CA2060624C - Benzimidazoles, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents

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

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Publication number
CA2060624C
CA2060624C CA002060624A CA2060624A CA2060624C CA 2060624 C CA2060624 C CA 2060624C CA 002060624 A CA002060624 A CA 002060624A CA 2060624 A CA2060624 A CA 2060624A CA 2060624 C CA2060624 C CA 2060624C
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Prior art keywords
methyl
group
benzimidazol
imidazo
biphenyl
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CA002060624A
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French (fr)
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CA2060624A1 (en
Inventor
Norbert Hauel
Berthold Narr
Uwe Ries
Jacques Van Meel
Wolfgang Wienen
Michael Entzeroth
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Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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Priority claimed from DE4103492A external-priority patent/DE4103492A1/en
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • 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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • 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
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    • 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
    • C07D403/10—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 linked by a carbon chain containing aromatic rings
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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Abstract

The invention relates to compounds of formula I
(see above formula) and addition salts thereof. As examples of groups R1, there are mentioned fluorine, chlorine, bromine, alkyl and cycloalkyl and as examples of groups R2 there are mentioned alkyleneimino, alkenyleneimino, malefic acid imido, benzimidazol-2-yl and 4,5,6,7-tetrahydrobenzimidazol-2-yl. R3 represents an alkyl or a cycloalkyl group and R4 represents a carboxyl or 1H-tetrazolyl group. The new compounds have useful pharmaceutical properties and are, in particular, angiotensin antagonists.

Description

The present invention is concerned with benzimidazole compounds, the isomers and salts thereof, which are useful pharmaceutically and especially as angiotensin antagonists.
The new benzimidazoles of the present invention 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.
EP-A-0 392 317 has already described benzimidazoles which are valuable as angiotensin antagonists.
It has now been found that the new benzimidazoles of general formula N
R2 / ~R3 N

which differ from the benzimidazoles described in the above-mentioned published applications by the group R2, and the compounds of general formula I wherein R2 denotes a pyridyl or imidazolyl group, constitute a selection from EP-A-0,400,835, r 2o6ofi2~
- la -are even more useful angiotensin-II antagonists than those known from the literature.
The present invention thus relates to the new benzimidazoles of the above general formula I and the salts thereof, particularly, for pharmaceutical use, the physiologically acceptable salts thereof with inorganic or organic acids, pharmaceutical compositions containing these compounds and processes for preparing them.
In general formula I above:
R1 represents a fluorine, chlorine or bromine atom, an alkyl, cycloalkyl, fluoromethyl, difluoromethyl or 2o sos24 trifluoromethyl group and RZ represents a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group, optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, wherein a methylene group may be replaced by a carbonyl or sulphonyl group, a malefic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group optionally substituted in the 1-position by C1_6-alkyl or a cycloalkyl group, whilst the phenyl nucleus of one of the abovementioned benzimidazole groups may additionally be substituted by a fluorine atom or by a methyl or trifluoromethyl group, RZ may represent an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, a pyridyl group or a carbon attached imidazolyl group optionally substituted in the 1-position by an alkyl or benzyl group, and which may also be substituted in the carbon skeleton by an alkyl group, R3 represents a C1_5-alkyl group or a C3_S-cycloalkyl group and H

-~ 206062 R4 represents a carboxy or 1H-tetrazolyl group, whilst, unless otherwise specified, an alkyl moiety mentioned hereinbefore may contain 1 to 3 carbon atoms in each case and a cycloalkyl moiety mentioned hereinbefore may contain 3 to 7 carbon atoms in each case.
As examples of the definitions of the groups R1 to R3 mentioned hereinbefore:
R1 may represent a fluorine, chlorine or bromine atom, a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, fluoromethyl, difluoromethyl or trifluoromethyl group, Rz may represent a 2-oxo-pyrrolidino, 2-oxo-piperidino, 2-oxo-hexamethyleneimino, propanesultam-1-yl, butanesultam-1-yl, pentanesultam-1-yl, malefic acid imido, 2-methyl-malefic acid imido, 2-phenyl-malefic acid imido, 2-methyl-3-phenyl-malefic acid imido, pyridin-2-yl, 4-methyl-imidazol-2-yl, 1-methyl-imidazol-4-yl, 1-methyl-imidazol-5-yl, 1-benzyl-imidazol-4-yl, 1-benzyl-imidazol-5-yl, 1,2-dimethyl-imidazol-4-yl, 1,2-dimethyl-imidazol-5-yl, 1-benzyl-2-methyl-imidazol-4-yl, 1-benzyl-2-methyl-imidazol-5-yl, benzimidazol-2-yl, 1-methyl-benzimidazol-2-yl, 1-ethyl-benzimidazol-2-yl, 1-n-propyl-benzimidazol-2-yl, 1-isopropyl-benzimidazol-2-yl, 1-n-butyl-benzimidazol-2-yl, 1-isobutyl-benzimidazol-2-yl, 1-n-pentyl-benzimidazol-2-yl, 1-n-hexyl-benzimidazol-2-yl, 1-cyclopropyl-benzimidazol-2-yl, 1-cyclobutyl-benzimidazol-2-yl, 1-cyclopentyl-benzimidazol-2-yl, 1-cyclohexyl-benzimidazol-2-yl, 5-methyl-benzimidazol-2-yl, 1,5-dimethyl-benzimidazol-2-yl, 1,6-dimethyl-benzimidazol-2-yl, 1,4-dimethyl-benzimidazol-2-yl, 5-fluoro-1-methyl-benzimidazol-2-yl, 6-fluoro-1-methyl-benzimidazol-2-yl, 5-trifluoromethyl-benzimidazol-2-yl, 5-trifluoromethyl-1-methyl-benzimidazol-2-yl, 4,5,6,7-tetrahydro-benzimidazol-2-yl, 4,5,6,7-tetrahydro-1-methyl-benzimidazol-2-yl, 4,5,6,7-tetrahydro-1-ethyl-benzimidazol-2-yl, 4,5,6,7-tetrahydro-1-n-butyl-benzimidazol-2-yl, 4,5,6,7-tetrahydro-1-n-hexyl-benzimidazol-2-yl, 4,5,6,7-tetrahydro-1-cyclopropyl-benzimidazol-2-yl, 4,5,6,7-tetrahydro-1-cyclohexyl-benzimidazol-2-yl, imidazo-[1,2-a]pyrimidin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo-[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group and R3 may represent a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, cyclopropyl, cyclobutyl or cyclopentyl group.
Preferred compounds of general formula I above are those wherein R1 represents a chlorine atom, or a C1-3-alkyl or a trifluoromethyl group, RZ represents a 5-, 6- or 7-membered alkyleneimino group wherein a methylene group is replaced by a carbonyl or sulphonyl group, a malefic acid imido group optionally mono- or disubstituted by a C1_3-alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol 2-yl group optionally substituted in the 1-position by a 2n 60624 C1_6-alkyl or by a cycloalkyl group, whilst the phenyl nucleus of one of the abovementioned benzimidazole groups may additionally be substituted by a fluorine atom or by a methyl or trifluoromethyl group, or RZ may represent an imidazo[2,1-b]thiazol-6-yl, imidazo(1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo(1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo(4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo(1,2-a]pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo(4,5-d]pyridazin-2-yl group, a pyridyl group or an imidazol-4-yl group substituted in the 1-position by a C1_3 alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a C1_3 alkyl group, R3 represents a C1_5-alkyl group or a C3_5-cycloalkyl group and Rq represents a carboxy or 1H-tetrazolyl group, and the salts thereof with inorganic or organic acids or bases.
Particularly preferred compounds of general formula I
above are those wherein R1 represents a methyl group or a chlorine atom and R2 represents a 5-, 6- or 7-membered alkyleneimino group, wherein a methylene group is replaced by a carbonyl or sulphonyl group, a malefic acid imido group optionally mono- or _. 2o sos24 disubstituted by a C1_3-alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group optionally substituted in the 1-position by a C1_3-alkyl group, whilst the phenyl nucleus of one of the abovementioned benzimidazole groups may additionally be substituted by a fluorine atom, or Rz may represent an imidazo[1,2-a]-pyridin-2-yl group, 5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl or imidazo[2,1-b]thiazol-6-yl group, an imidazol-4-yl group substituted in the 1-position by a C1_3 alkyl group, R3 represents a C1_5-alkyl group or a C3_5-cycloalkyl group and R4 represents a carboxy or 1H-tetrazolyl group, and the salts thereof with inorganic or organic acids or bases.
According to the invention, the compounds are obtained by the following processes:
a) Cyclising a compound of general formula (II), R2 w wherein R1 and RZ are defined as hereinbefore, one of the groups X1 or Y1 represents a group of general formula ,~y~
_.a.

