CA2089689A1 - Substituted biphenylyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents

Substituted biphenylyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them

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Publication number
CA2089689A1
CA2089689A1 CA002089689A CA2089689A CA2089689A1 CA 2089689 A1 CA2089689 A1 CA 2089689A1 CA 002089689 A CA002089689 A CA 002089689A CA 2089689 A CA2089689 A CA 2089689A CA 2089689 A1 CA2089689 A1 CA 2089689A1
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Prior art keywords
group
denotes
imidazol
methyl
substituted
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Abandoned
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CA002089689A
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French (fr)
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 DE19924204968 external-priority patent/DE4204968A1/en
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Publication of CA2089689A1 publication Critical patent/CA2089689A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Abstract The invention relates to substituted biphenylyl derivatives of general formula

Description

S013104J.40 DR.. KARL THOMAE GMBH Case 5/1084-FL
D-7950 Biberach 1 Foreign filing text Substituted biphenylyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them The present invention relates to new substituted biphenylyl derivatives of general formula A ~ ~ Ra CH2~Rc X (CH2)n Rb (I) the mixtures of position isomers thereof and the salts thereof, particularly, for pharmaceutical use, the physiologically acceptable salts thereof with inorganic or organic acîds or bases, which have valuable pharmacological properties, particularly angiotensin-antagonistic effects, preferably angiotensin-II-antagonistic effects.

In the above general formula n denotes the number 0, 1, 2 or 3 and X denotes a bond or n denotes the number 1, 2 or 3 and , .

X denotes an imino group optionally substituted by a Cl3-alkyl group, or an oxygen or sulphur atom, A denotes a 1,4-butadienylene group which is substituted by the groups Rt and R2 and wherein, additionally, an unsubstituted methine group may be replaced by a nitrogen atom, whilst R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group or a Ct3-alkyl group and R2 denotes a hydrogen atom, a Cl3-alkyl group, a C25-alkoxy group which is substituted in the 2-, 3-, 4- or 5-position by an imidazolyl, benzimidazolyl or tetrahydrobenzimidazolyl group, an alkanoylamino group having 2 to 5 carbon atoms in the alkanol moiety or a benzenesulphonylamino group, both of which may be substituted at the nitrogen atom by a C13-alkyl group, a phthalimino or homophthalimino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene group, a 5-, 6- or 7-membered alkyleneimino group in which a methylene group may be replaced by a carbonyl or sulphonyl group, a glutaric acid imino group wherein the n-propylene group may be substituted by one or two C13-alkyl groups or by a tetramethylene or pentamethylene group, a maleic acid imido group optionally mono- or ,, . ~
, . '' ' ' '`, ' `

.

disubstituted by a C13-alkyl group or by a phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl group optionally substituted in the l--position by a C16-alkyl group or a C37-cycloalkyl group, wherein the phenyl nucleus in a benzimidazol-2-yl group as mentioned above may additionally be substituted by a fluorine atom or by a methyl or trifluoromethyl group, an imidazol[2,1-b]thiazol-6-yl, imidazo[1,2-alpyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo~l,2-c]pyrimidin-2-yl, imidazo-[1,2-a]pyrazin-2-yl, imidazo[l,2-b]pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazot4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, whilst a phenyl group may be fused onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl or sulphonyl group r an imidazol-4-yl group optionally substituted in the 2-position by a C16-alkyl group or by a phenyl group and possibly substituted in the l-position by a C17-alkyl group which may be substituted in the 2-, 3-, 4-, 5-, 6-or 7-position by a carbo~y, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or l-oxido-thiomorpholinocarbonyl group, by a C14-alkyl group substituted in the 2-, 3- or 4-position by a hydroxy, alkoxy or imidazol-l-yl group, by an alkyl group which may be substituted by a trifluoromethyl or a C3 7-cycloalkyl group or by a phenyl group optionally mono-:' . . ' ' . . ~ ~ ' , - , -', or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, by an alkyl group substituted by two phenyl groups or by a C3 7-cycloalkyl group, whilst unless otherwise specified the above-mentioned alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms, a group which may be converted in vivo into a carboxy group, a carbonyl group which is substituted by a hydroxy group, by a Cl6-alkoxy group, wherein the methoxy group is additionally substituted by an alkanoyloxy, alkoxycarbonyloxy or cycloalkoxycarbonyloxy group, or by an amino group optionally mono- or disubstituted by alkyl groups, whilst in the above-mentioned groups the alkanoyl moiety may contain 2 or 3 carbon atoms, the alkyl and alkoxy moieties may each contain 1 to 6 carbon atoms and the cycloalkoxy moiety may contain 5 to 7 carbon atoms, or an R5-NR4-CO-NR3- group wherein R3 denotes a hydrogen atom, a C15-alkyl group or a cyclohexyl or benzyl group, R4 denotes a hydrogen atom~ a C16-alkyl group, an allyl, cyclohexyl, benzyl or phenyl group, R5 denotes a hydrogen atom or a Cl3-alkyl group or R4 and R5 together with ~he nitrogen atom between them denote an unbranched C4 5-cycloalkyleneimino group or a morpholino group or R3 and R4 together denote a C23-alkylene group, Ra denotes a C15-alkyl group, a C35-cycloalkyl group, an ., . . ~
: ': - . ' ' ' , ;
. .

alkoxy, alkylthio or alkylamino group each having 1 to 3 carbon atoms in each alkyl moiety, Rb denotes a group which may be converted into a carboxy group in vivo, a carboxy, cyano, hydroxysulphonyl, lH-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group, an alkanecarbonylaminosulphonyl, benzoylaminosulphonyl, alkanesulphonylaminocarbonyl, trifluoromethanesulphonyl-aminocarbonyl or phenylsulphonylaminocarbonyl group or, if n denotes the number 1 and X represents a bond, a bis(hydroxycarbonyl)methyl or bis(alkoxycarbonyl)methyl group, whilst in the above-mentioned groups the alkyl and alkoxy moieties may each contain 1 to 4 carbon atoms, and Rc denotes a hydrogen, fluorine, chlorine or bromine atom, a C14-alkyl group, an alkoxy, nitro, amino, alkylamino or dialkylamino group each having 1 to 3 carbon atoms in each alkyl moiety, whilst the phenyl nucleus of the above-mentioned phenyl groups may be mono- or disubstituted by chlorine or bromine atoms or by methyl or methoxy groups and the substituents may be identical or different.

The phrase "a group which may be converted into a carboxy group n yivo" indicates, for example, the esters of the formulae - CO - OR~, - CO - O - (HCR") - O - CO - R"' and - CO - O - (HCR") - O - CO - OR'I' wherein R' denotes a straight-chained or branched C16-alkyl group, a C57-cycloalkyl group, a benzyl, l-phenylethyl, :
.

- 6 - 20~9689 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, Rr' denotes a hydrogen atom or a methyl group and R"' denotes a strai~ht-chained or branched Cl6-alkyl group, a Cs7-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group.

The new compounds of formula I above have valuable properties. Thus, the compounds of formula I wherein Rb denotes a group which may be converted into a carboxy group n vivo, a carboxy, hydroxysulphonyl, lH-tetrazolyl, alkanecarbonylaminosulphonyl, benzoylaminosulphonyl, alkanesulphonylaminocarbonyl, trifluoromethanesulphonylaminocarbonyl or phenylsulphonylaminocarbonyl group or, if n indicates the number 1 and X denotes a bond, a bis(hydroxycarbonyl)methyl or bis(alkoxycarbonyl)methyl group, have in particular valuable pharmacological properties since they are angiotènsin-antagonists, especially angiotensin~II-antagonists. The other compounds of general formula I are valuable intermediate products for preparing the above-mentioned compounds.

The present invention thus relates to the new benzimidazol-l-yl, imidazo[4,5-b)pyridin-1-yl, imidazo[4,5-c~pyridin-1-yl, imidazo~4,5-b]pyridin-3-yl and imidazo[4,5-c]pyridin-3-yl-biphenylmethyl derivatives of the above general formula I, the mixtures of position isomers thereof and the salts thereof, more particularly for pharmaceutical use the compatible salts thereof, and processes for preparing them.

The present invention thus also relates to new -pharmaceutical compositions which contain one of the above-mentioned pharmacologically active compounds of 2~8~6~9 general formula I or a correspon~ing physiologically acceptable salt, and are suitable particularly for the treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina) and for preventing the progression of cardiac insufficiency after myocardial infarct, for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.

As examples of the groups Ra to Rb and X given hereinbefore, R~ may denote, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methyl-n-propyl, 2-methyl-n-propyl, tert.butyl, n-pentyl, l-methyl-1-butyl, 2-methyl-l-butyl, 3-methyl-1-butyl, 1,1-dimethyl-1-propyl, 2,2-dimethyl-1-propyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, ethylthio, n-propylthio, isopropylthio, methylamino, ethylamino, n-propylamino or isopropylamino group, Rb may denote a hydroxycarbonyl, hydroxysulphonyl, cyano, lH-tetrazolyl, l-triphenylmethyl-tetrazolyl, 2-triphenylmethyl-tetrazolyl, trifluoromethanesulphonyl-aminocarbonyl, methanesulphonylaminocarbonyl, ethanesulphonylaminocarbonyl, n-propanesulphonyl-aminocarbonyl, isopropanesulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, 4-fluorophenylsulphonyl-aminocarbonyl, 4-chlorophenylsulphonylaminocarbonyl, 4-bromophenylsulphonylaminocarbonyl, 4-methylphenylsulphonylaminocarbonyl, 4-methoxyphenylsulphonylaminocarbonyl, methylcarbonylaminosulphonyl, ethylcarbonylamino-sulphonyl, n-propylcarbonylaminosulphonyl-, n-butylcarbonylaminosulphonyl, benzoylaminosulphonyl, - 8 - 2~:8~8:~
bis(hydroxycarbonyl)methyl, bis(methoxycarbonyl)methyl, bi.s(ethoxycarbonyl)methyl, bis(n-propoxycarbonyl)methyl or bis(isopropoxycarbonyl)methyl group, Rc may denote a hydrogen, fluorine, chlorine or bromine atom, or a methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, l-methyl-n-propyl, 2-methyl-n-propyl, tert.butyl, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino or N-ethyl-methylamino group, X may denote a bond, an oxygen or sulphur atom, an imino, methylimino, ethylimino, n-propylimino or isopropylimino group, R1 may denote a hydrogen, fluorine, chlorine or bromine atom, or a methyl, ethyl, n-propyl, isopropyl or trifluoromethyl group, R2 may denote a hydrogen atom, an acetylamino, propionylamino, butanoylamino, pentanoylamino, benzoylamino, N-acetyl-methylamino, N-propionyl-methylamino, N-butanoyl-methylamino, N-pentanoyl-methylamino, N-benzoyl-methylamino, N-acetyl-ethylamino, N-propionyl-ethylamino, N-butanoyl-ethylamino, N-pentanoyl-ethylamino, N-benzoyl-ethylamino, N-acetyl-isopropylamino, N-propionyl-n-propylamino, N-butanoyl-n-propylamino, N-pentanoyl-isopropylamino, N-benzoyl-isopropylamino, 2-(imidazol-1-yl)-ethoxy, 3-(imidazol-1-yl)-propoxy, 4-(imidazol-1-yl)-butoxy, 5-(imidazol-1-yl)-pentoxy, 2-(benzimidazol-1-yl)-ethoxy, 3-(benz-imidazol-l-yl)-propoxy, 4-(benzimidazol-1-yl)-butoxy, 5-(benzimidazol-l-yl)-pentoxy, 2-(tetrahydrobenzimidazol-l-yl)-ethoxy, 3-(tetrahydrobenzimidazol-1-yl)-propoxy, 4-(tetrahydrobenzimidazol-1-yl)-butoxy, 5-:

