IE912563A1 - Benzimidazoles - Google Patents

Benzimidazoles

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Publication number
IE912563A1
IE912563A1 IE256391A IE256391A IE912563A1 IE 912563 A1 IE912563 A1 IE 912563A1 IE 256391 A IE256391 A IE 256391A IE 256391 A IE256391 A IE 256391A IE 912563 A1 IE912563 A1 IE 912563A1
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IE
Ireland
Prior art keywords
group
methyl
butyl
biphenyl
benzimidazol
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IE256391A
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Thomae Gmbh Dr K
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Priority claimed from DE4023369A external-priority patent/DE4023369A1/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of IE912563A1 publication Critical patent/IE912563A1/en

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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • 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
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • 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

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Abstract

The invention relates to benzimidazoles of the general formula <IMAGE> in which R1 to R4 are as defined in Claim 1, mixtures of their 1-, 3-isomers, and their salts, which have valuable properties. The novel compounds are, in particular, angiotensin antagonists.

Description

Benzimidazoles The present invention relates to new benzimidazoles, processes for their preparation and pharmaceutical compositions containing them.
US—A—4,880,804 describes inter alia 4(2-alkylbenzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acids and 4 '-[(2-alkyl-benzimidazol-l-yl)-methyl]-2-(lHtetrazol-5-yl)-biphenyls which are substituted in the benzimidazole ring by an alkanoylaminomethyl group and which are angiotension-II antagonists.
It has now been found that certain new benzimidazoles are even more useful angiotensin antagonists, particularly angiotensin-II antagonists.
Thus, according to one aspect the present invention provides compounds of formula I R (wherein R1 represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, a benzimidazolyl or benzoxazolyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a C^j-alkyl group, by a C^-alkoxy group or by a trifluoromethyl group, and in which the NH-group of the above-mentioned imidazole rings may additionally be substituted by a C16-alkyl group or by a C3.7-cycloalkyl group, an amino - 2 group substituted by a bicyclohexylcarbonyl, biphenylcarbonyl, or hydroxy (C5.7-cycloalkyl) amino carbonyl group which may additionally be substituted at the N-atom by a C.,_3-alkyl group, an aminocarbonylamino group substituted by a bicyclohexyl or biphenyl group and optionally also substituted by one or two C1.3-alkyl groups at the N-atom, with the exception of the 2-oxo3,4-tetramethylene-pyrrolidin-l-yl group, a 5-, 6- or 7membered alkyleneimino or alkenyleneimino group optionally substituted by one or two C^j-alkyl groups or by a tetramethylene or pentamethylene group, in which a methylene group is replaced by a carbonyl or sulphonyl group, a 3,4,5,6-tetrahydro-2(1H)-pyrimidinone group optionally substituted by a Cv3-alkyl or phenyl(Chalky 1) group, a straight-chained or branched hydroxy(C46-alkyl)amino