- NR8 - CH2 / ~ /

and the other group X1 or Y1 represents a group of the general formula Zl /Zz wherein R3 and R4 are defined as hereinbefore, RB represents a hydrogen atom or an R3C0- group, wherein R3 is defined as hereinbefore, Z1 and Zz, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups or Z1 and Zz, together represent an oxygen or sulphur atom, an optionally C1_3-alkyl substituted imino group, or a Cz_3-alkylenedioxy or Cz_3-alkylenedithio group, but one of the groups X1 or Y1 must represent a group of general formula - N(COR3) - CH2 /

or Z1~ /Zz - NH - C - R3.
optionally with reduction of the corresponding N-oxide =,s _8_ thus obtained.
The cyclisation is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of general formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, e.g. at temperatures between 0 and 250°C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide.
However, cyclisation may also be carried out without a solvent and/or condensing agent.
However, it is particularly advantageous to carry out the reaction by preparing a compound of general formula II in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of general formula R3COOH, or by acylation of a corresponding o-diamino compound. When the reduction of the nitro group is broken off at the hydroxylamine stage, the N-oxide of a compound of general formula I is obtained in the subsequent cyclisation. The resulting N-oxide is then converted by reduction into a corresponding compound of general formula I.
The subsequent reduction of the N-oxide of formula I
obtained is preferably carried out in a solvent such as 2osos24 _ g _ water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50°C, but preferably at ambient temperature.
b) Reaction of a benzimidazole of general formula R~
N
R2 / ~~R3 (III) , N
wherein R1 to R3 are defined as hereinbefore, with a biphenyl compound of general formula Z3 _ CH2 / \ / \ (IV).

wherein RQ is defined as hereinbefore and Z3 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group.
The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, B

... 20 60624 diethylether, tetrahydrofuran, dioxane, dimethyl-sulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, preferably at temperatures between 0 and 100°C, e.g. at temperatures between ambient temperature and 50°C.
In the reaction, a mixture of the 1- and 3- isomers is preferably obtained which can if desired subsequently be resolved into the corresponding 1- and 3- isomers, preferably by chromatography using a substrate such as silica gel or aluminium oxide.
c) In order to prepare a compound of general formula I
wherein RQ represents a carboxy group:
Converting a compound of general formula R~
N
R2 / \~ R3 N (Zl) / ~ /
CHz R ' wherein R1 to R3 are defined as hereinbefore and R9' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis.
For example, functional derivatives of the carboxy group such as unsubstituted or substituted amides, esters, 2060s2~

thiolesters, orthoesters, iminoethers, 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, tert.butylester, may be converted into a carboxy group by thermolysis and esters with aralkanols, e.g. benzylester, may be converted into a carboxy group by hydrogenolysis.
The hydrolysis is conveniently carried out in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10°C and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic or trifluoroacetic acid, any alcoholic hydroxy groups present may optionally be simultaneously converted into a corresponding acyloxy group such as a trifluoroacetoxy group.
If R4' in a compound of general formula V 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 50°C.
If R4' in a compound of general formula V represents, for example, a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an ... 20 sOS24~

acid such as p-toluenesulphonic acid, sulphuric, phosphoric or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40°C and 100°C.
If R4' in a compound of general formula V represents, for example, a benzyloxycarbonyl group, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. at ambient temperature, under a hydrogen pressure of 1 to 5 bar. During hydrogenolysis, other groups may be reduced at the same time, e.g. a nitro group may be reduced to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen may be replaced by a hydrogen atom.
d) In order to prepare a compound of general formula I
wherein RQ represents a 1H-tetrazolyl group:
Cleaving of a protective group from a compound of general formula N
\~ R3 N (VI).
/ \ / \
CHz R4 ~~
wherein R1, RZ and R3 are defined as hereinbefore and R4" represents a 1H-tetrazolyl group protected in the f-or 3-position by a protecting group.
Suitable protecting groups include, for example, triphenylmethyl, tributyl tin or triphenyl tin groups.
The cleaving of a protective group used 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 100°C, 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.
e) In order to prepare a compound of general formula I
wherein R9 represents a 1H-tetrazolyl group:
Reaction of a compound of general formula N
RZ ~ N~ R3 (VII).
CH., CN
wherein R1 to R3 are defined as hereinbefore, with hydrazoic acid or the salts thereof.
The reaction is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures ., _~.. 206062 between 80 and 150°C, preferably at 125°C. Conveniently, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g. 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 mixture by reacting aluminium chloride or tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric or 2N sulphuric acid.
f) In order to prepare compounds of general formula I
wherein RZ represents one of the above-mentioned imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl or imidazo[2,1-b]-thiazol-6-yl groups:
Reaction of a compound of general formula B'A~N
(VIII) , ~2 wherein one of the groups A, B, C or D represents an optionally methyl-substituted methine group or a nitrogen atom and the remaining groups A, B, C or D represent methine groups or A and B each represent a methine group and the -C=D- group represents a sulphur atom, with a compound of general formula ... 20 60624 N
Z4 - CH2 - CC , \~ R3 (IX).
N
\ /
CH., wherein . R4 R1, R3 and R4 are defined as hereinbefore and Z9 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom.
The reaction is expediently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, benzene, glycol, glycolmonomethylether, dimethyl-formamide or dioxane, e.g. at temperatures between 0 and 150°C, preferably at temperatures between 20 and 100°C.
However, the reaction may also be carried out without solvents.
g) In order to prepare compounds of general formula I
wherein RZ represents one of the above-mentioned benzimidazol-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, imidazo[4,5-d]pyridazin-2-yl or purin-8-yl groups:
Cyclisation of a compound of general formula ~A, X2 (X) , Clb wherein none, one or two of the groups Al, B1, C1 or D1 represent a nitrogen atom and Zo sos2~

the remaining groups Al, B1, C1 or D1 represent methine groups, R11 represents a hydrogen or fluorine atom or a methyl or trifluoromethyl group, one of the groups Xz or Y2 represents an R13-NH- group and the other XZ or Yz group represents a group of general formula N
_ NR14 _ C ~ R3 N
/ \ /
CH., wherein Rl, R3 and R4 are defined as he reinbefore, one of the groups R13 or R14 represents a hydrogen atom and the other R,3 or R19 group represents a hydrogen atom, a C1_6-alkyl group or a C3_~-cycloalkyl group, ZS and Z6, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups or ZS and Z6 together represent an oxygen or sulphur atom, an optionally C1_3-alkyl substituted imino group, or an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms, optionally followed by reduction of an N-oxide thus obtained and optional hydrolysis.
The cyclisation is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, sulpholan, dimethylformamide, tetralin or in an excess of the acylating agent used to prepare the compound of general formula X, e.g. in the corresponding J,i 20 ~os24 -1~-nitrile, anhydride, acid halide, ester or amide, e.g. at temperatures between 0 and 250°C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid anhydride or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide. However, the cyclisation may also be carried out without a solvent and/or condensing agent.
However, it is particularly advantageous to perform the reaction by preparing a compound of general formula X in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of general formula N
HOOC ~~ R3 N , (XI) / \ / \
CHz wherein R4 R1, R3 and R9 are defined as hereinbefore, or by acylating a corresponding o-diamino compound with a carboxylic acid of general formula XI.
When the reduction of the nitro group is broken off at the hydroxylamine stage, subsequent cyclisation produces the N-oxide of a compound of general formula I. The N-oxide thus obtained is then converted by reduction into a corresponding compound of general formula I.
The subsequent reduction of an N-oxide thus obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50°C, but preferably at ambient temperature.
The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10°C and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic or trifluoroacetic acid, any alcoholic hydroxy groups present may simultaneously be converted into a corresponding acyloxy group such as the trifluoroacetoxy group.
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 are split off again after the reaction.
Examples of protecting groups for a hydroxy group are trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.-butyl, benzyl and tetrahydropyranyl groups and ~r 2o sos24 protecting groups for an amino, alkylamino or imino group include the acetyl, benzoyl, ethoxycarbonyl and benzyl groups.
The optional subsequent cleaving of a protecting group is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is preferably split off by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.
An isomer mixture of a compound of general formula I
thus obtained may if desired be resolved by chromatography using a substrate such as silica gel or aluminium oxide.
Moreover, the compounds of general formula I obtained may be converted into the acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable salts thereof with inorganic or organic acids. Suitable acids for this purpose include hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric or malefic acid.
Furthermore, the new compounds of general formula I thus ;r t 2osos24 obtained, if they contain a carboxy or 1H-tetrazolyl group, may if desired subsequently be converted into the salts thereof with inorganic or organic bases, more particularly for pharmaceutical use into the physiologically acceptable addition salts thereof.
Suitable bases include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of general formulae II to XI used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature.
Thus, for example, a compound of general formula II is obtained by alkylation of a corresponding o-amino-nitro compound and subsequent reduction of the nitro group.
A compound of general formula III, V, VI, VII, IX or X
used as starting material is obtained by acylation of a corresponding o-phenylenediamine or a corresponding o-amino-nitro compound, followed by reduction of the nitro group and subsequent cyclisation of an o-diamino-phenyl compound thus obtained, optionally followed by the cleaving of any protecting group used or by cyclisation of a correspondingly substituted benzimidazole with a corresponding amine or by NH-alkylation of a corresponding 1H-benzimidazole, whilst the isomer mixture thus obtained may subsequently be resolved by conventional methods, e.g. chromatography. Some of the starting compounds mentioned above are described in EP-A-0 392 317.
For example, 2-n-butyl-5-(imidazo[1,2-a]pyridin-2-yl)-3H-benzimidazole is obtained by reacting p-amino-acetophenone with butyric acid chloride, followed by nitration, bromination, cyclisation with 2-aminopyridine ... 2o sos2~