-2~8~9 (tetrahydrobenzimidazol-l-yl)-pentoxy, acetylamino, propionylamino, butanoylamino, isobutanoylamino, pentanoylamino, phthalimino, homophthalimino, 1-oxo-isoindolin-2-yl, pyrrolidino, piperidino, hexamethyleneimino, 2-oxo-pyrrolidino, 2-oxo-piperidino, 2-oxo-hexamethyleneimino, propanesultam-l-yl, butanesultam-l-yl, pentanesultam-1-yl, glutarimino, 3,3-tetramethylene-glutarimino, 3,3-pentamethylene-glutarimino, 2,2-dimethyl-glutarimino, 3-methyl-glutarimino, 3,3-dimethyl-glutarimino, 3-ethyl-glutarimino, 3-ethyl-3-methyl-glutarimino, 1,3-cyclopentanedicarbonylimino, 2,4-dimethyl-glutarimino, 2,4-di-n-propyl-glutarimino, maleic acid imido, 2-methyl-maleic acid imido, 2-phenyl-maleic acid imido, 2,3-dimethyl-maleic acid imido, 3-methyl-2-phenyl-maleic acid imido, 2,3-diphenyl-maleic acid amido, pyrrolidin-2-yl, pyrrolidin-2-on-5-yl, piperidin-2-yl, piperidin-2-on-l-yl, piperidin-2-on-6-yl, pyridin-2-yl, quinolin-2-yl, isoquinolin-l-yl, isoquinolin-3-yl, 1-methyl-imidazol-4-yl, 1-ethyl-imidazol-4-yl, l-n-propyl-imidazol-4-yl, 1-isopropyl-imidazol-4-yl, 1-n-butyl-imidazol-4-yl, 1-isobutyl-imidazol-4-yl, l-n-pentyl-imidazol-4--yl, 1-isoamyl-imidazol-4-yl, l-n-hexyl-imidazol-4-yl, 1-n-hexyl-2-methyl-imidazol-4-yl, 1-(1-methyl-n-pentyl)-imidazol-4-yl, 1-(1-ethyl-n-butyl)-imidazol-4-yl, 1-~1-methyl-n-hexyl)-imidazol-4-yl, 1-(1-ethyl-n-pentyl)-imidazol-4-yl, l-(1-n-propyl-n-butyl)-imidazol-4-yl, 1-n-heptyl-imidazol-4-yl, 1-ethyl-2-methyl-imidazol-4-yl, 1-n-propyl-2-methyl-imidazol-4-yl, 1-isopropyl-2-methyl-imidazol-4-yl, 1-n-butyl-2-methyl-imidazol-4-yl, 1-isobutyl-2-methyl-imidazol-4-yl, l-n-pentyl-2-methyl-imidazol-4-yl, 1-isoamyl-2-methyl-imidazol-4-yl, 1-n-hexyl-2-methyl-imidazol-4-yl, l-n-heptyl-2-methyl-imidazol-4-yl, l-cyclopropyl-methyl-imidazol-4-yl, 1-cyclobutylmethyl-imidazol-4-yl, 1-cyclopentylmethyl-imidazol-4-yl, l-cyclohexylmethyl-imidazol-4-yl, 1-cycloheptylmethyl-imidazol-4-yl, 1-(2-.

~`~89~89 cyclopropylethyl)-imidazol-4-yl, 1-(2-cyclobutylethyl)-imidazol-4-yl, 1-(2-cyclopentylethyl)-imidazol-4-yl, 1-(2-cyclohexylethyl)-imidazol-4-yl, 1-(2-cycloheptylethyl)-imidazol-4-yl, 1-(3-cyclopropylpropyl)-imidazol-4-yl, 1-(3-cyclobutylpropyl)-imidazol-4-yl, 1-(3-cyclopentylpropyl)-imidazol-4-yl, 1-(3-cyclohexylpropyl)-imidazol-4-yl, 1-(3-cycloheptylpropyl)-imidazol-4-yl, 1-(2,2,2-trifluoroethyl)-imidazol-4-yl, 1-(3,3,3-trifluoropropyl)-imidazol-4-yl, 1-benzyl-imidazol-4-yl, 1-(2-phenylethyl)-imidazol-4-yl, 1-(3-phenyl-propyl)-imidazol-4-yl, 1-(4-fluoro-benzyl)-imidazol-4-yl, 1-(4-chloro-benzyl)-imidazol-4-yl, 1-(3-chloro-benzyl)-imidazol-4-yl, 1-(4-trifluoromethyl-benzyl)-imidazol-4-yl, l-(3-methyl-benzyl)-imidazol-4-yl, 1-(4-methyl-benzyl)-imidazol-4-yl, 1-(3-methoxy-benzyl)-imidazol-4-yl, l-(4-methoxy-benzyl)-imidazol-4-yl, 1-(3,4-dimethoxy-benzyl)-imidazol-4-yl, 1-(3,~-dimethoxy-benzyl)-imidazol-4-yl, 1-cyclopropylmethyl-2-methyl-imidazol-4-yl, 1-cyclobutylmethyl-2-methyl-imidazol-4-yl, l-cyclopentylmethyl-2-methyl-imidazol-4-yl, 1-cyclohexylmethyl-2-methyl-imidazol-4-yl, l-cyclo-heptylmethyl-2-methyl-imidazol-4-yl, 1-(2-cyclopropylethyl)-2-methyl-imidazol-4-yl, 1-(2-cyclobutylethyl)-2-methyl-imidazol-4-yl, 1-(2-cyclopentylethyl)-2-methyl-imidazol-4-yl, 1-(2-cyclohexylethyl)-2-methyl-imidazol-4-yl, 1-(2-cycloheptylethyl)-2-methyl-imidazol-4-yl, 1-(3-cyclopropylpropyl)-2-methyl-imidazol-4-yl, 1-(3-cyclobutylpropyl)-2-methyl-imidazol-4-yl, 1-(3-cyclopentylpropyl)-2-methyl-imidazol-4-yl, 1-(3-cyclohexylpropyl)-2-methyl-imidazol-4-yl, 1-(3-cycloheptylpropyl)-2-methyl-imidazol-4-yl, 1-(2,2,2-trifluoroethyl)-2-methyl-imidazol-4-yl, 1-(3,3,3-trifluoropropyl)-2-methyl-imidazol-4-yl, 1-benzyl-2-methyl-imidazol-4-yl, 1-(2-phenylethyl)-2-methyl-' ~

, .. . , - . : , , 208~g9 imidazol-4-yl, 1-(3-phenyl-propyl)-2-methyl-imidazol-4-yl, 1-(4-fluoro-benzyl)-2-methyl-imidazol-4-yl, 1-(4-chloro-benzyl)-2-methyl-imidazol-4-yl, 1-(3-chloro-benzyl)-2-methyl-imidazol-4-yl, 1-(4-trifluoromethyl-benzyl)-2-methyl-imidazol-4~yl, 1-(3-methyl-benzyl)-2-methyl-imidazol-4-yl, 1-(4-methyl-benzyl)-2-methyl-imidazol-4-yl, 1-(3-methoxy-benzyl)-2-methyl-imidazol-4-yl, l-(4-methoxy-benzyl)-2-methyl-imidazol-4-yl, 1-(3,4-dimethoxy-benzyl)-2-methyl-imidazol-4-yl, 1-(3,5-dimethoxy-benzyl)-2-methyl-imidazol-4-yl, 1-carboxymethyl-imidazol-4-yl, 1-(2-carboxyethyl)-imidazol-4-yl, 1-(3-carboxypropyl)-imidazol-4-yl, 1-(4-carboxybutyl)-imidazol-4-yl, 1-(5-carboxypentyl)-imidazol-4-yl, 1-(6-carboxyhexyl)-imidazol-4-yl, 1-(7-carboxyheptyl)-imidazol-4-yl, l-methoxycarbonylmethyl-imidazol-4-yl, 1-(2-methoxycarbonylethyl)-imidazol-4-yl, 1-(3-methoxycarbonylpropyl)-imidazol-4-yl, 1-(4-methoxycarbonylbutyl)-imidazol-4-yl, 1-(5-methoxycarbonylpentyl)-imidazol-4-yl, 1-(6-methoxycarbonylhexyl)-imidazol-4-yl, 1-(7-methoxycarbonylheptyl)-imidazol-4-yl, 1-ethoxycarbonyl-methyl-imidazol-4-yl, 1-(2-ethoxycarbonylethyl)-imidazol-4-yl, 1-(3-ethoxycarbonylpropyl)-imidazol-4-yl, 1-(4-ethoxycarbonylbutyl)-imidazol-4-yl, 1-(5-ethoxycarbonylpentyl)-im.idazol-4-yl, 1-(6-ethoxycarbonylhexyl)-imidazol-4-yl, 1-(7-ethoxycarbonylheptyl)-imidazol-4-yl, l-n-propoxycarbonylmethyl-imidazol-4-yl, 1-(2-n-propoxycarbonylethyl)-imidaæol-4-yl, 1-(3-n-propoxycarbonylpropyl)-imidazol-4-yl, 1-(4-n-propoxycarbonylbutyl)-imidazol-4-yl, 1-(5-n-propoxy-carbonylpentyl)-imidazol-4-yl, 1-(6-n-propoxycarbonylhexyl)-imidazol-4-yl, 1-(7-n-propoxycarbonylheptyl)-imidazol-4-yl, 1-isopropoxycarbonylmethyl-imidazol-4-yl, 1-(2-isopropoxy-carbonylethyl)-imidazol-4-yl, 1-(3-isopropoxycarbonylpropyl)-imidazol-4-yl, 1-(4-, .~.
` -208~6~

