-methyl-6-[2-(N-methylamino)-ethylaminocarbonyl]-lH-benzimidazol-l-yl]~methyl]-biphenyl-2-carboxylate in phosphorusoxychloride and isolating analogously to Example 10.
Yield: 30% of theory, C2sH30N42 (466.59) Rf value: 0.50 (methylene chloride/methanol/acetic acid = 2:1:0.02) Mass spectrum: (M+H)+ = 467 Exam~le 60 4'-[[2-n-Propyl-4-methyl-6-[1-(2-dimethylamino-ethyl)-4,5-diethyl-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid-dihydrate-trihydrochloride Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl~4-methyl-6-(4,5-diethyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-(2-dimethylamino-ethyl)-formamide/2-dimethylamino-ethylamine.
Yield: 14% of theory, Melting point: 210C (decomp.) C36M43N5O2 x 3 HCl x 2 H2O (723.21) Calculated: C 59.79 H 6.97 N 9.69 Cl 14.71 Found: 59.28 6.92 9.75 14.26 ' , ... . .
.
. : . ~ ,.
' ' ' ': ' , ' ' :

~37~

Example 61 4'-[[2-n-Propyl-4-methyl-6-[1-(2-morpholino-ethyl)-4,5-diethyl-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-(2-morpholino-ethyl)-formamide/2-morpholino-ethylamine.
Yield: 41% of theory, Melting point: from 196C (decomp.) 3sH45NsO3 (619.82) Mass spectrum: M+ = 619 Example 62 4'-[[2-n-Propyl-4-methyl-6-[1-(2-methoxy-ethyl)-4,5-diethyl-imidazol-2-yl]-lH-benzimidazol-1-yl]-methyl]-biphenvl-2-carboxylic acid hydrate Prepared analogously to Example 5 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and N-(2-methoxy-ethyl)-formamide/2-methoxy-ethylamine.
C3sH4~N4O3 x H20 (582.76) Calculated x H20 c 72.14 H 7.27 N 9.61 Found: 71.99 7.19 9.84 Mass spectrum: (M-H) = 563 Example 63 4'-[[2-n-Propyl-4-methyl-6-~4,5-diethyl-oxazol-2 yl]-lH-benzimidazol-l-yl]-methyll-biphenvl-2-carboxvlic acid Prepared analogously to Example 29 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(l-propionyl-n-propyl)-aminocarbonyl]-lH-benzimidazol-l-yl~-methyl]-biphenyl-2-carboxylate and phorusoxychloride.
Yield: 97% of theory, . , .
' ~ ' . ' .
- ~ ' .' .: -- . ~ : . .
' ', ' ~ ,' ~ ' '': ' , 2~3~

Melting point: 250-255C
C32H33N3O3 (507.64) Calculated: C 75.71 H 6.55 N 8.28 Found: 75.77 6.59 8.46 Mass spectrum: M~ = 507 Example 64 4'-[[2-n-Propyl-4-methyl-6-(4,5-diethyl-lH-imidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl-~phenvl Prepared analogously to Example 25b from 4'-[[2-n-propyl-4-methyl-6-[N-(1-propionyl-n-propyl)-aminocarbonyl]-lH-benzimidazol-l-yl]-methyl]-2-(2- -triphenylmethyl-tetrazol-5-yl)-biphenyl and ammonium acetate/glacial acetic acid.
Yield: 27% of theory, Melting point: 221 223C
C3ZH34N8 x H20 (530.69) Calculated: C 70.05 H 6.61 N 20.42 Found: 70.79 6.98 18.83 Mass spectrum: M~ = 530 Example 65 4'-[[2-n-Propyl-4-methyl 6-(4,5-climethyl-oxazol-2-yl]-l benzimidazol-l-yll-methylJ-bi~henyl-2~carboxylic acid Prepared analogously to Example 29 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(1-acetyl-ethyl)-aminocarbonyl]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and phosphorusoxychloride.
Yield: 88% of theory, Melting point: 259-260C (decomp.) C30H29N3O3 x 0-25 ~l2 (484.09) Calculated: C 74.44 H 6.14 N 8.68 Found: 74.33 6.14 8.69 Mass spectrum: M+ = 479 .
: .
' . .