to form the 6-n-butanoylamido-3-(imidazo[1,2-a]pyridin-2-yl)-nitrobenzene, which is subsequently converted into the desired compound by cyclisation, after reduction of the nitro group, or 2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-1H-benzimidazole may be obtained by nitration of methyl 3-methyl-4-n-butanoylamido-benzoate, subsequent reduction of the nitro group and cyclisation to yield 2-n-butyl-4-methyl-6-methoxycarbonyl-1H-benzimidazole, which is then converted into the desired compound using 2-methylamino-aniline with cyclisation.
The new compounds of general formula I and the physiologically acceptable salts thereof have valuable pharmacological properties. They are angiotensin antagonists, particularly angiotensin-II-antagonists.
By way of example, the following compounds were tested for their biological effects as described hereinafter:
A = 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid, B = 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, C = 4'-[[2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, D = 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid semihydrate, ,~~ '., .. 20 60624 E = 4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, F = 4'-[(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, G = 4'-[(2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, H = 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, I - 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, J = 4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrochloride and K = 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Descr~prion of method:Angiotensin II-recet~tor bondina The tissue (rats lung) is homogenised in Tris-buffer (50 mMol Tris, 150 mMol NaCl, 5 mMol EDTA, 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 37°C with 50 pM [lzsI] -antiotensin II (NEN, Dreieich, FRG) with a .... 20 60x24 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 Substance ICso [nM]

A 3.7 B 14.0 C 1.2 D 20.0 E 12.0 F 26.0 G 3.4 H 1.2 I 1.7 J 20.0 K 7.8 In addition, compounds A, B, C, D, E and G were tested on conscious renally hypertensive rats for their effect after oral administration using methods known from the literature. At a dosage of 10 mg/kg these compounds exhibited a hypotensive effect.
Moreover, when the above-mentioned compounds were administered in a dose of 30 mg/kg i.v. no toxic side effects, e.g. negative inotropic effects or disorders in heart rhythm, were observed. The compounds are therefore well tolerated.

2osos2~

In view of their pharmacological properties, the new compounds and the physiologically acceptable addition 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 addition 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 vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl-choline 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.
The dosage required to achieve these effects in adults is appropriately, when administered intravenously, 20 to 100 mg, preferably 30 to 70 mg, and, when administered orally, 50 to 200 mg, preferably 75 to 150 mg, 1 to 3 times a day. For this purpose, the compounds of general formula I prepared according to the invention, optionally in conjunction with other active substances, such as hypotensives, diuretics and/or calcium antagonists, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene-glycol, propylene-glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
Additional active substances which may be included in the combinations mentioned above might be, for example, bendroflumethiazide, chlorothiazide, hydrochloro-thiazide, spironolactone, benzothiazide, cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosine, atenolol, propranolol, (di)hydralazine-hydrochloride, diltiazem, felodipin, nicardipin, nifedipin, nisoldipin and nitrendipin. The dosage for these active substances is appropriately one fifth 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, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipin or 5 to 60 mg of nitrendipin.
The Examples which follow are intended to illustrate the invention:

_.. 20 60624 4'-[[2-n-Butyl-7-[5-(imidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid hydrate 0.7 g (1.15 mMol) of tert.-butyl 4'-[[2-n-butyl-7-[5-(imidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate are dissolved in 35 ml of methylene chloride, 5 ml of trifluoroacetic acid are added and the mixture is stirred for 12 hours at ambient temperature. It is diluted with methylene chloride and extracted with water and with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated down ~ vacuo. The crude product thus obtained is purified over a silica gel column (particle size: 0.063-0.02 mm, ethyl acetate/ethanol/ammonia - 90:10:0.1) and crystallised from acetone.
Yield: 0.19 g (29.9% of theory), Melting point: 185-187°C
C39H38N9O3 X H20 (550.70) Calculated: C 71.81 H 7.09 N 9.85 Found: 72.03 7.19 9.71 Mass spectrum: m/e = M+ 550 4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in dimethylformamide.
Yield: 63.9% of theory, Melting point: 261-263°C
C33H30N902 ( 514 . 6 0 ) B

2p 80624 Calculated: C 77.02 H 5.87 N 10.89 Found: 76.90 5.85 10.99 The following compounds are obtained analogously to Example 1:
4'-[[2-n-propyl-4-methyl-6-(1-n-propylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(1-n-hexylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(1-cyclopropylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4.3 g (66 mMol) of sodium azide and 3.5 g (66 mMol) of ammonium chloride are added to a solution of 1.60 g (3.3 mMol) of 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl in 50 ml of dimethylformamide and the mixture is stirred for 24 hours at 140°C. Then water is added and the precipitate is removed by suction filtering. The crude product thus obtained is purified by chromatography over silica gel (300 g of silica gel, methylene chloride + 6% ethanol).
Yield: 900 mg (51% of theory), Melting point: 228-230°C
;r, r ..: 206062 C33H30N8 (538.70) Calculated: C 73.58 H 5.61 N 20.80 Found: 73.48 5.55 20.70 The following compounds are obtained analogously to Example 2:
4'-[[2-n-propyl-4-methyl-6-(1-n-hexylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(1-cyclobutylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 49.0% of theory, Melting point: Sintering from 186°C
CZ9H31N.,OZS ( 541 . 70 ) Calculated: C 64.30 H 5.77 N 18.10 S 5.92 Found: 64.10 5.39 18.01 5.98 ... 2060624 4'-[[2-Ethyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-ethyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 60.0% of theory, Melting point: amorphous, sintering from 194°C
CZBHZ9N~O2S ( 527 . 70 ) Calculated: C 63.74 H 5.54 N 18.58 S 6.08 Found: 63.83 5.66 18.41 5.82 4'-[[2-n-Butyl-4-methyl-6-(butanesultam-'1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-butyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 48.0% of theory, Melting point: amorphous, sintering from 183°C
C3aH33N-,OzS (555.70) Calculated: C 64.84 H 5.99 N 17.64 S 5.77 Found: 64.53 5.66 17.63 5.55 4'-[[2-n-Propyl-4-ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-propyl-4-ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 27.0% of theory, ._ 20 60624 Melting point: amorphous, sintering from 189°C
C30H33N702'S ( 555 . 70 ) Calculated: C 64.84 H 5.99 N 17.64 S 5.77 Found: 64.81 5.68 17.87 5.31 4'-[[2-Ethyl-4-ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-ethyl-4-ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 39.0% of theory, Melting point: amorphous, sintering from 212°C
Cz9H31N~O2S ( 541. 70 ) Calculated: C 64.30 H 5.77 N 18.10 S 5.92 Found: 64.30 5.51 17.99 5.59 4'-[[2-n-Propyl-4-isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-propyl-4-isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Yield: 22.0% of theory, Melting point: amorphous C31H3sN~O2S (569.70) Calculated: C 65.35 H 6.19 N 17.21 S 5.63 Found: 65.13 6.10 17.54 5.40 20 fi0~24 4'-[[2-Ethyl-4-isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-ethyl-4-isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Yield: 24.0% of theory, Melting point: amorphous, sintering from 209°C
C30H33N7~2S ( 555 . 70 ) Calculated: C 64.84 H 5.99 N 17.64 S 5.77 Found: 64.99 5.71 17.43 5.71 4'-[[2-n-Propyl-4-trifluoromethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-propyl-4-trifluoromethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Yield: 17.0% of theory, Melting point: 199-203°C
CZ9HZ8F3N~OZS ( 595 . 70 ) Calculated: C 58.48 H 4.74 N 16.46 Found: 58.28 4.43 16.22 4'-[[2-n-Butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 48.0% of theory, Melting point: 233-235°C
C39H32N4~2 ( 528 . 70 ) Calculated: C 77.25 H 6.10 N 10.60 Found: 77.10 5.98 10.46 4'-[[2-n-Butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 41.0% of theory, Melting point: 235-237°C
C34H32N8 (552.70) Calculated: C 73.89 H 5.84 N 20.28 Found: 73.67 5.81 19.93 The following compounds are obtained analogously to Example 12:
4'-[[2-n-butyl-4-methyl-6-(1-ethylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-4-methyl-6-(1-cyclopropylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-4-methyl-6-(1-n-pentylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-4-methyl-6-(1-cyclopentylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl H