isopropoxycarbonylbutyl)-imidazol-4-yl, 1-(5-isopropoxycarbonylpentyl)-imidazol-4-yl, 1-(6-isopropoxycarbonylhexyl)-imidazol-4-yl, 1-(7-isopropoxycarbonylheptyl)-imidazol-4-yl, 1-aminocarbonylmethyl-imidazol-4-yl, 1-(2-aminocarbonylethyl)-imidazol-4-yl, 1-(3-amino-carbonylpropyl)-imidazol-4-yl, 1-(4-aminocarbonylbutyl)-imidazol-4-yl, 1-(5-aminocarbonylpentyl)-imidazol-4-yl, 1-(6-aminocarbonylhexyl)-imidazol-4-yl, 1-(7-aminocarbonylheptyl)-imidazol-4-yl, 1-methylaminocarbonylmethyl-imidazol-4-yl, 1-(2-methylami~ocarbonylethyl)-imidazol-4-yl, 1-(3-methylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-methylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-methylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-methylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-methylaminocarbonylheptyl)-imidazol-4-yl, 1-ethylaminocarbonylmethyl-imidazol-4-yl, 1-(2-ethylamino-carbonylethyl)-imidazol-4-yl, 1-(3-ethylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-ethylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-ethylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-ethylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-ethylaminocarbonylheptyl)-imidazol-4-yl, l-n-propylaminocarbonylmethyl-imidazol-4-yl, 1-(2-n-propylaminocarbonylethyl)-imidazol-4-yl, 1-(3-n-propylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-n-propylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-n-propylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-n-propylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-n-propylaminocarbonylheptyl)-imidazol-4-yl, 1-isopropylaminocarbonylmethyl-imidazol-4-yl, 1-(2-isopropylaminocarbonylethyl)-imidazol-4-yl, 1-(3-isopropylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-iso-propylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-isopropylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-isopropylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-- 13 - 2~896~9 isopropylaminocarbonylheptyl)-imidazol-4-yl, l-dimethylaminocarbonylmethyl-imidazol-4-yl, l-(2-dimethylaminocarbonylethyl)-imidazol-4-yl, 1-(3-di-methylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-dimethylaminocarbonylbutyl)-imidazol-4-yl, l-(5-di.methylaminocarbonylpentyl)-imidazol-4-yl, l-(6-dimethylaminocarbonylhexyl)-imidazol-4-yl, l-(7-dimethylaminocarbonylheptyl)-imidazol-4-yl, l-diethylaminocarbonylmethyl-imidazol-4-yl, l-(2-di-ethylaminocarbonylethyl)-imidazol-4-yl, l-(3-diethylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-diethylaminocarbonylbutyl)-imidazol-4-yl, l-(5-diethylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-diethylaminocarbonylhexyl)-imidazol-4-yl, l-(7-diethylaminocarbonylheptyl)-imidazol-4-yl, l-di-n-propylaminocarbonylmethyl-imidazol-4-yl, l-(2-di-n-propylaminocarbonylethyl)-imidazol-4-yl, l-(3-di-n-propylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-di-n-propylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-di-n-propylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-di-n-propylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-di-n-propylaminocarbonylheptyl)-imidazol-4-yl, 1-diisopropylaminocarbonylmethyl-imidazol-4-yl, 1-(2-diisopropylaminocarbonylethyl)-imidazol-4-yl, 1-(3-diisopropylaminocarbonylpropyl)-imidazol-4-yl, 1-~4-diisopropylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-diisopropylaminocarbonylpentyl)-imidazo.-4-yl, l-(6-diisopropylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-diisopropylaminocarbonylheptyl)-imidazol-4-yl, l-morpholinocarbonylmethyl-imidazol-4-yl, 1-(2-morpholinocarbonylethylJ-imidazol-4-yl, l-(3-morpholinocarbonylpropyl)-imidazol-4-yl, l-(4-morpholinocarbonylbutyl)-imidazol-4-yl, l-(5-morpholinocarbonylpentyl)-imidazol-4-yl, 1-(6-morpholinocarbonylhexyl)-imidazol-4-yl, l-(7-morpholinocarbonylheptyl)-imidazol-4-yl, l-thiomorpholinocarbonylmethyl-imidazol-4-yl, 1-(2-.. ~

~',, ' ., , ~:

2~8968~

thiomorpholinocarbonylethyl)-imidazol-4-yl, 1-(3-thiomorpholinocarbonylpropyl)-imidazol-4-yl, 1-(4-thiomorpholinocarbonylbutyl)-imidazol-4-yl, 1-~5-thiomorpholinocarbonylpentyl)-imidazol-4-yl, 1-(6-thiomorpholinocarbonylhexyl)-imidazol-4-yl, 1-(7-thio-morpholinocarbonylheptyl)-imidazol-4-yl, 1-oxidothiomorpholinocarbonylmethyl-imidazol-4-yl, 1-(2-oxidothiomorpholinocarbonylethyl)-imidazol-4-yl, 1-(3-oxidothiomorpholinocarbonylpropyl)-imidazol-4-yl, 1-(4-oxidothiomorpholinocarbonylbutyl)-imidazol-4-yl, 1-(5-oxidothiomorpholinocarbonylpentyl)-imidazol-4-yl, 1-(6-oxidothiomorpholinocarbonylhexyl)-imidazol-4-yl, 1-(7-oxidothiomorpholinocarbonylheptyl)-imidazol-4-yl, 1-carboxymethyl-2-methyl-imidazol-4-yl, 1-(2-carboxyethyl)-2-methyl-imidazol-4-yl, 1-(3-carboxypropyl)-2-methyl-imidazol-4-yl, 1-(4-carboxybutyl)-2-methyl-imidazol-4-yl, 1-(5-carboxypentyl)-2-methyl-imidazol-4-yl, 1-(6-carboxyhexyl)-2-methyl-imidazol-4-yl, 1-(7-carboxyheptyl)-2-methyl-imidazol-4-yl, 1-methoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-methoxycarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-methoxycarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-methoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-methoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-methoxyGarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-methoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1-ethoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-ethoxycarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-ethoxycarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-ethoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-ethoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-ethoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-ethoxycarbonylheptyl)-2-methyl-imidazol-4-yl, l-n-propoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-n-propoxycarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-n-propoxycarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-n-20~96~

propoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-n-propoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-~6-n-propoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-n-propoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1-isopropoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-isopropoxycarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-isopropoxycarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-isopropoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-isopropoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-isopropoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-isopropoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1-aminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-aminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-amino-carbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-aminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5- .
aminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-aminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-aminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-methylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-methylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-methylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-methylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-methylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-methylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-methylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-ethylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-ethylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-ethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-ethylaminocarbonylbutyl)-2-methyl-imidazol-~-yl, 1-(5-ethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-ethylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-ethylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, l-n-propylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-n-propylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-n-propylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-n-propylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-n-propylaminocarbonylpentyl)-2-methyl-imidazol-4-:' : .. '' ' ., : ~
:. - . . ~ .

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

208~

yl, l-(6-n-propylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-n-propylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-isopropylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-isopropylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-isopropylaminocarbonyl-propyl)-2-methyl-imidazol-4-yl, 1-(4-isopropylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-isopropylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-isopropylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, l-(7-isopropylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-dimethylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-dimethylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-dimethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-dimethylaminocarbonyl-butyl)-2-methyl-imidazol-4-yl, 1-(5-dimethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-dimethylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-dimethylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, l-diethylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-diethylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-diethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-diethylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-diethylaminocarbonylpentyl)-2-methyl-imidazol-~-yl, 1-(6-diethylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-diethylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-di-n-propylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-di-n-propylaminocarbonylethyl~-2-methyl-imidazol-4-yl, 1-(3-di-n-propylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-di-n-propylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-di-n-propylamino-carbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-di-n-propylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-di-n-propylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, l-diisopropylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-diisopropylaminocarbonylethyl)-2-methyl-imidazol-4-yl, l-(3-diisopropylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-diisopropylaminocarbonylbutyl)-2--.

, 2089~8~

methyl-imidazol-4-yl, 1-(5-diisopropylamino-carbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-diisopropylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1--(7-diisopropylaminocarbonylheptyl)-2-methyl-imidazol-4--yl, 1-morpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1--(2-morpholinocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-morpholinocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-morpholinocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-morpholinocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-morpholinocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-morpholinocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-thiomorpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-thiomorpholinocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-thiomorpholinocarbonylpropyl)-2-methyl-imidazol-4-yl, l-(4-thiomorpholinocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-thiomorpholinocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-thiomorpholinocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-thiomorpholinocarbonyl-heptyl)-2-methyl-imidazol-4-yl, 1-oxidothiomorpholinocarbonylmethyl-2-methyl-imidazol-4-yl, l-(2-oxidothiomorpholinocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-oxidothiomorpholinocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-oxidothiomorpholino-carbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-oxido-thiomorpholinocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-oxidothiomorpholinocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-oxidothiomorpholinocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-(2-hydroxyethyl)-imidazol-4-yl, 1-(3-hydroxypropyl)-imidazol-4-yl, 1-(4-hydroxybutyl)-imidazol-4-yl, 1-(2-methoxyethyl)-imidazol-4-yl, 1-(3-methoxypropyl)-imidazol-4-yl, 1-(4-methoxybutyl)-imidazol-4-yl, 1-(2-ethoxyethyl)-imidazol-4-yl, 1-(3-ethoxypropyl)-imidazol-4-yl, 1-(4-ethoxybutyl)-imidazol-4-yl, 1-(2-n-propoxyethyl)-imidazol-4-yl, 1-(3-n-propoxypropyl)-imidazol-4-yl, 1-(4-n-propoxybutyl)-imidazol-4-yl, 1-(2-isopropoxyethyl)-imidazol-4-yl, 1-(3-isopropoxypropyl)-imidazol-4-yl, 1-(4-.
- ~

' - , ' . ' " ,' .