carbonyl group, a maleic acid amido or maleic acid imido group optionally mono- or disubstituted by a C^j-alkyl or by a phenyl group, in which the substituents may be identical or different, an imidazoline or imidazole group optionally substituted by a C1.6-alkyl group or by a C3.7-cycloalkyl group, an imidazolidinedione group optionally substituted by a C^j-alkyl group, by a phenyl (C1.3-alkyl) group or by a tetramethylene, pentamethylene or hexamethylene group, a CV6-alkylsulphonyloxy group, a benzenesulphonyloxy group optionally substituted by a C.,_3-alkyl group, a CV3alkylamino or phenyl (C1.3-alkyl) amino group substituted by a C4.6-alkylsulphonyl group or by a phenyl (C^jalkyl) sulphonyl group, an amino or C1.3-alkylamino group substituted by a naphthalenesulphonyl group optionally substituted in the naphthalene ring by a di(CV3alkyl)amino group or by one or two CV3-alkoxy groups, a C3.5-alkoxy group substituted in the 3-, 4- or 5-position by an imidazolyl group, a C2.5-alkoxy group substituted in the 2-, 3-, 4- or 5-position by a benzimidazolyl or tetrahydrobenzimidazolyl group, a pyridazin-3-one or dihydro-pyridazin-3-one group optionally substituted in - 3 the 2-position by an optionally phenyl-substituted Chalky 1 group and optionally additionally substituted at a carbon atom by 1 or 2 Cv3~alkyl groups, a pyrrolidino, piperidino or hexamethyleneimino group substituted by two C^j-alkyl groups, a 7-nitrobenzofurazan-4-ylamino(C2.3-alkanoyl) amino group, a heptamethyleneimino, 1H, 3H-quinazolin-2,4-dion-3-yl, pentamethylene-oxazolin2-yl, benzofuran-carbonylamino or 7-nitro-benzofurazan4-yl-amino group, and where R3 represents a carboxy group and R2 represents an n-butyl group, R1 in the 6-position may also represent an amino group substituted by a phenylsulphonyl, cyclohexylmethylaminocarbonyl, 2-carboxycyclohexylmethylcarbonyl, 2-tert.butoxycarbonyl-cyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6-tetrahydrobenzoyl, N-methylphenylaminocarbonyl or 3-cyclohexylpropyl group, a methylamino group substituted by a propylsulphonyl, phenylsulphonyl, methylphenylsulphonyl or chlorophenylsulphonyl group, an n-pentylamino group substituted by a phenylsulphonyl or methoxyphenylsulphonyl group, an npropylamino group substituted by a methylphenylsulphonyl or methoxyphenylsulphonyl group, an isopropylamino group substituted by a benzoyl or chlorophenylsulphonyl group, an N-acetyl-cyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido, hexahydrohomophthalimido, N-methanesulphonyl-2-phenylethylamino, N-chlorophenylsulphonyl-benzylamino, piperidino, 4-methyl-piperidino or hexamethyleneimino group, and where R3 represents a carboxy group and R2 represents an n-butyl group, R1 in the 5- or 6-position may also represent a 2-oxo-l,2-dihydro-3,4-tetramethylenepyrrolidin-l-yl, 3-carboxy-propionyl or 3-carboxy-2methyl-propionyl group, and where R3 represents a carboxy group and R2 represents a - 4 methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R, in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R3 represents a tetrazolyl group and R2 represents an n-butyl group, R, in the 5- or 6-position may also represent an n-pentylamino group substituted by a methyl-aminocarbonyl or cyclohexylaminocarbonyl group, and R, in the 6-position may also represent a 3,3dimethyl-glutaric