2o sos2~

4'-[[2-n-Propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Yield: 51.0% of theory, Melting point: amorphous, from 140°C (sintering) C3oH31N~0 ( 505 . 60 ) Calculated: C 71.26 H 6.18 N 19.39 Found: 71.08 6.22 19.47 4'-[[2-n-Butyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-butyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Yield: 39.0% of theory, Melting point: amorphous, from 128°C (sintering) C31H33N70 ( 519 . 7 0 ) Calculated: C 71.65 H 6.40 N 18.87 Found: 71.44 6.23 18.59 4'-[[2-n-Propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)biphenyl by cleaving the 2osos24 triphenylmethyl group with methanolic hydrochloric acid.
Yield: 51.0% of theory, Melting point: amorphous, sintering from 115°C
C3oH31N~0 (505.60) Calculated: C 71.26 H 6.18 N 19.39 Found: 71.51 6.39 19.09 4'-[[2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 38.0% of theory, Melting point: 195-197°C (after evaporation and without recrystallisation) Melting point: 299-303°C (methylene chloride/ethanol =
20:1) C32HZgN4O2 ( 5 0 0 . 6 0 ) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.55 5.61 10.87 4' - [ [2-n-Propyl-4-methyl-6- (imidazo [1, 2-a] pyridin-2-yl) -benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 21.0% of theory, Melting point: sintering from 181°C
C32HZBN8 (524.60) Calculated: C 73.26 H 5.38 N 21.36 2osos24 Found: 73.10 5.24 21.13 The following compound may be prepared analogously to Example 17:
4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4' - [ [2-n-Butyl-4-methyl-6- (imidazo [1, 2-a] pyridin-2-yl) -benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 51.0% of theory, Melting point: 194-197°C
C33H30N9O2 ( 514 . 6 0 ) Calculated: C 77.02 H 5.88 N 10.89 Found: 76.81 5.78 10.64 4'-[[2-n-Butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 26.0% of theory, C33H30N8 ( 53 8 . 6 0 ) Calculated: C 73.58 H 5.61 N 20.80 Found: 73.39 5.40 20.92 .~ ., ..

__ 20 60624 4'-[[2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 47% of theory, Melting point: 224-226°C (after evaporation and without recrystallisation) Melting point: 294-297°C (methylene chloride/ethanol =
20:1) C31HZ~NSO2 ( 5 O l . 6 0 ) Calculated: C 74.23 H 5.43 N 13.96 Found: 74.10 5.31 13.66 4'-[[2-n-Propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 43% of theory, Melting point: 192-195°C (after evaporation and without recrystallisation) Melting point: >300°C (methylene chloride/ethanol -20:1) C3pH26NqO2S (506.64) Calculated: C 71.12 H 5.17 N 11.06 S 6.33 Found: 70.97 5.19 10.88 6.09 - 37 _ 20 6062 4'-[[2-n-Propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 21% of theory, Melting point: amorphous, sintering from 196°C
C30H26N8S (530. 67) Calculated: C 67.90 H 4.94 N 21.12 S 6.04 Found: 67.77 4.84 21.00 5.87 4'-[[2-n-Propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Yield: 28% of theory, Melting point: 202-205°C
C32H28N8 ( 524 . 64 ) Calculated: C 73.26 H 5.38 N 21.36 Found: 73.01 5.22 21.56 The following compounds are obtained analogously to Example 23:
4'-[[2-ethyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl .. 20 60624 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-Propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 43% of theory, Melting point: 239-242°C
C32HzaN902 ( 5 0 0 . 61 ) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.55 5.60 11.41 The following compounds are obtained analogously to Example 24:
4'-[[2-ethyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-Butyl-6-(2,3-dimethylmaleic acid imino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid-semihydrate Prepared analogously to Example A from tert.butyl 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 88.9% of theory, Melting point: 321-322°C
C'32H31NgOq x 0 . 5 H20 ( 53 0 . 62 ) Calculated: C 72.43 H 6.08 N 7.92 Found: 72.89 6.16 7.89 4'-[[6-(2,3-Dimethylmaleic acid imino)-2-n-propyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid semihydrate Prepared analogously to Example A from tert.butyl 4'-[[6-(2,3-dimethylmaleic acid imino)-2-n-propyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 75.4% of theory, Melting point: 329-331°C
C31Hz9N3O4 x 0 . 5 Hz0 ( 516 . 6 0 ) 20 sos24 .

Calculated: C 72.08 H 5.85 N 8.13 Found: 72.04 5.84 7.96 a 2 7 4'-[(2-n-Propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 64% of theory, Melting point: 217-219°C
C39H32N9O2 ( 52 8 . 7 0 ) Calculated: C 77.24 H 6.10 N 10.60 Found: 77.12 6.09 10.75 4'-[(2-n-Propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[(2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 15% of theory, Melting point: 215-217°C
C39H32N8 (552.70) Calculated: C 73.89 H 5.84 N 20.28 Found: 73.66 6.02 20.56 4'-[(2-Cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-B

[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 52% of theory, Melting point: 244-246°C
C33H28N9O2 ( 512 . 6 0 ) Calculated: C 77.32 H 5.51 N 10.93 Found: 77.75 5.71 10.94 4'-[(2-Cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 59% of theory, Melting point: 245-247°C
C33H2eNa (536.65) Calculated: C 73.86 H 5.26 N 20.88 Found: 73.95 5.42 20.90 4'-[(2-Cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 63% of theory, Melting point: 189-191°C
C39H3oN9O2 (526.60) Calculated: C 77.55 H 5.74 N 10.64 - 42 - 2o sos2~
Found: 77.35 5.92 10.40 4'-f(2-Cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-f(2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 61% of theory, Melting point: 197-199°C
C34H3oNe (550.70) Calculated: C 74.16 H 5.49 N 20.35 Found: 74.12 5.74 20.67 4'-f(2-n-Propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-f(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-y)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 34% of theory, Melting point: 250-252°C
C33HZgFNqO2 (532.60) Calculated: C 74.42 H 5.49 N 10.52 Found: 74.14 5.64 10.54 The following compound is obtained analogously to Example 33:
4'-f(2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid 2osos2~ a 4'-[(2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[(2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 16.5% of theory, Melting point: from 275°C (decomp.) C31H2-,N9 x H20 (543.65) Calculated: C 68.49 H 5.38 N 23.19 Found: 68.25 5.50 23.37 The following compound is obtained analogously to Example 34:
4'-[(2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 67% of theory, Melting point: from 240°C (sinters) C32H32NqO2 ( 5 04 . 64 ) Calculated: C 76.16 H 6.39 N 11.10 Found: 75.94 6.46 11.20 a. 2060fi24 The following compounds are obtained analogously to Example 35:
4'-[(2-n-butyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo [1, 2-a] pyridin-2-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid 4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 73.5% of theory, Melting point: from 275°C (decomp.) C32H32N8 ( 5 2 8 . 6 7 ) Calculated: C 72.70 H 6.10 N 21.20 Found: 72.40 6.07 21.48 The following compounds are obtained analogously to Example 36:
4'-[(2-n-butyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl __ 2060624 4'-[(2-n-Propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 76% of theory, Melting point: 243-245°C
C33Hz9FN902 ( 53 2 . 6 0 ) Calculated: 74.42 H 5.49 N 10.52 Found: 74.74 5.52 10.77 Mass spectrum: m/e = 532 4'-[(2-n-Propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 52.7% of theory, Melting point: 292-295°C
C32HZ~CN402 ( 53 5 . 06 ) Rf value: 0.30 (silica gel; methylene chloride/ethanol =
19:1) Calculated: C 71.90 H 5.08 N 10.45 C1 6.63 Found: 71.29 5.21 10.40 6.76 4'-[(2-n-Propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl hydrochloride Prepared analogously to Example 2 from 4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 54.8% of theory, Melting point: sintering from 204°C
C32HZ~C1N8 x HC1 (595.55) Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate - 1:1 and 1% glacial acetic acid) Calculated: C 62.55 H 4.71 N 18.85 C1 11.85 Found: 62.34 4.97 18.84 11.57 4'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl) benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid a) ~-MethX,l-4-butyr~lamino-5-nitro-acetop non 32.6 g (148 mmol) of 3-methyl-4-butyrylamino-acetophenone are added in batches at -15°C to 300 ml of fuming nitric acid with stirring, and stirred for a further 30 minutes at -15°C. The reaction mixture is then poured onto 3 litres of ice, with stirring, the crude product precipitated is suction filtered, washed with 400 ml of water, dried and purified by recrystallisation from ethanol/diethylether (1:1).
Yield: 23.8 g (61.0% of theory), Rf value: 0.32 (silica gel; methylene chloride), Rf value: 0.48 (silica gel; methylene chloride/methanol - 50:1) .