208~

isopropoxybutyl)-imidazol-4-yl, 1-(2-imidazol-1-yl-ethyl)-imidazol-4-yl, 1-(3-imidazol-1-yl-propyl)-imidazol-4-yl, 1-(4-imidazol-1-yl-butyl)-imidazol-4-yl, 1--(2,2-diphenyl-ethyl)-imidazol-4-yl, 1-(3,3-diphenyl-propyl)-imidazol-4-yl, 1-(4,4-diphenyl-butyl)-imidazol-4-yl, 1-(2-hydroxyethyl)-2-methyl-imidazol-4-yl, 1-(3-hydroxypropyl)-2-methyl-imidazol-4-yl, 1-(4-hydroxybutyl)-2-methyl-imidazol-4-yl, 1-(2-methoxy-ethyl)-2-methyl-imidazol-4-yl, l-(3-methoxypropyl)-2-methyl-imidazol-4-yl, 1-(4-methoxybutyl)-2-methyl-imidazol-4-yl, 1-(2-ethoxyethyl)-2-methyl-imidazol-4-yl, l-(3-ethoxypropyl)-2-methyl-imidazol-4-yl, 1-(4-ethoxybutyl)-2-methyl-imidazol-4-yl, 1-(2-n-propoxyethyl)-2-methyl-imidazol-4-yl, l-(3-n-propoxypropyl)-2-methyl-imidazol-4-yl, l-(4-n-propoxybutyl)-2-methyl-imidazol-4-yl, l-(2-isopropoxyethyl)-2-methyl-imidazol-4-yl, l-(3-isopropoxypropyl)-2-methyl-imidazol-4-yl, l-(4-isopropoxybutyl)-2-methyl-imidazol-4-yl, l-(2-imidazol-1-yl-ethyl)-2-methyl-imidazol-4-yl, 1-(3-imidazol-1-yl-propyl)-2-methyl-imidazol-4-yl, 1-(4-imidazol-1-yl-butyl)-2-methyl-imidazol-4-yl, 1-(2,2-diphenyl-ethyl)-2-methyl-imidazol-4-yl, 1-(3,3-diphenyl-propyl)-2-methyl-imidazol-4-yl, 1-(4,4-diphenyl-butyl)-2-methyl-imidazol-4-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, l-ethylbenzimidazol-2-yl, 1-n-propylbenzimidazol-2-yl, l-isopropylbenzimidazol-2.yl, l-n-butylbenzimidazol-2-yl, 1-isobutylbenzimidazol-2-yl, 1-n-pentylbenzimidazol-2-yl, 1-n-hexylbenzimidazol-2-yl, 1-cyclopropyl-benzimidazol-2-yl, l-cyclobutylbenzimidazol-2-yl, 1-cyclopentylbenzimidazol-2-yl, l-cyclohexylbenzimidazol-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, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo-[1,2-a]pyrimidin-2-yl, imidazo~l,2-a]pyrimidin-2-yl, imidazo[4,5-b~pyridin-2-yl, imidazot4,5-c]pyridin-2-yl, imidazo[2,1-b]thiazol-6-yl, imidazotl,2-clpyrimidin-2-yl, imidazo[l,2-a]pyrazin-2-yl, imidazo[l,2-b]pyidazin-2--yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, imidazo[4,5-d]pyridazin-2-yl, 4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-benzyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2H-pyridazin-3-on-6-yl, 2-methyl-pyridazin-3-on-6-yl, 2-benzyl-pyridazin-3-on-6-yl, aminocarbonylamino, methylaminocarbonylamino, dimethylaminocarbonylamino, N-methylaminocarbonyl-methylamino, N-(dimethylamino-carbonyl)-methylamino, N-dimethylaminocarbonyl-ethylamino, N-dimethylaminocarbonyl-isopropylamino, N-(dimethylaminocarbonyl)-n-pentylamino, N-methylaminocarbonyl-ethylamino, N-methylaminocarbonyl-n-pentylamino, N-methylaminocarbonyl-cyclohexylamino, ethylaminocarbonylamino, N-ethylaminocarbonyl-methylamino, N-ethylaminocarbonyl-ethylamino, N-ethylaminocarbonyl-cyclohexylamino, diethylaminocarbonyl-amino, N-(diethylaminocarbonyl)-methylamino, N-(diethylaminocarbonyl)-ethylamino, N-(diethylaminocarbonyl)-n-butylamino, isopropylaminocarbonylamino, N-isopropylaminocarbonyl-methylamino, n-butylaminocarbonylamino, N-(n-butylaminocarbonyl)-methylamino, N-(n butylaminocarbonyl)-ethylamino, N-(n-butylaminocarbonyl)-isopropylamino, N-(n-butylaminocarbonyl)-n-butylamino, N-(n-butylaminocarbonyl)-cyclohexylamino, N-(di-(n-butyl)-aminocarbonyl)-amino, N-(di-(n-butyl)-aminocarbonyl)-methylamino, N-(di-(n-butyl)-aminocarbonyl)-ethylamino, N-(di-(n-butyl)-aminocarbonyl)-n-butylamino, N-(n-pentylaminocarbonyl)-methylamino, N-(n-pentylamino-carbonyl)-ethylamino, N-(n-hexylaminocarbonyl)-ethylamino, n-hexylaminocarbonylamino, N-(n-o 2089689 hexylaminocarbonyl)-n-butylamino, N-(n-hexylaminocarbonyl)-n-pentylamino, N-(n-hexyl-aminocarbonyl)-cyclohexylamino, di-(n-hexyl)-aminocarbonylamino, N-(di-(n-hexyl)-aminocarbonyl)-methylamino, N-(N'-(n-hexyl)-methyla~inocarbonyl)-amino, cyclohexylaminocarbonylamino, N-cyclohexylaminocarbonyl-methylamino, N-cyclohexylaminocarbonyl~ethylamino, N-cyclohexylaminocarbonyl-n-butylamino, N-cyclohexylaminocarbonyl-isobutylamino, N-cyclohexylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbonyl-cyclohexylamino, N-(ethyl-cyclohexylaminocarbonyl)-methylamino, N-(propyl-cyclohexylaminocarbonyl)-methylamino, N-(n-butyl-cyclohexylaminocarbonyl)-methylamino, allyl-aminocarbonylamino, benzylaminocarbonylamino, N-benzylaminocarbonyl-isobutylamino, phenylamino-carbonylamino, pyrrolidinocarbonylamino, pyrrolidinocarbonylmethylamino, pipe~idinocarbonylamino, hexamethyleneiminocarbonylamino, morpholinocarbonylamino, 3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-methyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-ethyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-n-propyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl, 3-isopropyl-3,4,5,~-tetrahydro-2-pyrimidon-1-yl, carboxy, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, N-methyl-ethylaminocarbonyl or N-ethyl-isopropylaminocarbonyl group, and as examples of the definitions of the groups R2 and Rb given hereinbefore, the group which may be converted in vivo into a carboxy group may additionally be a methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, tert.butyloxycarbonyl, n-pentyloxycarbonyl, isoamyloxycarbonyl, n-hexyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, 1-phenylethyloxycarbonyl, 2-phenylethyloxycarbonyl, 3-phenylpropyloxycarbonyl, methoxymethoxycarbonyl, cinnamyloxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxy-methoxycarbonyl, isobutyryloxymethoxycarbonyl, n-pentanoyloxymethoxycarbonyl, isopentanoyloxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl, n-hexanoyloxymethoxycarbonyl, cyclopentanoyloxymethoxy-carbonyl, cyclohexanoyloxymethoxycarbonyl, phenylacetoxymethoxycarbonyl, 2-phenylpropionyloxy-methoxycarbonyl, 3-phenylpropionyloxymethoxycarbonyl, 4-phenylbutyryloxymethoxycarbonyl, benzoyloxy-methoxycarbonyl, l-acetoxyethoxycarbonyl, 1-propionyloxyethoxycarbonyl, l-n-butyryloxyethoxy-carbonyl, l-isobutyryloxyethoxycarbonyl, l-n- .
pentanoyloxyethoxycarbonyl, l-isopentanoyloxy-ethoxycarbonyl, 1-pivaloyloxyethoxycarbonyl, l-n-hexanoyloxyethoxycarbonyl, l-cyclopentanoyloxy-ethoxycarbonyl, 1-cyclohexanoyloxyethoxycarbonyl, 1-phenylacetoxyethoxycarbonyl, l-(l-phenylpropionyloxy)-ethoxycarbonyl, l-(2-phenylpropionyloxy)-ethoxycarbonyl, 1-(3-phenylbutyryloxy)-ethoxycarbonyl, 1-benzoyloxyethoxycarbonyl, methoxycarbonyloxymethoxy-carbonyl, ethoxycarbonyloxymethoxycarbonyl, n-propyloxycarbonyloxymethoxycarbonyl, isopropyl-oxycarbonyloxymethoxycarbonyl, n-butyloxycarbonyloXy-methoxycarbonyl, isobutyloxycarbonyloxymethoxycarbonyl, tert.butyloxycarbonyloxymethoxycarbonyl, n-pentyloxycarbonyloxymethoxycarbonyl, isoamyloxycarbonyl-oxymethoxycarbonyl, n-hexyloxycarbonyloxy-methoxycarbonyl, cyclopPntyloxycarbonyloxy-methoxycarbonyl, cyclohexyloxycarbonyloxymethoxy-carbonyl, benzyloxycarbonyloxymethoxycarbonyl, 1-phenylethoxycarbonyloxymethoxycarbonyl, 2-208~689 phenylethoxycarbonyloxymethoxycarbonyl, 3-phenylpropyloxycarbonyloxymethoxycarbonyl, cinnamyloxycarbonyloxymethoxycarbonyl, 1-(methoxycarbonyloxy)-ethoxycarbonyl, 1-(ethoxycarbonyloxy)-ethoxycarbonyl, 1-(n-propyloxycarbonyloxy)-ethoxycarbonyl, 1-(isopropyloxy-carbonyloxy)-ethoxycarbonyl, l-(n-butyloxycarbonyloxy)-ethoxycarbonyl, 1-(isobutyloxycarbonyloxy)-ethoxycarbonyl, l-(tert.butyloxycarbonyloxy)-ethoxycarbonyl, l-(n-pentyloxycarbonyloxy)-ethoxycarbonyl, l-(isoamyloxycarbonyloxy)-ethoxycarbonyl, 1-(n-hexyloxycarbonyloxy)-ethoxycarbonyl, l-(cyclopentyloxycarbonyloxy)-ethoxycarbonyl, l-(cyclohexyloxycarbonyloxy)-ethoxycarbonyl, l-(benzyloxycarbonyloxy)-ethoxycarbonyl, l-(l-phenylethoxycarbonyloxy)-ethoxycarbonyl, 1-(2-phenylethoxycarbonyloxy)-ethoxycarbonyl, 1-(3-phenylpropyloxycarbonyloxy)-ethoxycarbonyl or 1-(cinnamyloxycarbonyloxy)-ethoxycarbonyl group.

Preferred compounds of general formula I above are those wherein n denotes the number 0, 1, 2 or 3 and X denotes a bond or n denotes the number 1, 2 or 3 and X is an oxygen atom, A denotes a 1,4-butadienylene group substituted by the groups Rl and R2 and wherein additionally the methine group in position 7 of the benzimidazole thus formed may be replaced by a nitrogen atom, whilst R~ denotes a hydrogen atom or in the 4-position a 2~8~68~

fluorine, chlorine or bromine atom, a trifluoromethyl group or a Cl3-alkyl group and R2 denotes a hydrogen atom, a Cl3-alkyl group, in the 6-position an alkanoylamino group having 2 to 5 carbon atoms in the alkanoyl moiety or a benzenesulphonylamino group, both of which may be substituted at the nitrogen atom by a C13-alkyl group, in the 6-position a phthalimino or homophthalimino -:
group, whilst a carbonyl group in a phthalimino group -may be replaced by a methylene group, in the 6-position a 5-, 6- or 7-membered alkyleneimino gxoup wherein a methylene group is replaced by a carbonyl or sulphonyl group, in the 6-position a maleic acid imido group optionally mono- or disubstituted by a Cl3-alkyl group or by a phenyl group, wherein the substituents may be identical or different, in the 6-position a benzimidazol-2-yl group optionally substituted in the l-position by a C16-alkyl group or a C37-cycloalkyl group, whilst the phenyl nucleus in a benzimidazol-2-yl group as mentioned above may additionally be substituted by a fluorine atom or a methyl or trifluoromethyl group, 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[l,2-a]pyrimidin-2-yl or imidazo[4,5-b]pyridin 2-yl ~roup, in the 6-position an imidazol-4-yl group which may be , ~ .

2~8~89 substituted in the l-position by a Cl7-alkyl group (which may be substituted in the 2-, 3-, 4-, 5-, 6- or 7-position by a carboxy, alkoxycarbonyl, aminocarbonyl, a:Lkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or l-oxido-thiomorpholinocarbonyl group), by a C14-alkyl group (substituted in the 2-, 3- or 4-position by a hydroxy, alkoxy or imidazol-1-yl group), by an alkyl group substituted by a trifluoromethyl group, by a C3 7-cycloalkyl group, by a phenyl group (optionally mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups), by an alkyl group substituted by two phenyl groups, or by a C3 7-cycloalkyl group, whilst unless otherwise specified the above-mentioned alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms, in the 7-position a group which may be converted in vivo into a carboxy group, in the 7-position a carbonyl group which is substit~ted by a hydroxy group, by a Cl6-alkoxy group (wherein the methoxy group is additionally substituted by an alkanoyloxy, alkoxycarbonyloxy or cycloalkoxycarbonyloxy group), or by an amino group optionally mono- or disubstituted by alkyl groups, whilst in the above-mentioned groups the alkanoyl moiety may contain 2 or 3 car~on atoms, the alkyl and alkoxy moieties may each contain 1 to 6 carbon atoms and the cycloalkoxy moiety may contain 5 to 7 carbon atoms, or in the 6-position an Rs-NR4-Co-NR3- group wherein R3 denotes a hydrogen atom, a C15-alkyl group or a cyclohexyl or benzyl group, R4 denotes a hydrogen atom, a Cl6-alkyl group or an - ~ ' . ~ .
, 2 ~

allyl, cyclohexyl, benzyl or phenyl group, R5 denotes a hydrogen atom or a Cl3-alkyl group or R4 and Rs together with the nitrogen atom between them denote an unbranched C4 6-cycloalkyleneimino group or a morpholino group or R3 and R4 together denote a C23-alkylene group, R~ denotes a C24-alkyl group, a C34-cycloalkyl group or a C23-alkoxy group, Fb denotes a group which may be converted in vivo into a carboxy group, or a carboxy or lH-tetrazolyl group and Rc denotes a hydrogen atom, the mixtures of position isomers thereof and the salts thereof.