2~37~

Example 66 4'-[[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl a) 4' [[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydro~enzimidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-2'-thvdroxycarbamimidoyl)-biphenyl To a solution of 8.4 g (0.12 Mol) of hydroxylamine-hydrochloride in 30 ml of dimethylsulfoxide are added 30ml of a sodium methoxide solution (30% in methanol) at room temperature. ~fter 10 minutes, 4.5 g (10 mMol) of 4'-[[2-n-propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-2'-cyano-biphenyl are added to this solution and the suspension obtained is heated to 90C for 12 hours.
After cooling to room temperature the reaction mixture is poured into 200 ml of ice water. The precepitate obtained is suction filtered, washed with water, dissolved in methylene chloride and chromatographed on silica gel (particle size: 0.023-0.063 mm) using as eluant mixtures of ethyl acetate, ethanol and concentrated ammonia (19:1:0.06, 19:1:0.08, l9:1:o.1 and 9:1:0.2). The uniform fractions are combined, evaporated, triturated with ether and dried.
Yield: 1.2 g (25~ of theory), Melting point: 221-224C (decomp.) b) 4'-[[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,3-tetrahydrobenzimidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl To a solution of 0.5 g (1 m~ol) of 4'-[[2-n-propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl]-lH-benzimidazol-l-yl]-methyl]-2'-(hydroxycarbamimidoyl)-. . . ~ ., - - ~
.
.
.' ' :' , biphenyl and 0.14 ml (l mMol) of triethylamine in 40 ml of tetrahydrofuran is added a solution of 0.1 ml (1 mMol) of ethyl chloroformate in l ml of methylene chloride at 5C. After 2 hours at room temperature, the precipitate formed is suction filtered. After evaporation of the filtrate the residue obtained is dissolved in 5 ml of xylene and refluxed for 90 minutes.
After cooling to room temperature, the reaction mixture is mixed with 20 ml of ethyl acetate, washed with water and dried over magnesium sulfate. After evaporating the organic phase, the Gbtained residue is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant methylene chloride with increasing amounts of ethanol (0 to iO%). The uniform fractions are combined, evaporated, triturated with ether and dried.
Yield: 80 mg (14% of theory), Melting point: 199C (decomp.) R~-value: 0.33 (silica gel; ethyl acetate/methanol =
3:1) C34H34N62 (558.59) Mass spectrum: (M-H)- = 557 .
The following compound may be obtained analogously to Example 66:

4'-[[2-n-Propyl-4-methyl-6-(1,4,5-trimethyl-imidazol-2-yl]-lH-benzimidazol-1-yl]-methyl]-2'-~2,5-dihydro-5-oxo-1,2 4-oxadiazol-3-vl)-biPhenyl In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I, particularly those compounds wherein Rs denotes a group metabolically convertable in vivo into a carboxy group, or Rs denotes a carboxy or lH-tetrazolyl group, may be used as the active substance:

::
. ' ' .
:

:

2~37~

~xample I

Ampoules containing 50 mg of active substance per 5 ml Active substance 50 mg KH2PO4 2 mg Na2HP04 x 2H20 50 mg NaCl 12 mg Water for injections ad5 ml Preparation:

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

Exam~le II

Ampoules containing 100 mg of active ~ubstance per 5 ml Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene-glycol block polymer250 mg Water for injections ad5 ml Pre~aration:

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.

.
~ ' . " ' ' :' . . ' .: , , .
' ` ~ .
2~3 ~

Example III

Tablets containing 50 mg of active substance Active substance 50.0 mg Calcium phosphate 70.0 mg Lactose 40.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 1.5 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 o F active substance Active substance 50.0 mg Lysine 25.0 mg Lactose 60.0 mg Corn starch 34.0 mg Gelatin 10.0 mg Magnesium stearate 1.0 mq 180.0 mg Preparation:

The active substance is mixed with the excipients and 2~37~

moistened with an aqueous gelatin solution. After screening and drying the granules are mixed with magnesium stearate and compressed to form cores.

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

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

. .

2~37~

Example 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 Polyvinylpyrrolidone2.8 mg Microcrystalline cellulose 60.0 mg Magnesium stearate 1.2 mg ` 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.