2osos24 b) 3-Methyl-4-butyrylamino-5-nitro-1-bromoacetophenone A solution of 16.0 g (200 mmol) of bromine in 140 ml of dioxane is added dropwise to a solution of 23.8 g (90 mmol) of 3-methyl-4-butyrylamino-5-nitro-acetophenone in 900 ml of dichloromethane at ambient temperature, with stirring, so slowly that total decolorisation of the reaction mixture occurs constantly. The mixture is then stirred for a further two hours, then the reaction mixture is evaporated to dryness in vacuo, the residue obtained is triturated with about 20 ml of dichloromethane/diethylether (1:1), suction filtered and then dried. 23g (74% of theory) of 3-methyl-4-butyrylamino-5-nitro-Z~-bromoacetophenone are thus obtained, still containing about 10% starting material.
The product is further reacted without any more purification.
Rf value: 0.69 (silica gel; methylene chloride/methanol - 50:1) Rf value: 0.84 (silica gel; methylene chloride/methanol - 9:1) .
c) ~-Butvrvlamino-3-nitro-5-(imidazo-4-yl)-toluene A solution of 6.8 g (20 mmol) of 3-methyl-4-butyrylamino-5-nitro-~a-bromoacetophenone in 20 ml of formamide is heated to 140°C for two hours. The cooled solution is then poured into about 50 ml of 1N ammonia and stirred for about 15 minutes. The crude product precipitated is suction filtered, washed with about 50 ml of water and dried. In this way, 4.4 g (75% of theory) of the product are obtained, which is further reacted without any more purification.
Rf value: 0.29 (silica gel; methylene chloride/methanol - 9:1) d) 2-Bud,vrylamino-3-nitro-5-(1-methyl-imidazol-4-yl)-toluene 1.3 g (9.5 mmol) of methyliodide are added dropwise at ambient temperature to a solution of 2.5 g (8.7 mmol) of 2-butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene and 5.2 g (30 mmol) of potassium carbonate dehydrate in 30 ml of dimethylsulfoxide and the mixture is then stirred for two hours. The reaction mixture is then stirred into about 150 ml of water and extracted four times with 25 ml of ethylacetate. The organic extracts are washed with about 30 ml of water, dried and evaporated down.
The crude product thus obtained is purified by column chromatography (300 g of silica gel, eluant: methylene chloride/methanol = 30:1).
Yield: 640 mg (24% of theory), Rf value: 0.54 (silica gel; methylene chloride/methanol - 9:1) e) 640 mg (2.1 mmol) of 2-butyrylamino-3-nitro-5-(1-methyl-imidazol-4-yl)-toluene are hydrogenated in 30 ml of methanol after the addition of about 200 mg of palladium/charcoal (20%) at ambient temperature under a hydrogen pressure of 5 bar. After all the hydrogen has been absorbed the catalyst is removed by filtering and the filtrate is evaporated down. The crude product obtained is further reacted without any more purification.
Yield: 600 mg (100% of theory), Rf value: 0.23 (silica gel; methylene chloride/methanol - 9:1) f) 600 mg (2.1 mmol) of 2-butyrylamino-3-amino-5-(1-methyl-imidazol-4-yl)-toluene are refluxed for one hour in 10 ml of glacial acetic acid. Then the mixture is evaporated to dryness in vacuo, the residue is mixed with about 15 ml of water, made alkaline with ammonia and extracted four times with about 10 ml of ethylacetate. The organic extracts are washed with about 15 ml of water, dried and finally evaporated down.
The crude product thus obtained is further reacted without any more purification.
Yield: 420 mg (79% of theory), Rf value: 0.37 (silica gel; methylene chloride/methanol - 9:1) g) TPrr.buty -4'-280 mg (0.8 mmol) of tert.butyl-4'-bromomethyl-biphenyl-2-carboxylate are added to a solution of 200 mg (0.79 mmol) of 2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole and 90 mg (0.8 mmol) of potassium tert.butoxide in 5 ml of dimethylsulfoxide and the mixture is stirred for 90 minutes at ambient temperature, then stirred into about 40 ml of water, extracted four times with about 10 ml of ethylacetate, then the organic extracts are washed with 10 ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel, eluant:
dichloromethane/methanol = 30:1).
Yield: 230 mg (56% of theory), Rf value: 0.61 (silica gel; methylene chloride/methanol - 9:1) h) A solution of 230 mg (0.44 mmol) of tert.butyl-4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane was stirred overnight at ambient temperature and then evaporated to dryness. The residue was dissolved in f'l about 5 ml of dilute sodium hydroxide solution, the solution was neutralised with acetic acid, the precipitate was suction filtered, washed with water and dried.
Yield: 120 mg (59% of theory);
Melting point: 293-295°C
Rf value: 0.39 (silica gel; methylene chloride/methanol - 9:1) The following compounds are obtained analogously to Example 40:
4'-[(2-n-propyl-4-methyl-6-(1-ethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl) benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 24% of theory, Melting point: 255-257°C
Rf value: 0.24 (silica gel, methylene chloride/methanol =
9:1) CZ9HZ8N8 x H20 (506.62) Calculated: C 68.75 H 5.97 N 22.12 Found: 68.90 5.97 22.03 ri 2o sos24 The following compounds are obtained analogously to Example 41:
4'-[(2-n-propyl-4-methyl-6-(1-ethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl) benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-vl)-bi~henyl Prepared analogously to Example 2 from 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 21% of theory, Melting point: amorphous Rf value: 0.27(silica gel, methylene chloride/ethanol =
9:1) CsiH3oNe ( 514 . 64 ) Calculated: C 72.35 H 5.88 N 21.78 Found: 72.01 5.82 21.44 4'-[(2-n-Propyl-4-methyl-6-(8-methyl-imidazo-[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(8-methyl-imidazo-[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87% of theory, Melting point: 295-297°C
Rf value: 0.34 (silica gel, methylene chloride/ethanol =
9:1) C33H30N9O2 x H20 ( 5 3 2 . 6 5 ) Calculated: C 74.41 H 6.06 N 10.52 Found: 74.81 6.05 10.43 4'-[(2-n-Propyl-4-methyl-6-(2-pyridyl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 2 from 4'-[(2-n-propyl-4-methyl-6-(2-pyridyl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 56% of theory, Melting point: from 136°C (decomp.) C3oH2-,N7 x 0 . 5 H20 ( 4 94 . 6 0 ) Calculated: C 72.85 H 5.71 N 19.83 Found: 72.45 6.01 19.83 4'-((2-n-Propyl-4-methyl-6-(8-methyl-imidazo[1,2-a] pyridin-2-yl) -benzimidazol-1-yl) -methyl] -2- (1H-tetrazol-5-yl)-biahenyl Prepared analogously to Example 2 from 4'-[(2-n-propyl-4-methyl-6-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 19% of theory, Melting point: amorphous Rf value: 0.36 (silica gel, methylene chloride/ethanol =
9:1) ., 2060624 C33H30N8 ( 5 3 8 . 61 ) Mass spectrum: m/e = 538 4'-[(2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-r~arhnxyl i c~ ari r3 Prepared analogously to Example A from tert.butyl 4'-[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 50% of theory, Melting point: > 300°C
Rf value: 0.16 (silica gel, methylene chloride/ethanol =
9:1) 4'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 84% of theory, Melting point: 285-286°C
Rf value: 0.55 (silica gel, methylene chloride/methanol =
9:1) 4'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-hcn~imi ~aa~~i -1 girl) -methyll -2- (1H-tetrazol-5-yl) -bi~henvl Prepared analogously to Example 2 from 4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 18% of theory, Melting point: amorphous Rf value: 0.29 (silica gel, methylene chloride/methanol =
9:1) CsiH3zNs ( 516 . 66 ) Mass spectrum: m/e = 516 4'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl) hPn~im~~a~n1-1-girl)-methyll-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride.
4'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-~'1P1'l7~mi ~a~~1 -1 =yl) -methyll -2- (1H-tetrazol-5-yl) -biphenvl Prepared analogously to Example 2 from 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Ampoules containing 50 mg of active substance per 5 ml Active substance 50 mg KH2P09 2 mg Na2HP04 x 2H20 50 mg NaCl 12 mg Water for injections ~ 5 ml a 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.
Ampoules containing 100 mg of active substance per 5 ml Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene-glycol block polymer 250 mg Water for injections ~ 5 ml 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.
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 ma 200.0 mg w. 2o sos24 The active substance, CaHP04, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50°C in a circulating air dryer and screened again.
After the lubricant has been added, the granules are compressed in a tablet making machine.
Coated tablets containing 50 mg of active substance Active substance 50.0 mg Lysine 25.0 mg Lactose 60.0 mg Corn starch 34.0 g Gelatin 10.0 mg Magnesium stearate 1.0 mg' 180.0 mg The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying the granules are mixed with magnesium stearate and compressed to form tablet cores.
The cores thus produced are covered with a coating by known methods. A colouring may be added to the coating suspension or solution.
i?