Particularly preferred compounds of general formula I
above are those wherein n denotes the number 0, 1, 2 or 3 and X denotes a bond, A denotes a 1,4-butadienylene group which is substituted by the groups R1 and R2 and wherein additionally the methine group in position 7 of the benzimidazole thus formed may be replaced by a nitrogen atom, wherein R1 is a hydrogen atom or in the 4-position a methyl group and , ~ '' : - -, .

2~g~

R2 in the 6-position is a l-isopropyl-imidazol-4-yl or 1-m,ethyl-benzimidazol-2-yl group or in the 7-position represent a group which may be converted into a carboxy group in vivo or a carboxy group, Ra denotes a C24-n-alkyl group, Rb denotes a group which may be converted into a carboxy group ~n vivo, a carboxy or lH-tetrazolyl group and Rc denotes a hydrogen atom, the mixtures of position isomers thereof and the salts thereof.
..
According to the invention, the compounds of the invention are obtained by the following processes:

a) reacting a compound of general formula ,~

(II) wherein A and R~ are as hereinbefore defined, with a biphenyl compound of general formula Z1- CH2 ~ =
X--(CH~n--Rb (III) : . :: .
.

.

2a89~89 - 2~ -wherein n, X, Rb and Rc are as hereinbefore defined and Zt denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group, optionally with subsequent hydrolysis.

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

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 ~emperatures between -10C and 120C, e.g at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

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 carrier such as silica gel or aluminium oxide.

b) In order to prepare a compound of general formula I
wherein Rb denotes a carboxy group:

converting a compound of general formula ~C ~Ra {~
X--(CH~n--Rbl (IV) wherein n, X, A, Ra and Rc are as hereinbefore defined and Rb' denotes a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, into a corresponding carboxy compound.

For example, functional derivatives of the carboxy group such as unsubstituted or substituted amides, esters, 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 -10C and 120C, e.g. at temperatures between .

:, ~ . . ..
..
..

':

20896~9 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 Rb' in a compound of general formula IV represents a cyano or aminocarbonyl group, these groups may also be converted into a carboxy group with a nitrite, e.g.
sodium nitrite, in the presence of an acid such as sulphuric acid, which may also be simultaneously used as solvent, at temperatures between 0 and 50C.

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

If Rb' in a compound of general formula IV 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 500c, 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 2089~89 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.

c) In order to prepare a compound of general formula I
wherein Rb represents a lH-tetrazolyl group:

Cleaving of a protective group from a compound of general formula ~a CH2~Rc X--(CH2~n--Rb (V) wherein n, X, A, R~ and Rc are defined as hereinbefore and R~" represents a lH-tetrazolyl group protected in the 1-or 2-position by a protecting group.

Suitable protecting groups include, for example, ~-cyanoethyl, 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 100C, but preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at ~. . , ., . - ::

2089~89 elevated temperatures, e.g. at temperatures between 100 and 150C, preferably at temperatures between 120 and 140C.

d) In order to prepare a compound of general formula I
wherein R4 represents a lH-tetrazolyl group:

Reaction of a compound of general formula A ~ ~ Ra C H2 ~Rc X--(CH2)n -1--CN

(VI) wherein n, X, A, Ra and Rc 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 between 80 and 150C, preferably at 125C.
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 alumi~ium 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 a~ide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric or 2N
sulphuric acid.

' '-' ` " ' : ' - ' : - . , - :
.

~ ' . .

208~68~

e) In order to prepare a compound of general formula I
wherein n denotes the number 1, X is a bond and Rb denotes a bis(hydroxycarbonyl)methyl or bis(alkoxycarbonyl)methyl group: -reaction of a compound of general formula N ~

CH2~ ~Rc (VII) wherein n, A, Ra and Rc are as hereinbefore defined and Z2 denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group, with a compound of general formula CH2(CooR6)2 (VIII) wherein R6 in each case denotes a C14-alkyl group, if necessary with subsequent hydrolysis and/or decarboxylation.

The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethyl-sulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, triethylamine or pyridine, 208968~

whilst the latter two may simultaneously also be used as solvent, preferably at temperatures between 0 and 100C, e.g. at temperatures between ambient temperature and 50C.

The subsequent hydrol~sis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, trichloroacetic acid 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 -10C and 120C, e.g at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

The subsequent decarboxylation is expediently carried out in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between 50C and 120C, e.g. at temperatures between 60C and the boiling temperature of the reaction mixture.

f) In order to prepare a compound of general formula I
wherein R2 denotes an Rs-NR4-CONR3- group:

reaction of a compound of general formula ~ N
CH2~Rc X--(CH2)n--Rb (IX) .: .

, ' : ~ ' . ' ' ~

w:ith a compound of general formula N - C0 - Z3 (X) wherein R~, Rb, Rc, R4, R5, X and n are as hereinbefore defined, Al denotes a 1,4-butadienylene group substituted by R
and by the R3NH group, wherein R1 and R3 are as hereinbefore defined, and Z3 denotes a nucleophilic leaving group such as a chlorine or bromine atom or Z3 and R~ together denote a nitrogen-carbon bond.

The reaction is expediently carried out in a solvent or mixture of solvents such as dichloromethane, chloroform, diethylether, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide, pyridine, benzene or toluene, at temperatures between 0 and 150C, but preferably at temperatures between 50 and 120C.

g) In order to prepare a compound of general formula I
wherein R2 denotes an alkanoylamino group having 2 to 5 carbon atoms in the alkanoyl moiety or a benzenesulphonylamino group, both of which may be substituted at the nitrogen atom by a C13-alkyl group, or a phthalimino or homophthalimino group in which a carbonyl group in a phthalimino group may be replaced by a methylene group, or a 5-, 6- or 7-membered alkyleneimino group in which a methylene group is replaced by a carbonyl or sulphonyl group, or a glutaric acid imino group which the n-propylene group may be substituted by one or two C13-alkyl groups or by a tetramethylene or pentamethylene group, or a maleic acid imido group optionally mono- or disubstituted by a Cl3-: , .
:-.

2089~89 alkyl group or by a phenyl group, wherein the substituents may be identical or different:

reaction of a compound of general formula CH2 ~3,RC

--(CH2)n--Rb (IX) with a compound of general formula z4 - U - R7 (XI) wherein Ra~ Rb, Rc, R4, F~, X and n are as hereinbefore defined, A
denotes a 1,4-butadienylene group substituted by R1 and by the R3NH group, wherein Rl and R3 are as hereinbefore defined, Z4 denotes a hydroxy group or a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom, U denotes a carbonyl or sulphonyl group and R7 denotes a Cl4-alkyl group, a phenyl, o-hydroxycarbonylphenyl, o-hydroxycarbonylphenylmethyl or o-hydroxycarbonylmethylphenyl group, a 3-hydroxycarbonylpropylene group optionally substituted by one or two C13-alkyl groups or by a tetramethylene or pentamethylene group or a 2-hydroxycarbonylethenylene group optionally mono- or disubstituted by a C13-alkyl group or by a phenyl group, wherein the substituents may 20~8~

be identical or different, or R3 and R7 together denote an n-propylene, n-butylene or n-hexylene group or, if Z4 denotes a hydroxy group, with the reactive derivatives thereof such as the acid halides, acid anhydrides or acid esters thereof.

Examples of reactive derivatives of a compound of formula XI include the esters thereof, such as the methyl, ethyl or benzyl esters, the thioesters thereof such as the methylthio or ethylthio esters, the halides thereof such as the acid chloride, the anhydrides or imidazolides thereof and the orthoesters thereof.

The reaction is expediently carried out in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide or in an excess of the acylating agent as solvent, with a corresponding carboxylic acid in the presence of an acid activating or dehydrating agent such as thionylchloride, with the anhydrides thereof such as acetic acid anhydride, with the esters thereof such as ethyl acetate, with the halides thereof such as acetyl chloride or methanesulphonyl chloride, optionally in the presence of an inorganic or tertiary organic base, such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, at temperatures between -25 and 100C, but preferably at temperatures between -10 and 80C.

If according to the invention a compound of general formula I is obtained wherein R2 or Rb or Rz and Rb each denote a carboxy group, this may be converted by esterification into a corresponding compound of general formula I wherein R2 or Rb or R2 and Rb denote a group which may be converted in vivo into a carboxy group.

20~9~89 The conversion of a carboxyl group into a group which is converted metabolically into a carboxy group in vivo is conveniently carried out by esterification with a corresponding alcohol or with a corresponding reactive acyl derivative, usefully in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylfor~amide or in an excess of the acylating agent as solvent, optionally in the presence of an acid activating or dehydrating agent such as thionyl chloride, with the anhydrides, esters or halides thereof, optionally in the presence of an inorganic or tertiary organic base such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, whilst the latter two may simultaneously serve as solvent, at temperatures between -25 and 100C, but preferably at temperatures between -10 and 80~C.

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 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 208968~

between o and lOO~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 ger.eral 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 acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Furthermore, the new compounds of general formula I thus obtained, if they contain a carboxy or lH-tetrazolyl group, may if desired subsequently be converted into the salts thereof with inorganic or organic bases, more particularly for pharmaceutical use into the physiologically acceptable 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 .

208968~

cases or may be obtained by methods known from the literature.

Thus, for example, a compound of general formula II is obtained by acylation of a corresponding o-amino-nitro compound, subsequent reduction of the nitro group followed by cyclisation or by reacting a corresponding o-diamino compound with a corresponding tetraalkyl-orthocarbonate.

A compound of general formula II wherein Ra denotes an amino or alkylamino group is obtained by cyclising a corresponding o-diamino compound with a carbonic acid diester, subsequent halogenation of the resulting 2-hydroxy compound and reaction with a corresponding amine.

The compounds of general formulae IV, V, VI, VII and IX
used as starting materials are obtained by cyclising a corresponding o-phenylenediamine or by reducing a corresponding o-amino-nitro compound, followed by reduction of the nitro group and cyclisation of an o-diaminophenyl compound thus obtained or by N~-alkylation of a corresponding lH-benzimidazole, whilst the isomer mixture thus obtained may subsequently be resolved by conventional methods, e.g. chromatography.