acid imido or 4,4-tetramethyleneglutaric acid imido group, and where R3 represents a tetrazolyl group and R2 represents an ethyl or n-propyl group, R, in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and where R3 represents a tert.butoxycarbonyl group and R2 represents an n-butyl group, R1 in the 6-position may also represent a 2-carboxycyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group; Rj represents a hydrogen atom or a straight-chained or branched Cv5-alkyl group in which a methylene group may optionally be replaced by a sulphur atom; R3 represents a carboxy, cyano, ΙΗ-tetrazolyl or 1triphenylmethyl-tetrazolyl group or a (C14~alkoxy)carbonyl group; and r4 represents a hydrogen, fluorine, chlorine or bromine atom); and isomers, especially the 1-,3-isomer mixtures, and salts thereof, in particular, for pharmaceutical use the physiologically acceptable salts thereof with organic or inorganic acids or bases.
The following are examples of the definitions of the - 5 groups R1 and R2 as mentioned hereinbefore: R1 may represent a benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, l-ethyl-benzimidazol-2-yl, 1-npropyl-benzimidazol-2-yl, l-isopropyl-benzimidazol-2-yl, l-n-butyl-benzimidazol-2-yl, l-n-pentyl-benzimidazol-2yl, l-n-hexyl-benzimidazol-2-yl, 1-cyclopropylbenzimidazol-2-yl, l-cyclopentyl-benzimidazol-2-yl, 1cyclohexyl-benzimidazol-2-yl, 1-cycloheptylbenzimidazol-2-yl, 1,5-dimethyl-benzimidazol-2-yl, 1,6dimethyl-begzimidazol-2-yl, l-methyl-5-methoxybenzimidazol-2-yl, l-methyl-5-fluoro-benzimidazol-2-yl, 1- methyl-5-chloro-benziroidazol-2-yl, l-methyl-5-bromobenzimidazol-2-yl, l-methyl-5-trifluoromethylbenzimidazol-2-yl, tetrahydro-benzimidazol-2-yl, 1methyl-tetrahydro-benzimidazol-2-yl, 1-ethyl-tetrahydrobenzimidazol-2-yl, l-n-propyl-tetrahydro-benzimidazol-2yl, l-isopropyl-tetrahydro-benzimidazol-2-yl, 1-n-butyltetrahydro-benzimidazol-2-yl, 1-n-pentyl-tetrahydrobenzimidazol-2-yl, l-n-hexyl-tetrahydro-benzimidazol-2yl, l-cyclopropyl-tetrahydro-benzimidazol-2-yl, 1cyclopentyl-tetrahydro-benzimidazol-2-yl, 1-cyclohexyltetrahydro-benzimidazol-2-yl, 1-cycloheptyl-tetrahydrobenzimidazol-2-yl, benzoxazol-2-yl, 5-methyl-benzoxazol2- yl, 5-methoxy-benzoxazol-2-yl, 5-trifluoromethy1benzoxazol-2-yl, 5-fluoro-benzoxazol-2-yl, 5-chlorobenzoxazol-2-yl, 5-bromo-benzoxazol-2-yl, 4-biphenylylcarbonylamino, 4-cyclohexylcarbonylamino, N-methyl-4biphenylylcarbonylamino, N-ethyl-4-cyclohexylcarbonylamino, N-n-propyl-4-biphenylylcarbonylamino, Nisopropyl-4-cyclohexylcarbonylamino, 2-hydroxycyclopentylamino, 2-hydroxy-cyclohexylamino, 2-hydroxycycloheptylamino, 3-hydroxy-cyclopentylamino, 3-hydroxycyclohexylamino, 3-hydroxy-cycloheptylamino, 4-hydroxycyclohexylamino, 4-hydroxy-cycloheptylamino, N-methyl-2hydroxy-cyclopentylamino, N-ethyl-2-hydroxycyclohexylamino, N-isopropyl-2-hydroxy-cycloheptylamino, \ -6N-methyl-3-hydroxy-cyclopentylamino, N-ethy1-3-hydroxy cyclohexylamino, N-n-propyl-3-hydroxy-cycloheptylamino N-methyl-4-hydroxy-cyclohexylamino, N-ethyl-4-hydroxycycloheptylamino, 4-biphenylylaminocarbonylamino, 