Coated tablets containing 100 mg of active substance Active substance 100.0 mg Lysine 50.0 mg Lactose 86.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 2.8 mg Microcrystalline cellulose 60.0 mg Magnesium stearate 1.2 ma 350.0 mg 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 45°C.
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.
Capsules containing 250 mg of active substance Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 ma 320.0 mg 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 gelatine capsules.
Example 57 Oral suspension containing 50 mg of active substance per ml Active substance 50.0 mg Hydroxyethylcellulose 50.0 mg Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg Water ~ 5.0 ml Distilled water is heated to 70°C. Hydroxyethyl-cellulose 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.

2o sos24 Suppositories containing 100 mg of active substance Active substance 100.0 mg Solid fat 1600.0 ma 1700.0 mg The hard fat is melted. At 40°C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38°C and poured into slightly chilled suppository moulds.
;4F

Claims (21)

1. Benzimidazoles of general formula wherein R1 represents a fluorine, chlorine or bromine atom, an alkyl, cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group and R2 represents a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group, optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, wherein a methylene group may be replaced by a carbonyl or sulphonyl group, a malefic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group optionally substituted in the 1-position by C1-6-alkyl or a cycloalkyl group, whilst the phenyl nucleus of the benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group may additionally be substituted by a fluorine atom or by a methyl or trifluoromethyl group, R2 may represent an imidazo
[2,1-b] thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]-pyrimidin-2-yl, imidazo [4, 5-b] pyridin-2-yl, imidazo [4,5-c]-pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]-pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, a pyridyl group or a carbon attached imidazolyl group optionally substituted in the 1-position by an alkyl or benzyl group, and which may also be substituted in the carbon skeleton by an alkyl group, R3 represents a C1-5-alkyl group or a C3-5-cycloalkyl group and R4 represents a carboxy or 1H-tetrazolyl group, and the salts thereof with inorganic or organic acids or bases, whilst, unless otherwise specified, an alkyl moiety as mentioned hereinbefore may in each case contain 1 to 3 carbon atoms and a cycloalkyl moiety mentioned hereinbefore may contain from 3 to 7 carbon atoms.
2. Benzimidazoles of general formula I according to claim 1, wherein R1 represents a chlorine atom, or a C1-3-alkyl or a trifluoromethyl group, R2 represents a 5-, 6- or 7-membered alkyleneimino group wherein a methylene group is replaced by a carbonyl or sulphonyl group, a malefic acid imido group optionally mono- or disubstituted by a C1-3-alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group optionally substituted in the 1-position by a C1-6-alkyl or by a cycloalkyl group, whilst the phenyl nucleus of the benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group may additionally be substituted by a fluorine atom or by a methyl or trifluoromethyl group, or R2 may represent an imidazo [2,1-b] thiazol-6-yl, imidazo [1,2-a] pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]-pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]-pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]-pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, a pyridyl group or an imidazol-4-yl group substituted in the 1-position by a C1-3 alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a C1-3 alkyl group, R3 represents a C1-5-alkyl group or a C3-5-cycloalkyl group and R4 represents a carboxy or 1H-tetrazolyl group, and the salts thereof with inorganic or organic acids or bases.
3. Benzimidazoles of general formula I according to claim 1, wherein R1 represents a methyl group or a chlorine atom and R2 represents a 5-, 6- or 7-membered alkyleneimino group, wherein a methylene group is replaced by a carbonyl or sulphonyl group, a malefic acid imido group optionally mono- or disubstituted by a C1-3-alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group optionally substituted in the 1-position by a C1-3-alkyl group, whilst the phenyl nucleus of the benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl group may additionally be substituted by a fluorine atom, or R2 may represent an imidazo[1,2-a]-pyridin-2-yl group, 5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl, imidazo[1,2-a]-pyrimidin-2-yl or imidazo[2,1-b]thiazol-6-yl group, an imidazol-4-yl group substituted in the 1-position by a C1-3 alkyl group, R3 represents a C1-5-alkyl group or a C3-5-cycloalkyl group and R4 represents a carboxy or 1H-tetrazolyl group, and the salts thereof with inorganic or organic acids or bases.
4. The following benzimidazoles of general formula I
according to claim 1:

(a) 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid, (b) 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (c) 4'-[[2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (d) 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methylbenzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid, (e) 4'-(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, (f) 4'-[(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, (g) 4'-[(2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (h) 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, (i) 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (j) 4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (k) 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid, (1) 4'-([2-ethyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (m) 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (n) 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid, (o) 4'-([2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (p) 4' - [[2-n-propyl-4-methyl-6- (imidazo [2, 1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (q) 4'-[(2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, and (r) 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid, and the salts thereof with inorganic or organic acids or bases.
5. 4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid and the salts thereof with inorganic or organic acids or bases.
6. 4'-[(2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and the salts thereof with inorganic or organic acids or bases.
7. Physiologically acceptable salts of the compounds according to any one of claims 1 to 6 with inorganic or organic acids or bases.
8. Pharmaceutical compositions containing a compound according to any one of claims 1 to 6 or a physiologically acceptable salt according to claim 7 together with an inert carrier or diluent.
9. Use of a compound according to any one of claims 1 to 7 for preparing a pharmaceutical composition with an angiotensin-antagonist activity.
10. Use of a compound according to any one of claims 1 to 6 or a physiologically acceptable salt thereof as an angiotensin-antagonist.
11. Use of a compound according to any one of claims 1 to 6 or a physiologically acceptable salt thereof in the manufacture of a pharmaceutical composition for use as an angiotensin-antagonist.
12. Use of a compound according to any one of claims 1 to 6 or a physiologically acceptable salt thereof for the treatment of hypertension, pulmonary diseases, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic nephropathy, glaucoma, gastrointestinal and bladder diseases or to prevent the progession of cardiac insufficiency after myocardial infarction.
13. Use of a compound according to any one of claims 1 to 6 or a physiologically acceptable salt thereof for the treatment of depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function as well as other central nervous system disorders.
14. Use of a compound according to any one of claims 1 to 6 or a physiologically acceptable salt thereof in the manufacture of a pharmaceutical composition for use in the treatment of hypertension, pulmonary diseases, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic nephropathy, glaucoma, gastrointestinal and bladder diseases or to prevent the progession of cardiac insufficiency after myocardial infarction.
15. Use of a compound according to any one of claims 1 to 6 or a physiologically acceptable salt thereof in the manufacture of a pharmaceutical composition for use in the treatment of depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function as well as other central nervous system disorders.
16. Process for preparing a pharmaceutical composition according to claim 8, characterised in that a compound according to any one of claims 1 to 7 is incorporated in an inert carrier or diluent by a non-chemical method.
17. Process for preparing a benzimidazole according to any one of claims 1 to 7, characterised in that a) a compound of general formula wherein R1 and R2 are defined as in any one of claims 1 to 6, one of the groups X1 or Y1 represents a group of general formula and the other group X1 or Y1 represents a group of the general formula wherein R2 and R4 are defined as in any one of claims 1 to 6, R8 represents a hydrogen atom or an R3CO- group, wherein R3 is as defined in any one of claims 1 to 6, Z1 and Z2, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups or Z1 and Z2 together represent an oxygen or sulphur atom, an optionally C1-3-alkyl substituted imino group, an alkylenedioxy or alkylenedithio group, each having 2 or 3 carbon atoms, but one of the groups X1 or Y1 must represent a group of general formula or is cyclised and a corresponding N-oxide which might thus be obtained is reduced or b) a benzimidazole of general formula wherein R1 to R3 are as defined in any one of claims 1 to 6, is reacted with a biphenyl compound of general formula wherein R4 is as defined in any one of claims 1 to 6 and Z3 represents a nucleophilic leaving group, or c) in order to prepare a compound of general formula I
wherein R4 represents a carboxy group, a compound of general formula wherein R1 to R3 are as defined in any one of claims 1 to 6 and R4' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, is converted into a corresponding carboxy compound or d) in order to prepare a compound of general formula I
wherein R4 represents a 1H-tetrazolyl group, a protecting group is split off from a compound of general formula wherein R1, R2 and R3 are defined as hereinbefore and R4" represents a 1H-tetrazolyl group protected in the 1- or 3- position by a protecting group, or (e) in order to prepare a compound of general formula I
wherein R4 represents a 1H-tetrazolyl group, a compound of general formula wherein R1 to R3 are defined as hereinbefore, is reacted with hydrazoic acid or the salts thereof or (f) in order to prepare compounds of general formula I
wherein R2 represents one of the imidazo[1,2-a]-pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-c]-pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo-[1,2-b]pyridazin-2-yl or imidazo[2,1-b]thiazol-6-yl groups mentioned hereinbefore, a compound of general formula wherein one of the groups A, B, C or D represents an optionally methyl-substituted methine group or a nitrogen atom and the remaining groups A, B, C or D represent methine groups or A and B each represent methine and the -C=D- group represents a sulphur atom, is reacted with a compound of general formula wherein R1, R3 and R4 are as defined in any one of claims 1 to 6 and Z4 represents a nucleophilic leaving group or g) in order to prepare compounds of general formula I
wherein R2 represents one of the benzimidazol-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, imidazo[4,5-d]pyridazin-2-yl or purin-8-yl groups mentioned in any one of claims 1 to 6, a compound of general formula wherein none, one or two of the groups A1, B1, C1 or D1 represents a nitrogen atom and the remaining groups A1, B1, C1 or D1 represent methine groups, R11 represents a hydrogen or fluorine atom or a methyl or trifluoromethyl group, one of the groups X2 or Y2 represents an R13-NH- group and the other X2 or Y2 group represents a group of general formula wherein R1, R3, and R4 are as defined in any one of claims 1 to 6, one of the groups R13 or R14 represents a hydrogen atom and the other R13 or R14 group represents a hydrogen atom, a C1-6-alkyl group or a C3-7-cycloalkyl group, Z5 and Z6, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups or Z5 and Z6 together represent an oxygen or sulphur atom, an optionally C1-3-alkyl-substituted imino group, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms, is cyclised and any corresponding N-oxide which is thus obtained is reduced and a compound thus obtained is subsequently hydrolysed, if required, and if necessary a protecting group used during the reactions a) to g) in order to protect reactive groups is cleaved and if required, an isomer mixture thus obtained is resolved into its isomers, and if required a compound of general formula I thus obtained is converted into a salt thereof.
18. A process according to claim 17 which includes the step of converting an obtained compound of formula I into a physiologically acceptable salt thereof.
19. A process according to claim 17(f) or 18 wherein Z4 represents a chlorine or bromine atom.
20. A commercial package containing, as active ingredient, a compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, together with instructions for its use for the treatment of hypertension, pulmonary diseases, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic nephropathy, glaucoma, gastrointestinal and bladder diseases or to prevent the progression of cardiac insufficiency after myocardial infarction.
21. A commercial package containing, as active ingredient, a compound according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, together with instructions for its use for the treatment of depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function as well as other central nervous system disorders.
CA002060624A 1991-02-06 1992-02-04 Benzimidazoles, pharmaceutical compositions containing these compounds and processes for preparing them Expired - Lifetime CA2060624C (en)