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 compounds according to the invention were tested for their biological effects as described hereinafter:

A = 2-n-propyl-4-methyl-1-[3-(tetrazol-5-yl-methyl)-4-- ' , 20896~9 phenyl-benzyl]-benzimidazole, B = 2-n-propyl-4-methyl-1-[3-(2-hydroxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole, C = 2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-[3-(2-hydroxycarbonyl-ethyl~-4-phenyl-benzyl]-benzimidazole, D = 2-ethyl-5,7-dimethyl-3-~3-(tetrazol-5-yl-methyl)-4-phenyl-benzyl~-imidazo[4,5-b]pyridine and E = 2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-1-[3-(2-tetrazol-5-yl-ethyl)-4-phenyl-benzyl]
benzimidazole Descri~tion of method Anaiotensin II-receptor bondinq 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 37C with 50 pM tl25I]-angiotensin II (NEN, Dreieich, FRG) with increasing concentrations of the test substance in a total volume of 0.25 ml. Incubation is ended by rapid filtration through glass fibre filter mats. The filters are each washed with 4 ml of ice cold buffer (25 mMol Tris, 2.5 mMol MgCl2, 0.1% BSA, pH 7.40). The bound radioactivity is measured using a gamma-counter. The corresponding ICso value is obtained from the dose-activity curve.

In the test described, substances A to E show the : -2089~

following IC50 values:

Substance ICso [nM]

_ _ 6.9 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.

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 aaceptable 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 arterioscle~osi~ 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 conventional inert 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 aaid, 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 2~8968~

4~ 27169-~08 propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipin or S to 60 mg of nitrendipin.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use for treatment of any of the abovementioned indications.
The Examples which follow are intended to illustrate the invention:

.

: ~ ~, ., 2089~89 Example 1 2-n-Propyl-4-methyl-1-(3-hydroxycarbonyl-4-phenyl-benzyl)-benzimidazole a) 3-Methoxycarbonyl-4-~henYl-benzylbromide 1.0 g (4.4 mMol) of 3-methoxycarbonyl-4-phenyl-toluene, 890 mg (5.0 mMol) of N-bromosuccinimide and about 30 mg of azo-bis-isobutyronitrile are refluxed in 30 ml of carbon tetrachloride for 30 minutes under W -radiation.
Then the succinimide formed is filtered off, the filtrate is washed twice with 50 ml of water, dried and evaporated to dryness. The product thus obtained, which still contains about 10% of starting material, is reacted further without any more purification.
Yield: 1.3 g (100% of theory), Rf value: 0.34 (silica gel; petroleum ether/ethyl acetate = 9:1) b) 2-n-Propyl-4-methyl-1-(3-methoxycarbonyl-4-phenyl-benzYl)-benzimidazole _ _ A solution of 10.45 g (60 mMol) of 2-n-propyl-4-methyl-benzimidazole, 8.1 g (72 mMol~ of potassium tert.butoxide and 22.0 g (72 mMol) of 3-methoxycarbonyl-4-phenyl-benzylbromide in 300 ml of N,N-dimethylformamide is stirred for about 2 hours at ambient temperature and then stirred into about 600 ml of water. The mixture thus obtained i9 extracted four times with about 60 ml of ethyl acetate each time, the combined organic extracts are washed with about 50 ml of water, dried and evaporated down. The crude product thus obtained is purified by column chromatography (1 kg silica gel: eluant: petroleum ether/ethyl acetate =
2~
Yield: 16.8 g (70% of theory), ~ ~ .
.~ . .~ . .
: .. .

20~968~

Oil, Rf value: 0.30 tsilica gel; petroleum ether/ethyl acetate = 2:1) c) 2-n-Propyl-4-methyl-1-(3-hydroxycarbonyl-4-phenyl-benzyl)-benzimidazole 1.00 g ~2.5 mMol) of 2-n-propyl-4-methyl-1-(3-methoxycarbonyl-4-phenyl-benzyl)-benzimidazole is refluxed for 1.5 hours in a mixture of 10 ml 2N sodium hydroxide solution and 5 ml methanol. Then the methanol is distilled off, about 10 ml of water are added and the mixture is acidified with glacial acetic acid. The product precipitated is suction filtered, washed with about 5 ml of water and dried at 60C.
Yield: 580 mg (60~ of theory), Melting point: 258-260C
C25H24N2O2 (384.49) Calculated: C 78.09 H 6.29 N 7.29 Found: 77.92 6.44 7.33 Rf value: 0.54 (silica gel: methylene chloride/ethanol =
9 : 1 ) Example 2 2-n-Propyl-4-methyl-1-~3-(tetrazol-5-yl-methyl)-4-phenyl-benzyl]-benzimidazole a) 2-n-Propyl-4-methyl-1-(3-chloromethyl-4-phenyl-benz~l)-benzimidazole A solution of 3.2 g (8.6 mMol) of 2-n-propyl-4-methyl-l-(3-hydroxymethyl-4-phenyl-benzyl)-benzimidazole in 5 ml of thionyl chloride is heated to 100C for 10 minutes.
Then the excess thionyl chloride is distilled ofP, the residue obtained is stirred with about 20 g of ice and the solution thus obtained is neutralised with 5% sodium ., :

~8~89 hydrogen carbonate solution. It is then extracted three times with about 15 ml of methylene chloride, the combined organic extracts are dried, filtered over activated charcoal and evaporated down.
Yield: 3.3 g (100% of theory), Oil, Rf value: 0.63 (silica gel; petroleum eth~r/ethyl acetate = 1:1) b) 2-n-Propyl-4-methyl-l-(3-cyanomethyl-4-phenyl-benzyl)-benzimidazole To a solution of 3.3 g (8.6 mMol) of 2-n-propyl-4-methyl-l-(3-chloromethyl-4-phenyl-benzyl)-benzimidazole in 10 ml of dimethylsulphoxide are added 640 mg (13 mMol) of sodium cyanide and the mixture is stirred for two hours at 80C, then stirred into about 40 ml of 5% sodium chloride solution and extracted four times with about 20 ml of methylene chloride. The combined organic extracts are washed with 30 ml of an iron(II)-sulphate solution, dried and evaporated down. The crude product thus obtained is purified by column chromatography (150 g silica gel; eluant: petroleum ether/ethyl acetate = 2:1).
Yield: 2.2 g (68% of theory), Oil, Rf value: 0.50 (silica gel; petroleum ether/ethyl acetate = 1:1) c) 2-n-Propyl-4-methyl-1-t3-(tetrazol-5-yl-methyl)-4-~henvl-benzvll-benzimidazole A solution of 1.2 g (3.2 mMol) of 2-n-propyl-4-methyl-1-(3-cyanomethyl-4-phenyl-benzyl)-benzimidazole, 3.4 g (64 mMol) of ammonium chloride and 4.2 g (64 mMol) of sodium azide in 25 ml of dimethylformamide is stirred for 3 hours at 140C. It is then stirred into about 60 ml of a 5% sodium chloride solution, the crude product precipitated is suction filtered and purified by .

2~8~689 column chromatography (lOO g silica gel, eluant:
methylene chloride/ethanol 20:1) Yield: 1.0 g (75% of theory), Melting point: 183-185C
C26H26N6 (422.55) Calculated: C 73.90 H 6.20 N 19.89 Found: 73.81 6.44 19.78 Rf value: 0.53 (silica gel; methylene chloride/ethanol =
9 : 1 ) Mass spectrum: m/e = 422 Example 3 2-n-Propyl-4-methyl-1-[3-(2-hydroxycarbonyl-ethyl)-4-phenyl-benzyl~-benzimidazole a) 2-n-Propyl-4-methyl-1-[3-(2,2-bis-ethoxycarbonyl-ethvl)-4-~henyl-benzYll-benzimidazole To a solution of 6.24 g (39 mMol) of diethyl-malonate and 4.4 g (39 mMol) of potassium tert.butoxide in 75 ml of dimethylsulphoxide, at ambient temperature, a solution of 12.6 g (32.4 mMol) of 2-n-propyl-4-methyl-1-(3-chloromethyl-4-phenyl-benzyl)-benzimidazole in 25 ml of dimethylsulphoxide is added dropwise. After stirring overnight the reaction mixture is stirred into about 400 ml of a 5% sodium ahloride solution, the mixture is then extracted three times with about 80 ml of ethyl acetate, the organic extracts are washed with about 100 ml of water, evaporated down and purified by column chromatography (500 g silica gel; eluant: petroleum ether/ethyl acetate = 1:1).
Yield: 7.0 (42% of theory), Oil, Rf value: 0.51 (silica gel; petroleum ether/ethyl acetate = 1:1) Oil, Rf value: 0.83 (silica gel; methylene 2089~89 chloride/ethanol = 4:1) b) 2-n-Propyl-4-methyl-1-[3-(2,2-bis-hydroxycarbonyl-ethyl)-4-phenYl-benzYll-benzimidazole A mixture of 7.0 g (13.6 mMol) of 2-n-propyl-4-methyl-1-[3-(2,2-bis-ethoxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole, 20 ml of ethanol and 25 ml of 2N sodium hydroxide solution is refluxed for 90 minutes. It is then concentrated by evaporation, the residue is dissolved in about 60 ml of water and this solution is washed once with about 30 ml of diethylether. The aqueous phase is then acidified with glacial acetic acid, the product which crystallises out is suction filtered, washed with about 40 ml of water and dried.
Yield: 5.1 g (82% of theory), R~ value: 0.50 (silica gel; methylene chloride/ethanol =
4:1) c) 2-n-Propyl-4-methyl-1-[3-(2-hydroxycarbonyl-ethyl)-4-phen~l-benz~l~-benzimidazole 5.1 g (11 mMol) of 2-n-propyl-4-methyl-1-[3-~2,2-bis-hydroxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole are heated to 140C for 30 minutes. The solid product obtained after cooling is triturated with diethylether, suction filtered and dried.
Yield: 4.1 g (91% of theory), Melting point: 201-203~C
c27H28N202 (412-54) Calculated: C 78.62 H 6.84 N 6~79 Found: 78.57 6.90 6.79 Mass spectrum: m/e = 412 . :

Exam~le 4 2-n-Propyl-4-methyl-1-~3-(2-tetrazol-5-yl-ethyl)-4-phenyl-benzyl]-benzimidazole a) 2-n-Propyl-4-methyl-1-[3-(2-aminocarbonyl-ethyl)-4-Phenyl-benzyll-benzimidazole A mixture of 3.0 g (7.3 mMol) of 2-n-propyl-4-methyl-1-[3-(2-hydroxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole, 4.5 ml of thionyl chloride, 60 ml of methylene chloride and 3 drops of dimethylformamide is refluxed for one hour and then evaporated to dryness.
The residue obtained is dissolved in 10 ml of tetrahydrofuran and added dropwise, with stirring, to 30 ml of concentrated ammonia. After it has all been added, the mixture is diluted with about 30 ml of water, then the tetrahydrofuran is distilled off, the product precipitated is suction filtered, washed with water and dried at 60C.
Yield: 2.9 (97% of theory), Rf value: 0.41 (silica gel; methylene chlorideJethanol =
19:1) b) 2-n-Propyl-4-methyl-1-[3-(2-cyanoethyl)-4-phenyl-benzvll-benzimidazole A solution of 2.9 g (7.0 mMol) of 2-n-propyl-4-methyl-1-[3-(2-aminocarbonyl-eth~1)-4-phenyl-benzyl]-benzimidazole in 40 ml of phosphorus oxychloride is refluxed for 45 minutes. Then the excess phosphorus oxychloride is distilled off, the residue is decomposed with about 40 ml of ice water and the mixture is then made alkaline with concentrated ammonia, with cooling.
The aqueous phase is decanted off from the crude product precipitated, the residue is dissolved in about 60 ml of methylene chloride, filtered over activated charcoal and 2089~8~

evaporated to dryness.
Yield: 2.7 g (98% of theory), Rf~value: 0.46 (silica gel; methylene chloride/ethanol =
19 : 1 ) .

c) 2-n-Propyl-4-methyl-1-[3-(2-tetrazol-5-yl-ethyl)-4-phenvl-benzvll-benzimidazole A solution of 2.7 g (6.86 mMol) of 2-n-propyl-4-methyl-l-t3-(2-cyanoethyl)-4-phenyl-benzyl]-benzimidazole, 7.4 g (137 mMol) of ammonium chloride and 9.0 g (137 mMol) of sodium azide in 80 ml of dimethylformamide is heated to 140C for 4 hours, then stirred into about 200 ml of 5% sodium chloride solution and the mixture is extracted four times with about 40 ml of methylene chloride. The combined organic extracts are washed with about 100 ml of water, dried and evaporated down and the crude product thus obtained is purified by column chromatography (130 g silica gel; eluant = methylene chloride plus 5 to 8% ethanol).
Yield: 1.0 g (33% of theory), Melting point: from 78~C (sintering) C27H28N6 (436.57) Calculated: C 74.28 H 6.46 N 19.25 Found: 73.94 6.61 18.98 Mass spectrum: m/e = 436 Exam~le 5 2-n-Propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-t3-(2-hydroxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole .

Prepared analogously to Example 3 from 2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-~3-(2,2-bis-hydroxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole.
Yield: 80% of theory, .

2~89~9 Melting point: from 114C (sintering) c35H34N4o2 (542-69) Calculated: C 77.46 H 6.31 N 10.32 Found: 77.03 6.41 10.09 Rf value: 0.86 (silica gel; methylene chloride/ethanol =
9 ; 1 ) Mass spectrum: (M+H)' = 543 Exam~le 6 2-n-Propyl-4-methyl-6~ isopropyl-imidazol-4-yl)-l-t3-(tetrazol-5-yl-methyl)-4-phenyl-benzyl]-benzimidazole _ Prepared analogously to Example 2 from 2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-1-(3-cyanomethyl-4-phenyl-benzyl)-benzimidazole.

Exam~le 7 2-n-Propyl-4-methyl-6~ isopropyl-imidazol-4-yl)-1-t3-(2-hydroxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole Prepared analogously to Example 3 from 2-n-propyl-4-methyl-6~ isopropyl-imidazol-4-yl)-1-[3-(2,2-bis-hydroxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole.

Exam~le 8 2-Ethyl-5,7-dimethyl-3-[3-(tetrazol-5-yl-methyl)-4-phenyl-benzyl]-imidazo[4,5-b)pyridine Prepared analogously to Example ~ from 2-ethyl-5,7-dimethyl-3-(3-cyanomethyl-4-phenyl-benzyl)-: ~, 2089~89 imidazo[4~s-b]pyridine and sodium azide in dimethylformamide.
Yield: 30% of theory, Melting point: 209-211C
Cz5H2sN7 (423.54) Calculated: C 70.90 H 5.95 N 23.15 Found: 70.89 6.09 22.99 Mass spectrum: m/e = 423 Example 9 2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-1-t3-(2-tetrazol-5-yl-ethyl)-4-phenyl-benzyl]-benzimidazole Prepared analogously to Example 4 from 2-n-propyl-4- ~.
methyl-6-(1-isopropyl-imidazol-4-yl)-1-[3-(2-cyano-ethyl)-4-phenyl-benzyl]-benzimidazole and sodium azide in dimethylformamide.
Yield: 50~ of theory, Melting point: from 118C (sintering) C33H36N8 (544.71) Mass spectrum: (M~H)~ a 545 Rf value: 0.33 ~silica gel; methylene chloride/ethanol =
9 1) !

'' ~ ,' ~ " ' ~ '-` .

2~89689 In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I, particularly those compounds wherein Rb represents a group which may be converted into a carboxy group in vivo, a carboxy- or lH-tetrazolyl group, may be used as the active substance:

Exam~le 1 Ampoules containing 50 mg of active substance per 5 ml Active substance 50 mg KH2PO4 2 mg Na2HPO4 x 2Hz~ 50 mg NaCl 12 mg Water for injections ad5 ml Pre~aration:

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

Exam~le II

Ampoules containing 100 mg of active substance per 5 ml .

Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene-glycol block polymer250 mg Water for injections ad5 ml Preparation:

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

Example III

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

The active substance, CaHPO4, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50C in a circulating air dryer and screened again.

After the lubricant has been added, the granules are compr~ssed in a tablet making machine.

Exam~le IV

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 mg . , . . . , :
: . -- , :
.

208~689 Gelatin 10.0 mg Magnesium stearate 1.0 ma 180.0 mg Preparation:

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

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

Example V

Coated tablets containing 100 mg of active substance Active substance 100.0 mg Lysine ` 50.0 mg Lactose 86.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone2.8 mg Microcrystalline cellulose 60.0 mg Magnesium stearate 1.2 ma 350.0 mg PreParation:

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

, .' 208968~

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

Example VI

Capsules containing 250 mg of active substance -Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 mq 320.0 mg PreDaration:

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 si2e 1 hard gelatine capsules.

Example VII

Oral suspension containing 50 mg of active substance per 5 ml Active substance 50.0 mg Hydroxyethylcellulose50.0 mg Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg Water ad 5.0 ml ':" ~' " - ' '.~ ' ' ' ' ' ' .''' ~' ' - . .
.

208968~

Pre~ ration:

Distilled water is heated to 70C. 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.

Example VIII

Suppositories co~taining 100 mg of active substance -Active substance 100.0 mg Solid fat 1600~0 mq 1700.0 mg Preparation:

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

Claims (15)