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

Exam~le VI

Capsules containing 250 mg of active substance Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 mg 320.0 mg 2i~3~

Pre~aration:

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

Example VII

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

Active substance 50.0 mg Hydroxyethylcellulose50.0 mg Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg Water ad 5.0 ml Pre~aration:

The distilled water is heated to 70C and the hydroxyethylcellulose is dissolved therein with stirring. With 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.

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

, . . ~ , : .

- . ..
', : . , , .. : .
, 2~g~7~

Exam~e VIII

Suppositories containing 100 mg of active substance Active substance 100.0 mg Solid fat 1600.0 mq 1700.0 mg Preparation:

The 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 denotes a hydrogen, fluorine, chlorine or bromine atom or a fluoromethyl, difluoromethyl, trifluoromethyl or alkyl group;

R2 denotes an imidazol-2-yl group optionally substituted in the 1-position by the group Ra, wherein Ra denotes a phenyl or phenylalkyl group, in which the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different, a C3-7-cycloalkyl group or a C1-6-alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or from position 2 by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino or morpholino group, a 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl group, an imidazolium-2-yl group substituted in the l- and 3-positions by groups Rb, which groups may be identical or different, wherein Rb denotes a phenylalkyl group in which the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different, or Rb denotes a C1-6-alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, an oxazol-2-yl or thiazol-2-yl group, whilst in the above mentioned imidazol-2-yl, imidazolium-2-yl, oxazol-2-yl or thiazol-2-yl moieties, the 4-, 5-positions may be substituted by a C15-alkyl group or by a phenyl group, wherein the substituents may be identical or different, or an n-propylene or n-butylene bridge may be added via the 4-, 5-positions, an oxazolin-2-yl or imidazolin-2-yl group substituted in the 4-position by the groups R9 and R10 and in the 5-position by the group R8, wherein an imino group may additionally be substituted by Ra or by an R8CO-(R9CR10)-NRa-CO- group, wherein Ra is as hereinbefore defined, and R8, R9 and R10, which may be identical or different, denote hydrogen atoms, C1-5-alkyl groups or phenyl groups;

R3 denotes a C1-5-alkyl group, a C3-5-cycloalkyl group, a C1-4-alkoxy or C1-4-alkylthio group; and R4 denotes a hydrogen atom or a group of formula wherein R5 denotes a group metabolically convertable in vivo into a carboxy group, or denotes a carboxy, cyano,
2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group, whilst unless otherwise specified any alkyl or alkoxy group contains 1 to 3 carbon atoms, and the phrase "a group metabolically convertable in vivo into a carboxy group" as used herein denotes the esters thereof 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 C1-6-alkyl group, a C5-7-cycloalkyl group, a 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, a C5-7-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group);

and the 3-isomers, the 1-, 3-isomer mixtures and the salts thereof.

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

R2 denotes an imidazol-2-yl group optionally substituted in the 1-position by the group Ra, wherein Ra denotes a phenyl group, a phenyl(C1-3-alkyl) group, a C5-7-cycloalkyl group or a C1-5-alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, by a trifluoromethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group or from position 2 by a hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, pyrrolidino, piperidino or morpholino group, a 5,5-spiro-cyclopentano-dihydroimidazol-4-on-2-yl group, an imidazolium-2-yl group substituted in the 1- and 3-positions by groups Rb, which may be identical or different, wherein Rb denotes a C1-3-alkyl or phenyl(C1-3-alkyl) group, an oxazol-2-yl or thiazol-2-yl group, whilst in the above-mentioned imidazol-2-yl, imidazolium-2-yl, oxazol-2-yl or thiazol-2-yl moieties, the 4-, 5-positions may be substituted by a C1-4-alkyl group or by a phenyl group, wherein the substituents may be identical or different, or an n-butylene bridge may be added via the 4-, 5-positions, an oxazolin-2-yl or imidazolin-2-yl group substituted by the groups R8, R9 and R10, wherein an imino group may additionally be substituted by Ra, wherein R8, R9, R10 and Ra each represent a hydrogen atom or a C1-4-alkyl group;