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DE4103492A DE4103492A1 (en) 1991-02-06 1991-02-06 New 1-(1,4-bi:phenyl-methyl) benzimidazole(s) as angiotensin II antagonists
DE4117121A DE4117121A1 (en) 1991-02-06 1991-05-25 BENZIMIDAZOLE, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
DEP4117121.7 1991-05-25
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Families Citing this family (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4225756A1 (en) 1992-01-22 1994-03-10 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
DE4224133A1 (en) * 1992-07-22 1994-01-27 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
DE4224752A1 (en) * 1992-04-11 1994-02-03 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
TW274551B (en) * 1991-04-16 1996-04-21 Takeda Pharm Industry Co Ltd
DE4207904A1 (en) * 1992-03-12 1993-09-16 Thomae Gmbh Dr K SUBSTITUTED BENZIMIDAZOLYL DERIVATIVES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
US5972990A (en) † 1992-04-10 1999-10-26 Brigham And Women's Hospital, Inc. Methods for reducing risk of repeat myocardial infarction and increasing survival in heart attack victims
GB9218449D0 (en) 1992-08-29 1992-10-14 Boots Co Plc Therapeutic agents
DE4315349A1 (en) * 1992-10-06 1994-11-10 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
JP3057471B2 (en) 1993-06-07 2000-06-26 武田薬品工業株式会社 Agent for preventing or treating angiotensin II-mediated diseases
DE4408497A1 (en) * 1994-03-14 1995-09-21 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
MY119312A (en) * 1995-10-06 2005-05-31 Novartis Ag At 1-receptor antagonists for preventing and treating postischemic renal failure and for protecting ischemic kidneys
TW453999B (en) * 1997-06-27 2001-09-11 Fujisawa Pharmaceutical Co Benzimidazole derivatives
DE69838042T2 (en) * 1997-10-17 2008-03-06 Ark Therapeutics Ltd. Use of inhibitors of the renin-angiotensin system
WO1999047512A1 (en) * 1998-03-16 1999-09-23 Colgene Corporation 2-(2,6-dioxopiperidin-3-yl)isoindoline derivatives, their preparation and their use as inhibitors of inflammatory cytokines
WO2000027397A1 (en) * 1998-11-06 2000-05-18 Glaxo Group Limited Antihypertensive medicaments containing lacidipine and telmisartan
EP1013273A1 (en) * 1998-12-23 2000-06-28 Novartis AG Use of AT-1 receptor antagonist or AT-2 receptor modulator for treating diseases associated with an increase of AT-1 or AT-2 receptors
NZ553010A (en) * 1998-12-23 2008-09-26 Novartis Ag Use of AT-1 receptor antagonist or AT-2 receptor modulator for treating diseases associated with an increase of AT-1 or AT-2 receptors
DE19901921C2 (en) * 1999-01-19 2001-01-04 Boehringer Ingelheim Pharma Polymorphs of telmisartan, process for their preparation and their use in the manufacture of a medicament
US6358986B1 (en) 1999-01-19 2002-03-19 Boehringer Ingelheim Pharma Kg Polymorphs of telmisartan
SE9903028D0 (en) 1999-08-27 1999-08-27 Astra Ab New use
PE20020617A1 (en) 2000-08-22 2002-08-05 Novartis Ag COMPOSITION INCLUDING AN AT1 RECEPTOR ANTAGONIST AND AN INSULIN SECRETION POTENTIAL OR AN INSULIN SENSITIZER
US6737432B2 (en) 2001-10-31 2004-05-18 Boehringer Ingelheim Pharma Kg Crystalline form of telmisartan sodium
DE10153737A1 (en) * 2001-10-31 2003-05-28 Boehringer Ingelheim Pharma Crystalline sodium salt of telmisartan, process for its preparation and its use for the manufacture of a medicament
ME02761B (en) 2002-01-16 2011-05-10 Boehringer Ingelheim Pharma Bilayer pharmaceutical tablet comprising telmisartan and a diuretic and preparation thereof
EG24716A (en) 2002-05-17 2010-06-07 Novartis Ag Combination of organic compounds
DE10335027A1 (en) 2003-07-31 2005-02-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of telmisartan and simvastatin for treatment or prophylaxis of cardiovascular, cardiopulmonary and renal diseases e.g. hypertension combined with hyperlipidemia or atherosclerosis
DE10306179A1 (en) 2003-02-13 2004-08-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Composition useful for preventing stroke comprises dipyridamole or its salt, acetyl salicylic acid and an angiotensin II antagonist
DE10314702A1 (en) 2003-03-31 2004-10-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for the preparation of telmisartan
DE10319450A1 (en) * 2003-04-30 2004-11-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical formulation of telmisartan sodium salt
US9029363B2 (en) 2003-04-30 2015-05-12 Boehringer Ingelheim International Gmbh Telmisartan sodium salt pharmaceutical formulation
DE10319592A1 (en) * 2003-05-02 2004-11-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Treatment of diabetic retinopathy with angiotensin II receptor blockers
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
GB0316546D0 (en) 2003-07-15 2003-08-20 Novartis Ag Process for the manufacture of organic compounds
AU2004293013B2 (en) 2003-11-19 2011-04-28 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
GB2414019A (en) * 2004-05-11 2005-11-16 Cipla Ltd One-step preparation of telmisartan by condensation and hydrolysis
KR20080112424A (en) 2004-10-15 2008-12-24 테바 파마슈티컬 인더스트리즈 리미티드 How to prepare telmisartan
NZ555325A (en) 2004-10-27 2009-07-31 Daiichi Sankyo Co Ltd Benzene compound having 2 or more substituents
ITMI20050801A1 (en) 2005-05-03 2006-11-04 Dipharma Spa PROCEDURE FOR THE PREPARATION OF TELMISARTAN
WO2006136916A2 (en) * 2005-06-20 2006-12-28 Glenmark Pharmaceuticals Limited Substantially pure micronized particles of telmisartan and pharmaceutical compositions containing same
US7884214B2 (en) * 2005-07-19 2011-02-08 Matrix Laboratories Limited Process for the preparation of Telmisartan
ES2246742B1 (en) * 2005-09-06 2007-02-01 Prous Institute For Biomedical Research S.A. USE OF A DERIVATIVE OF IMIDAZOLE.
EP1908469A1 (en) 2006-10-06 2008-04-09 Boehringer Ingelheim Vetmedica Gmbh Angiotensin II receptor antagonist for the treatment of systemic diseases in cats
US8242151B2 (en) 2007-02-07 2012-08-14 Kyowa Hakko Kirin Co., Ltd. Tricyclic compounds
FR2916757B1 (en) * 2007-05-30 2009-07-17 Servier Lab NOVEL DIAZENIUMDIOLATE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
EP2998314B1 (en) 2007-06-04 2020-01-22 Bausch Health Ireland Limited Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
TWI406850B (en) * 2007-06-05 2013-09-01 Theravance Inc Dual-acting benzoimidazole antihypertensive agents
EA200901619A1 (en) * 2007-07-03 2010-04-30 Крка, Товарна Здравил, Д. Д., Ново Место METHOD OF OBTAINING TELMISARTANA
ATE555099T1 (en) * 2007-12-11 2012-05-15 Theravance Inc DUAL-ACTING BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS ANHYDROGENIC PRESSURE LOWERING AGENTS
EP2103609A1 (en) 2008-03-20 2009-09-23 Lek Pharmaceuticals D.D. Catalyzed carbonylation in the synthesis of angiotensin ii antagonists