1. Substituted biphenylyl derivatives of the general formula (I) wherein n denotes the number 0, 1, 2 or 3 and X denotes a bond or n denotes the number 1, 2 or 3 and X denotes an imino group optionally substituted by a C1-3-alkyl group, or an oxygen or sulphur atom, A denotes a 1,4-butadienylene group which is substituted by the groups R1 and R2 and wherein, additionally, an unsubstituted methine group may be replaced by a nitrogen atom, whilst R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group or a C1-3-alkyl group and R2 denotes a hydrogen atom, a C1-3-alkyl group, a C2-5-alkoxy group which is substituted in the 2-, 3-, 4- or 5-position by an imidazolyl, benzimidazolyl or tetrahydrobenzimidazolyl group, an alkanoylamino group having 2 to 5 carbon atoms in the alkanol moiety or a benzenesulphonylamino group, both of which may be substituted at the nitrogen atom by a C1-3-alkyl group, a phthalimino or homophthalimino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene group, a 5-, 6- or 7-membered alkyleneimino group in which a methylene group may be replaced by a carbonyl or sulphonyl group, a glutaric acid imino group wherein the n-propylene group may be substituted by one or two C1-3-alkyl groups or by a tetramethylene or pentamethylene group, a maleic acid imido group optionally mono- or disubstituted by a C1-3-alkyl group or by a phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl group optionally substituted in the 1-position by a C1-6-alkyl group or a C3-7-cycloalkyl group, wherein the phenyl nucleus in a benzimidazol-2-yl group as mentioned above may additionally be substituted by a fluorine atom or by a methyl or trifluoromethyl group, an imidazol[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazotl,2-a]pyridin-2-yl, imidazotl,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo-[1,2-a[pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, whilst a phenyl group may be fused onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl or sulphonyl group, an imidazol-4-yl group optionally substituted in the 2-position by a C1-6-alkyl group or by a phenyl group and possibly substituted in the 1-position by a C1-7-alkyl group (which may be substituted in the 2-, 3-, 4-, 5-, 6- or 7-position by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido-thiomorpholinocarbonyl group), by a C1-4-alkyl group substituted in the 2-, 3- or 4-position by a hydroxy, alkoxy or imidazol-1-yl group, by an alkyl group (which may be substituted by a trifluoromethyl group, by a C3-7-cycloalkyl group or by a phenyl group optionally mono-or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups), by an alkyl group substituted by two phenyl groups, or by a C3-7-cycloalkyl group, whilst unless otherwise specified the above-mentioned alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms, a group which may be converted in vivo into a carboxy group, a carbonyl group which is substituted by a hydroxy group, by a C1-6-alkoxy group, wherein the methoxy group is additionally substituted by an alkanoyloxy, alkoxycarbonyloxy or cycloalkoxycarbonyloxy group, or by an amino group optionally mono- or disubstituted by alkyl groups, whilst in the above-mentioned groups the alkanoyl moiety may contain 2 or 3 carbon atoms, the alkyl and alkoxy moieties may each contain 1 to 6 carbon atoms and the cycloalkoxy moiety may contain 5 to 7 carbon atoms, or an R5-NR4-CO-NR3- group wherein R3 denotes a hydrogen atom, a C1-5-alkyl group or a cyclohexyl or benzyl group, R4 denotes a hydrogen atom, a Cl-6-alkyl group, an allyl, cyclohexyl, benzyl or phenyl group, R5 denotes a hydrogen atom or a C1-3-alkyl group or R4 and R5 together with the nitrogen atom between them denote an unbranched C4-6-cycloalkyleneimino group or a morpholino group or R3 and R4 together denote a C2-3-alkylene group, Ra denotes a Cl-5-alkyl group, a C3-5-cycloalkyl group, an alkoxy, alkylthio or alkylamino group each having 1 to 3 carbon atoms in each alkyl moiety, Rb denotes a group which may be converted into a carboxy group in vivo, a carboxy, cyano, hydroxysulphonyl, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group, an alkanecarbonylaminosulphonyl, benzoylaminosulphonyl, alkanesulphonylaminocarbonyl, trifluoromethanesulphonyl-aminocarbonyl or phenylsulphonylaminocarbonyl group or, if n denotes the number 1 and X indicates a bond, a bis(hydroxycarbonyl)methyl or bis(alkoxycarbonyl)methyl group, whilst in the above-mentioned groups the alkyl and alkoxy moieties may each contain 1 to 4 carbon atoms, and Rc denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-4-alkyl group, an alkoxy, nitro, amino, alkylamino or dialkylamino group each having 1 to 3 carbon atoms in each alkyl moiety, whilst the phenyl nucleus of the above-mentioned phenyl groups may be mono- or disubstituted by chlorine or bromine atoms or by methyl or methoxy groups and the substituents may be identical or different, the mixtures of position isomers thereof and the salts thereof.
2. Substituted biphenylyl derivatives of general formula I according to claim l, wherein n denotes the number 0, l, 2 or 3 and X denotes a bond or n denotes the number l, 2 or 3 and X is an oxygen atom, A denotes a l,4-butadienylene group substituted by the groups R1 and R2 and wherein additionally the methine group in position 7 of the benzimidazole thus formed may be replaced by a nitrogen atom, whilst R1 denotes a hydrogen atom or in the 4-position a fluorine, chlorine or bromine atom, a trifluoromethyl group or a C1-3-alkyl group and R2 denotes a hydrogen atom, a C1-3-alkyl group, in the 6-position an alkanoylamino group having 2 to 5 carbon atoms in the alkanoyl moiety or a benzenesulphonylamino group, both of which may be substituted at the nitrogen atom by a C1-3-alkyl group, in the 6-position a phthalimino or homophthalimino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene group, in the 6-position a 5-, 6- or 7-membered alkyleneimino group wherein a methylene group is replaced by a carbonyl or sulphonyl group, in the 6-position a maleic acid imido group optionally mono- or disubstituted by a C1-3-alkyl group or by a phenyl group, wherein the substituents may be identical or different, in the 6-position a benzimidazol-2-yl group optionally substituted in the l-position by a C1-6-alkyl group or a C3-7-cycloalkyl group, whilst the phenyl nucleus in a benzimidazol-2-yl group as mentioned above may additionally be substituted by a fluorine atom or a methyl or trifluoromethyl group, an imidazo[2,1-b]thiazol-6-yl, imidazo[l,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl or imidazo[4,5-b]pyridin-2-yl group, in the 6-position an imidazol-4-yl group which may be substituted in the l-position by a C1-7-alkyl group (which may be substituted in the 2-, 3-, 4-, 5-, 6- or 7-position by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido-thiomorpholinocarbonyl group), by a C1-4-alkyl group (substituted in the 2-, 3- or 4-position by a hydroxy, alkoxy or imidazol-l-yl group), by an alkyl group substituted by a trifluoromethyl group, a C3-7-cycloalkyl group or a phenyl group (optionally mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups), by an alkyl group substituted by two phenyl groups, or by a C3-7-cycloalkyl group, whilst unless otherwise specified the above-mentioned alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms, in the 7-position a group which may be converted in vivo into a carboxy group, in the 7-position a carbonyl group which is substituted by a hydroxy group, by a C1-6-alkoxy group, wherein the methoxy group is additionally substituted by an alkanoyloxy, alkoxycarbonyloxy or cycloalkoxycarbonyloxy group, or by an amino group optionally mono- or disubstituted by alkyl groups, whilst in the above-mentioned groups the alkanoyl moiety may contain 2 or 3 carbon atoms, the alkyl and alkoxy moieties may each contain 1 to 6 carbon atoms and the cycloalkoxy moiety may contain 5 to 7 carbon atoms, or in the 6-position an R5-NR4-CO-NR3- group wherein R3 denotes a hydrogen atom, a C1-5-alkyl group or a cyclohexyl or benzyl group, R4 denotes a hydrogen atom, a C1-6-alkyl group or an allyl, cyclohexyl, benzyl or phenyl group, R5 denotes a hydrogen atom or a C1-3-alkyl group or R4 and R5 together with the nitrogen atom between them denote an unbranched C4-6-cycloalkyleneimino group or a morpholino group or R3 and R4 toqether denote a C2-3-alkylene group, Ra denotes a C2-4-alkyl group, a C3-4-cycloalkyl group or a C2-3-alkoxy group, Rb denotes a group which may be converted in vivo into a carboxy group, or a carboxy or lH-tetrazolyl group and Rc denotes a hydrogen atom, the mixtures of position isomers thereof and the salts thereof.
3. Substituted biphenylyl derivatives of general formula I according to claim 1 wherein n denotes the number 0, 1, 2 or 3 and X denotes a bond, A denotes a 1,4-butadienylene group which is substituted by the groups R1 and R2 and wherein additionally the methine group in position 7 of the benzimidazole thus formed may be replaced by a nitrogen atom, wherein R1 is a hydrogen atom or in the 4-position a methyl group and R2 in the 6-position is a 1-isopropyl-imidazol-4-yl or 1-methyl-benzimidazol-2-yl group or in the 7-position represents a group which may be converted into a carboxy group in vivo or a carboxy group, Ra denotes a C2-4-n-alkyl group, Rb denotes a group which may be converted into a carboxy group in vivo, a carboxy or 1H-tetrazolyl group and Rc denotes a hydrogen atom, the mixtures of position isomers thereof and the salts thereof.
4. Substituted biphenylyl derivatives of general formula I according to claim 1, wherein A, X, Ra to Rc and n are defined as in claims 1 to 3, with the proviso that Rb denotes a carboxy or lH-tetrazol-5-yl group or R2 or Rb or R2 and Rb denote a group of the formulae - CO - OR', - CO - O - (HCR") - O - CO - R"' and - CO - O - (HCR") - O - CO - OR"' which may be converted in vivo into a carboxy group, wherein R' denotes a straight-chained or branched C1-6-alkyl group, a C5-7-cycloalkyl group, a benzyl, l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, R" denotes a hydrogen atom or a methyl group and R"' denotes a straight-chained or branched C1-6-alkyl group, a C5-7-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group, the mixtures of position isomers thereof and the salts thereof.
5. The compound 2-n-propyl-4-methyl-1-[3-(tetrazol-5-yl-methyl)-4-phenyl-benzyl]-benzimidazole, the mixtures of position isomers thereof and the salts thereof.
6. The compound 2-n-propyl-4-methyl-1-[3-(2-hydroxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole, the mixtures of position isomers thereof and the salts thereof.
7. The compound 2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-[3-(2-hydroxycarbonyl-ethyl)-4-phenyl-benzyl]-benzimidazole, the mixtures of position isomers thereof and the salts thereof.
8. The compound 2-ethyl-5,7-dimethyl-3-[3-ttetrazol-5-yl-methyl)-4-phenyl-benzyl]-imidazo[4,5-b]pyridine, the mixtures of position isomers thereof and the salts thereof.
9. The compound 2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-1-[3-(2-tetrazol-5-yl-ethyl)-4-phenyl-benzyl]-benzimidazole, the mixtures of position isomers thereof and the salts thereof.
10. Physiologically acceptable salts of the compounds according to any one of claims 1 to 9 with inorganic or organic acids or bases.
11. Pharmaceutical compositions containing a compound according to any one of claims 1 to 9 or a physiologically acceptable salt thereof, together with an inert carrier or diluent.
12. Use of a compound according to any one of claims 1 to 9, or a physiologically acceptable salt thereof as an angiotensin-antagonistic agent.
13. A process for preparing a pharmaceutical composition, which process comprises admixing a compound according to any one of claims 1 to 9, or a physiologically acceptable salt thereof, with a suitable carrier or diluent.
14. A commercial package containing, as active pharmaceutical ingredient, a compound according to any one of claims 1 to 9 or a physiologically acceptable salt thereof, together with instructions for its use for the treatment of hypertension and cardiac insufficiency, for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for preventing the progression of cardiac insufficiency after myocardial infarct, for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
15. A process for preparing a substituted biphenylyl derivative of general formula I according to any one of claims 1 to 9, or a physiologically acceptable salt thereof, characterised in that a) a compound of general formula (II) wherein A and Ra are as defined in any one of claims 1 to 9, is reacted with a biphenyl compound of general formula (III) wherein n, X, Rb and Rc are as defined in any one of claims 1 to 9 and Z1 denotes a nucleophilic leaving group, and if required a compound thus obtained is hydrolysed, or b) in order to prepare a compound of general formula I
wherein Rb denotes a carboxy group, a compound of general formula (IV) wherein n, X, A, Ra and Rc are as deflned ln any one of claims 1 to 9 and Rb' denotes a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, is converted into a corresponding carboxy compound, or c) in order to prepare a compound of general formula I

wherein Rb denotes a 1H-tetrazolyl group, a protecting group is cleaved from a compound of general formula (V) wherein n, X, A, Ra and Rc are as defined in claims 1 to 9 and Rb" denotes a 1H-tetrazolyl group protected in the 1- or 2-position by a protecting group, or d) in order to prepare a compound of general formula I
wherein Rb denotes a 1H-tetrazolyl group, a compound of general formula (VI) wherein n, X, A, Ra and Rc are as defined in any one of claims 1 to 9, is reacted with hydrazoic acid or with a salt thereof, or e) in order to prepare a compound of general formula I
wherein n denotes the number 1, X denotes a bond and Rb denotes a bis(hydroxycarbonyl)methyl or bis(alkoxycarbonyl)methyl group, a compound of general formula (VII) wherein n, A, Ra and Rc are as defined in any one of claims 1 to 9 and R2 denotes a nucleophllic leaving group, is reacted with a compound of general formula CH2(COOR6)2 (VIII) wherein R6 denotes a C1-5-alkyl group, and if required a compound thus obtained is subsequently hydrolysed or decarboxylated, or f) in order to prepare a compound of general formula I
wherein R2 denotes an R5-NR4-CONR3- group, a compound of general formula (IX) is reacted with a compound of general formula (X) wherein Ra, Rb, Rc, R4, R5, X and n are as defined in any one of claims 1 to 9, A1 denotes a 1,4-butadienylene group substltuted by R1 and by the R3NH group, wherein R1 and R3 are as defined in any one of claims 1 to 9, and Z3 denotes a nucleophilic leaving group or Z3 and R5 together denote a nitrogen-carbon bond, or g) in order to prepare a compound of general formula I
wherein R2 denotes an alkanoylamino group having 2 to 5 carbon atoms in the alkanoyl moiety or a benzenesulphonylamino group, both of which may be substituted at the nitrogen atom by a C1-3-alkyl group, or a phthalimino or homophthalimino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene group, or a 5-, 6- or 7-membered alkyleneimino group in which a methylene group is replaced by a carbonyl or sulphonyl group, or a glutaric acid imino group which the n-propylene group may be substituted by one or two C1-3-alkyl groups or by a tetramethylene or pentamethylene group, or a maleic acid imido group optionally mono- or dlsubstituted by a C1-3-alkyl group or by a phenyl group, wherein the substituents may be identical or different, a compound of general formula (IX) is reacted with a compound of general formula Z4 - U R7 (XI) wherein Ra, Rb, Rc, R4, R5, X and n are as defined in any one of claims 1 to 9, A1 denotes a 1,4-butadienylene group which is substituted by R1 and by the R3NH group, wherein R1 and R3 are as defined in any one of claims 1 to 9, Z4 denotes a hydroxy group or a nucleophilic leaving group, U denotes a carbonyl or sulphonyl group and R7 denotes a C1-5-alkyl group, a phenyl, o-hydroxycarbonylphenyl, o-hydroxycarbonylphenylmethyl or o-hydroxycarbonylmethylphenyl group, a 3-hydroxycarbonylpropylene group optionally substituted by one or two C1-3-alkyl groups or by a tetramethylene or pentamethylene group or a 2-hydroxycarbonylethylene group optionally mono- or disubstituted by a C1-3-alkyl group or by a phenyl group, wherein the substituents may be identlcal or different, or R3 and R7 together denote an n-propylene, n-butylene or n-hexylene group or, if Z4 denotes a hydroxy group, with the reactive derivatives thereof, and subsequently, if required, a compound of general formula I thus obtained wherein R2 or Rb or R2 and Rb denote a carboxy group is converted by esterification into a corresponding compound of general formula I wherein R2 or Rb or R2 and Rb denote a group which may be converted in vivo into a carboxy group, and if required a protecting group used to protect reactive groups during reactions a) to g) is cleaved and/or if required, a mixture of position isomers of a compound of general formula I thus obtained is resolved by isomer separation or a compound of general formula I thus obtained is converted into a salt thereof.
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