R3 denotes a C2-5 -alkyl group, a C3-5 - cycloalkyl group, a C2-4- alkoxy or C2-4- alkylthio group; and R4 denotes a 4- biphenylylmethyl group substituted in the 2'-position by the group R5, wherein R5 denotes a group metabolically convertable in vivo into a carboxy group, or denotes a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group;

whilst the expression "a group metabolically convertable in vivo into a carboxy group" as used hereinbefore denotes the esters thereof of the formulae - CO - OR', - CO - O - (HCR") - O - CO - R"' and - CO - O - (HCR") - O - CO - OR"' wherein R' denotes a straight-chained or branched C1-4-alkyl group or a C5-7-cycloalkyl group, R" denotes a hydrogen atom or a methyl group, and R"' denotes a straight-chained or branched C1-4-alkyl group or a C5-7-cycloalkyl group;

and the 3-isomers, the 1-, 3-isomer mixtures and the salts thereof.
3. Compounds of formula I as claimed in claim 1 or claim 2, wherein R2 is in the 6-position; and R1 in the 4-position denotes a fluorine, chlorine or bromine atom, a trifluoromethyl group or a C1-3-alkyl group;

and the 3-isomers, the 1-, 3-isomer mixtures and the salts thereof.
4. Compounds of formula I as claimed in claim 3, wherein R2 is in the 6-position;

and the 3-isomers, 1-, 3-isomer mixtures and the salts thereof.
5. Compounds as claimed in claim 1 being:

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

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

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

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

(e) 4'-[[2-ethyl-4-methyl-6-(1-phenyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid;

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

(g) 4'-[[2-ethyl-4-methyl-6-(1-ethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-Z-(lH-tetrazol-5-yl)-biphenyl;

(h) 4'-[[2-n-propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid;

(i) 4'-[[2-n-propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid; or (k) 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-1,5-dimethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid;

and the salts thereof.
6. A compound as claimed in any one of claims 1 to 5 being a physiologically acceptable salt of a compound of formula I as claimed in any one of claims 1 to 5.
7. A pharmaceutical composition containing a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients.
8. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps:

a) (to prepare compounds of formula I wherein R2 denotes an oxazol-2-yl, thiazol-2-yl or imidazol-2-yl group, in which an n-butylene bridge is added via the 4,5-positions and additionally the imino group in the imidazole ring may be substituted by a C1-6-alkyl group, by a phenyl(C1-3alkyl) group or by a phenyl group) reacting a compound of formula II
(II) (wherein R1, R3 and R6 are as defined in any one of claims 1 to 5 and X denotes an oxygen or sulphur atom or an imino group optionally substituted by a C1-6-alkyl group, by a phenyl(C1-3alkyl) group or by a phenyl group) with an .alpha.-haloketone of formula III
(III) (wherein Z1 denotes a halogen atom);

b) (to prepare compounds of formula I wherein R2 denotes one of the imidazol-2-yl groups mentioned in any one of claims 1 to 5 optionally substituted in the 1-position by the group Ra) reacting a compound of formula IV
(IV) (wherein R1, R3 and R4 are as defined in any one of claims 1 to 5 and R2' denotes one of the oxazol-2-yl groups mentioned in any one of claims 1 to 5) with an amine of formula V
H2N - R6 (V) (wherein R6 has the meanings given for Ra in any one of claims 1 to 5 or denotes a hydrogen atom);

c) (to prepare compounds of formula I wherein R4 denotes a group of the formula reacting a compound of formula VI

(VI) (wherein R1, R3 and R4 are as defined in any one of claims l to 5 and R2" has the meanings given for R2 in any one of claims l to 5, with the exception of the imidazol-2-yl and imidazolin-2-yl groups unsubstituted in the l-position) with a biphenyl compound of formula VII
(VII) (wherein R5 is as defined in any one of claims l to 5 and Z2 denotes a nucleophilic leaving group);

d) (to prepare a compound of formula I wherein R5 denotes a carboxy group) converting a compound of formula VIII
(VIII) (wherein R1, R2 and R3 are as defined in any one of claims 1 to 5 and R5' denotes a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a compound of formula I by hydrolysis, thermolysis or hydrogenolysis;