EP2103588A1 (en) 2008-03-20 2009-09-23 Lek Pharmaceuticals D.D. 2'-Halobiphenyl-4-yl intermediates in the synthesis of angiotensin II antagonists
PL2279159T3 (en) * 2008-03-20 2014-05-30 Lek Pharmaceuticals 2'-halobiphenyl-4-yl intermediates in the synthesis of angiotensin ii antagonists
WO2009123483A1 (en) 2008-03-31 2009-10-08 Zaklady Farmaceutyczne Polpharma Sa Process for preparation of telmisartan
WO2009135646A2 (en) 2008-05-05 2009-11-12 Farmaprojects, Sa Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale
EP2123648A1 (en) 2008-05-20 2009-11-25 Chemo Ibérica, S.A. A process for the preparation of Telmisartan.
EP2328910B1 (en) 2008-06-04 2014-08-06 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2010004385A1 (en) * 2008-06-17 2010-01-14 Aurobindo Pharma Limited Process for the preparation of pure 4'-[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid
EP2149566A1 (en) 2008-07-15 2010-02-03 Chemo Ibérica, S.A. A process for the preparation of telmisartan
CA2730603C (en) 2008-07-16 2019-09-24 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8486980B2 (en) 2008-08-06 2013-07-16 Kyowa Hakko Kirin Co., Ltd. Tricyclic compound
WO2010093601A1 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use
WO2010146187A2 (en) 2009-06-19 2010-12-23 Krka, Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of telmisartan
EP2277866A1 (en) 2009-06-22 2011-01-26 Inke, S.A. Process for preparing telmisartan
EP2448575A2 (en) 2009-07-02 2012-05-09 Bilgic Mahmut Pharmaceutical composition increasing solubility and stability
EP2448576A2 (en) 2009-07-02 2012-05-09 Mahmut Bilgic Solubility enhancing pharmaceutical composition
TR200906506A2 (en) 2009-08-24 2011-03-21 Bi̇lgi̇ç Mahmut Solid dosage forms containing telmisartan.
EP2305650A1 (en) 2009-09-21 2011-04-06 Chemo Ibérica, S.A. Novel process for the preparation of telmisartan
CN101798300B (en) * 2010-02-23 2013-09-25 陈志龙 N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like
EP2575808A1 (en) 2010-05-28 2013-04-10 Mahmut Bilgic Combination of antihypertensive agents
WO2011161123A2 (en) 2010-06-21 2011-12-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Multilayer pharmaceutical tablet comprising telmisartan and a diuretic
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
WO2012055941A1 (en) 2010-10-27 2012-05-03 Krka,Tovarna Zdravil, D. D., Novo Mesto Multilayer pharmaceutical composition comprising telmisartan and amlodipine
MX2014002163A (en) 2011-08-26 2014-09-25 Wockhardt Ltd Methods for treating cardiovascular disorders.
EP2612658A1 (en) 2012-01-05 2013-07-10 Laboratorios Lesvi, S.L. Pharmaceutical compositions of 4'-[(1,4'dimethyl-2'-propyl[2,6'-bi-1h-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid and is 6-chloro-3,4-dihydro-2h-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
EP2968439A2 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
RS65632B1 (en) 2013-06-05 2024-07-31 Bausch Health Ireland Ltd Ultra-pure agonists of guanylate cyclase c, method of making and using same
CN105473581B (en) 2013-06-21 2019-04-23 齐尼思表观遗传学有限公司 The dicyclic compound newly replaced as bromine structural domain inhibitor
CN109939113B (en) * 2013-06-21 2022-02-15 恒翼生物医药科技(上海)有限公司 Bicyclic bromodomain inhibitors
JP6542212B2 (en) 2013-07-31 2019-07-10 ゼニス・エピジェネティクス・リミテッドＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｌｔｄ． Novel quinazolinones as bromodomain inhibitors
EP2979691A1 (en) 2014-07-30 2016-02-03 Boehringer Ingelheim International GmbH Oral disintegrating tablet
EP3227281A4 (en) 2014-12-01 2018-05-30 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
CA2966449A1 (en) 2014-12-11 2016-06-16 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
JP2017538721A (en) 2014-12-17 2017-12-28 ゼニス・エピジェネティクス・リミテッドＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｌｔｄ． Bromodomain inhibitors
JP5871294B1 (en) 2015-02-27 2016-03-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Immediate release oral tablets
KR20170001921A (en) 2015-06-26 2017-01-05 대원제약주식회사 A pharmaceutical composition comprising telmisartan with increased stability and a preparation method thereof
KR20170012703A (en) 2015-07-22 2017-02-03 대원제약주식회사 A pharmaceutical composition comprising telmisartan and a preparation method thereof
JP6411662B2 (en) 2016-05-30 2018-10-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Fixed volume formulation
KR101872726B1 (en) 2016-07-28 2018-06-29 주식회사 씨트리 Telmisartan methanesulfonate and pharmaceutical composition comprising the same
CA3067918A1 (en) 2017-07-07 2019-01-10 Boehringer Ingelheim Vetmedica Gmbh Angiotensin ii receptor antagonish for the prevention or treatment of hypertension in cats
AU2019241702B2 (en) * 2018-03-30 2023-07-27 Orizuru Therapeutics, Inc Heterocyclic compound
WO2023001880A1 (en) 2021-07-22 2023-01-26 Krka, D. D., Novo Mesto Bilayer tablet comprising telmisartan and indapamide
EP4412660A1 (en) * 2021-10-04 2024-08-14 Bolt Biotherapeutics, Inc. Asymmetric bis-benzimidazole sting agonist immunoconjugates and uses thereof
TW202508593A (en) 2023-05-24 2025-03-01 德商百靈佳殷格翰維美迪加股份有限公司 Combination treatment and/or prevention of cardiac diseases in non-human mammals comprising one or more sglt-2 inhibitors and pimobendan and/or telmisartan
TW202508455A (en) 2023-05-24 2025-03-01 德商百靈佳殷格翰維美迪加股份有限公司 Combination treatment and/or prevention of renal diseases and/or hypertension in non-human mammals comprising one or more sglt-2 inhibitors and telmisartan
US20250195525A1 (en) 2023-12-15 2025-06-19 Boehringer Ingelheim Vetmedica Gmbh Angiotensin ii receptor antagonist for the prevention of systemic diseases in cats

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4880804A (en) * 1988-01-07 1989-11-14 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking benzimidazoles
DE3928177A1 (en) * 1989-04-08 1991-02-28 Thomae Gmbh Dr K BENZIMIDAZOLE, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
EP0400835A1 (en) * 1989-05-15 1990-12-05 Merck & Co. Inc. Substituted benzimidazoles as angiotensin II antagonists
IE64514B1 (en) * 1989-05-23 1995-08-09 Zeneca Ltd Azaindenes
GB8911854D0 (en) * 1989-05-23 1989-07-12 Ici Plc Heterocyclic compounds
IL94390A (en) * 1989-05-30 1996-03-31 Merck & Co Inc Di-substituted imidazo fused 6-membered nitrogen-containing heterocycles and pharmaceutical compositions containing them
IE70593B1 (en) * 1989-09-29 1996-12-11 Eisai Co Ltd Biphenylmethane derivative the use of it and pharmacological compositions containing same
US5196444A (en) * 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
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

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IE920373A1 (en) 1992-08-12
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