e) (to prepare compounds of formula I wherein R2 denotes a 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl group) treating a benzimidazole of formula IX
(IX) (wherein R1, R3 and R4 are as defined in any one of claims 1 to 5 and R2"' denotes an imidazol-2-yl group in which an n-butylene bridge is added via the 4,5-position) with a base in the presence of air and light;

f) (to prepare a compound of formula I wherein R5 denotes a 1H-tetrazolyl group) cleaving a protecting group from a compound of formula X
(X) (wherein R1, R2 and R3 are as defined in any one of claims 1 to 5 and R5" denotes a 1H-tetrazolyl or 2H-tetrazolyl group protected in the 1- or 2-position by a protecting group);

g) (to prepare a compound of formula I wherein R5 denotes a 1H-tetrazolyl group) reacting a compound of formula XI
(XI) (wherein R1, R2 and R3 are as defined in any one of claims 1 to 5) with hydrazoic acid or a salt thereof;

h) (to prepare compounds of formula I in which R2 denotes one of the imidazol-2-yl groups mentioned in any one of claims 1 to 5, which may be substituted in the 1-position by a phenylalkyl group (whilst the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different), or by a C1-6-alkyl group, whilst the alkyl group may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, or R2 denotes one of the imidazolium-2-yl groups mentioned in claims 1 to 5) reacting a compound of formula XII

(XII) (wherein R1 and R3 are as defined in any one of claims l to 5, R2"" denotes one of the imidazol-2-yl groups unsubstituted in the 1-position mentioned for R2 in any one of in claims 1 to 5 and R5"' denotes a carboxy group or a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, or a 1H-tetrazolyl or 2H-tetrazolyl group protected by a protecting group) with a compound of formula XIII
Z3 - R7 (XIII) (wherein R7 denotes a phenylalkyl group (whilst the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different), or a C1-6-alkyl group, whilst the alkyl group may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, and Z3 denotes a nucleophilic leaving group) and subsequently if necessary any protecting group used is cleaved;

i) (to prepare compounds of formula I wherein R2 denotes one of the imidazol-2-yl groups mentioned in any one of claims l to 5 substituted by the groups R8, R9 and R10, but wherein R9 or R10 must represent a hydrogen atom) reacting an aminoketone of formula XIV
(XIV) (wherein R1, R3, R4, R8, R9 and R10 are as defined in any one of claims 1 to 5, but R9 or R10 must represent a hydrogen atom, and Ra' has the meanings given for Ra in any one of claims l to 5 or represents a hydrogen atom) with an ammonium salt of a lower aliphatic carboxylic acid;

j) (to prepare compounds of formula I wherein R2 denotes one of the oxazolin-2-yl or imidazolin-2-yl groups mentioned in any one claims l to 5) dehydrating a compound of formula XV
(XV) (wherein R1, R3, R4, R8, R9 and R10 are as defined in any one of claims 1 to 5 and Y denotes a hydroxy or HNRa group wherein Ra is as defined in any one of claims l to 5);

k) (to prepare compounds of formula I wherein R2 denotes one of the imidazolin-2-yl groups mentioned in any one of claims 1 to 5) reacting a compound of formula XVI
(XVI) (wherein R1, R3 and R4 are as defined in any one of claims 1 to 5 and R2""' denotes one of the oxazolin-2-yl groups mentioned for R2 in any one of claims 1 to 5 and substituted by the groups R8, R9 and R10) with an amine of formula XVII

H2N-(R8CH)-(R9CR10)-NH2 (XVII) (wherein R8, R9 and R10 are as defined in any one of claims 1 to 5);

1) (to prepare compounds of formula I wherein R2 denotes one of the oxazol-2-yl groups mentioned in any one of claims 1 to 5 and substituted by the groups R8, R9 and R10) dehydrating an aminoketone of formula XVIII
(XVIII) (wherein R1, R3, R4, R8, R9 and R10 are as defined in any one of claims l to 5, but R9 or R10 must denote a hydrogen atom);

m) (to prepare compounds of formula I wherein R2 denotes one of the imidazol-2-yl groups mentioned in any one of claims l to 5, substituted by the groups R8, R9 and R10) dehydrogenating a compound of formula XIX
(XIX) (wherein R1, R3 and R4 are as defined in any one of claims l to 5 and R2""" denotes one of the imidazolin-2-yl groups mentioned for R2 in any one of claims 1 to 5 and substituted by the groups R8, R9 and R10, but wherein R9 or R10 must denote a hydrogen atom);

n) (to prepare compounds of formula I wherein R5 denotes a 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group) reacting an amidoxime of formula XX
(XX) (wherein R1, R2 and R3 are as defined in any one of claims l to 5) optionally prepared in the reaction mixture, with a compound of formula XXI

Z4 - CO - OR11 (XXI) (wherein Z4 denotes a nucleophilic leaving group and R11 denotes an alkyl, aryl or aralkyl group) and subsequently cyclising an acylated amidoxime thus obtained;

o) converting a compound of formula I thus obtained into a salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound; and p) performing a process as defined in any one of steps (a) to (o) above on a corresponding protected compound and subsequently removing the protecting group used.
9. A compound of formula I as claimed in any one of claims l to 5 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent having an angiotensin-antagonistic activity.
10. Use of a compound as claimed in claim 9 for the treatment of hypertension and cardiac insufficiency, for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
11. Use of a compound as claimed in claim 9 for treating pulmonary diseases, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy.
12 . Use of a compound as claimed in claim 9 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, for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, 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 l to 5 or a physiologically acceptable salt thereof.
14 . A method of treatment as claimed in claim 13 to combat pulmonary diseases, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy.
15 . A method of treatment as claimed in claim 13 to alleviate central nervous system disorders.
16 . A compound of formula I as claimed in claim 1 or a pharmaceutical composition thereof as herein disclosed in any one of the Examples.
17 . Each and every novel compound, composition, process, use and method as herein disclosed.
CA002093785A 1992-04-11 1993-04-08 Benzimidazoles Abandoned CA2093785A1 (en)

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DEP4212250.3 1992-04-11
DE4212250A DE4212250A1 (en) 1992-04-11 1992-04-11 New 1-phenyl:benzyl -benzimidazole derivs. with alkylene-bridged heterocyclic gp. - used as angiotensin II antagonists e.g. for treating cardiovascular, pulmonary or CNS disorders
DE4224752A DE4224752A1 (en) 1992-04-11 1992-07-27 Benzimidazoles, medicaments containing these compounds and process for their preparation
DEP4224752.7 1992-07-27

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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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EP0816348B1 (en) * 1996-06-28 2003-02-05 Dow AgroSciences LLC Heterocyclic n-acetonylbenzamides and their use as fungicides
TWI406850B (en) * 2007-06-05 2013-09-01 Theravance Inc Dual-acting benzoimidazole antihypertensive agents
ES2385773T3 (en) * 2007-12-11 2012-07-31 Theravance, Inc. Benzoimidazole derivatives, double-acting, and their use as antihypertensive agents
CN101798287A (en) * 2010-03-18 2010-08-11 北京理工大学 [(4-methyl-2-propyl-N-methoxyl-substituted benzene alkyl-1H-benzimidazole-6-formamide)-1-yl] methyldiphenyl compound and preparation method thereof
CN105073744B (en) 2012-12-21 2019-11-08 齐尼思表观遗传学有限公司 Novel heterocyclic compounds as bromine structural domain inhibitor
WO2016087942A1 (en) 2014-12-01 2016-06-09 Zenith Epigenetics Corp. Substituted pyridines as bromodomain inhibitors

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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
EP0470543A1 (en) * 1990-08-10 1992-02-12 Dr. Karl Thomae GmbH Heterocyclic imidazoles, remedies containing them and processes for their preparation
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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DE4224752A1 (en) 1994-02-03
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KR930021734A (en) 1993-11-22
JPH0625234A (en) 1994-02-01
NO931342L (en) 1993-10-12
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CZ62193A3 (en) 1994-01-19
PL298449A1 (en) 1994-04-18
NZ247373A (en) 1995-06-27
IL105356A0 (en) 1993-08-18
SK32493A3 (en) 1994-02-02
HUT64059A (en) 1993-11-29
AU3679693A (en) 1993-10-14
FI931599A (en) 1993-10-12

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