4bicyclohexylaminocarbonylamino, N-(4-biphenylylaminocarbonyl)-methylamino, N-(4-bicyclohexylaminocarbonyl) methylamino, N-(methyl-4-biphenylylaminocarbonyl)methylamino, N-(methyl-4-bicyclohexylaminocarbonyl)methylamino, N-(4-biphenylylaminocarbonyl)-ethylamino, N-(4-bicyclohexylaminocarbonyl)-isopropylamino, N(ethyl-4-biphenylylaminocarbonyl)-methylamino, N(methyl-4-bicyclohexylaminocarbonyl)-ethylamino, pyrrolidin-2-on-l-yl, piperidin-2-on-l-yl, hexamethyleneimino-2-on-l-yl, propanesultam-l-yl, butanesultam-l-yl, pentanesultam-l-yl, 3,4,5,6tetrahydro-2(1H)-pyrimidon-l-yl, 3-methyl-3,4,5,6tetrahydro-2(1H)-pyrimidon-lyl, 3-ethyl-3,4,5,6tetrahydro-2(1H)-pyrimidon-l-yl, 3-n-propyl-3,4,5,6tetrahydro-2(1H)-pyrimidon-l-yl, 3-isopropyl-3,4,5,6tetrahydro-2(1H)-pyrimidon-l-yl, 3-benzyl-3,4,5,6tetrahydro-2(1H)-pyrimidon-l-yl, 3-(2-phenylethyl)3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(3phenylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 4-hydroxybutylamino, 5-hydroxypentylamino, 6-hydroxyhexylamino, maleic acid imido, 2-methyl-maleic acid imido, 2-phenyl-maleic acid imido, 2,3-dimethyl-maleic acid imido, 2,3-diphenyl-maleic acid imido, 2-methylmaleic acid amido, 3-methyl-maleic acid amido, 2,3dimethyl-maleic acid amido, 2-phenyl-maleic acid amido 3-phenyl-maleic acid amido, 2,3-diphenyl-maleic acid amido, 3-methyl-2-phenyl-maleic acid amido, 2-methyl-3 phenyl-maleic acid amido, imidazolin-2-yl, 1-methylimidazolin-2-yl, l-ethyl-imidazolin-2-yl, 1-propylimidazolin-2-yl, imidazolidin-2,4-dion-3-yl, 5-methylimidazolidin-2,4-dion-3-yl, 5-ethyl-imidazolidin-2,4dion-3-yl, 5-n-propyl-imidazolidin-2,4-dion-3-yl, 5benzyl-imidazolidin-2,4-dion-3-yl, 5-(2-phenylethyl)\ imidazolidin-2,4-dion-3-yl, 5-(3-phenylpropyl)imidazolidin-2,4-dion-3-yl, 5,5-tetramethyleneimidazolidin-2,4-dion-3-yl, 5, 5-pentamethyleneimidazolidin-2,4-dion-3-yl, 5,5-hexamethyleneimidazolidin-2,4-dion-3-yl, 5,5-dimethyl-imidazolidin2,4-dion-3-yl, 5,5-diethyl-imidazolidin-2,4-dion-3-yl, methanesulphonyloxy, ethanesulphonyloxy, propanesulphonyloxy, butanesulphonyloxy, pentanesulphonyloxy, hexanesulphonyloxy, benzenesulphonyloxy, p-toluenesulphonyloxy, N-n-butanesulphonyl-methylamino, N-n-pentanesulphonyl-methylamino, N-n-hexanesulphonylmethylamino, N-phenylmethanesulphonyl-methylamino, N-(2 phenylethanesulphonyl)-methylamino, N-(3-phenylpropanesulphonyl)-methylamino, N-n-butanesulphonyl-ethylamino, N-n-pentanesulphonyl-isopropylamino, N-nhexanesulphonyl-ethylamino, N-phenylmethanesulphonylethylamino, N-(2-phenylethanesulphonyl)-n-propylamino, N-(3-phenylpropanesulphonyl)-ethylamino, naphthalen-1sulphonylamino, naphthalen-2-sulphonylamino, 5dimethylamino-naphthalen-l-sulphonylamino, N(naphthalen-l-sulphonyl)-methylamino, N-(naphthalen-2sulphonyl)-ethylamino, N-(5-dimethylamino-naphthalen-lsulphony 1 )-methylamino, N-(5-methoxynaphthalen-lsulphonyl)-methylamino, N-(5,6-dimethoxy-naphthalen-2sulphonyl)-ethylamino, 3-(imidazol-l-yl)-propoxy, 4(imidazol-l-yl)-butoxy, 5-(imidazol-l-yl)-pentoxy, 2(benzimidazol-l-yl)-ethoxy, 3-(benzimidazol-l-yl)propoxy, 4-(benzimidazol-l-yl)-butoxy, 5-(benzimidazoll-yl) -pentoxy , 2-(tetrahydrobenzimidazol-l-yl)-ethoxy, 3-(tetrahydrobenzimidazol-l-yl)-propoxy, 4-(tetrahydrobenzimidazol-l-yl)-butoxy, 5-(tetrahydrobenzimidazol-lyl) -pentoxy, 4,5-dihydro-2H-pyridazin-3-on-6-yl, 2methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-ethyl-4,5dihydro-2H-pyridazin-3-on-6-yl, 2-n-propyl-4,5-dihydro2H-pyridazin-3-on-6-yl, 2-isopropyl-4,5-dihydro-2Hpyridazin-3-on-6-yl, 2-benzyl-4,5-dihydro-2H-pyridazin3-on-6-yl, 2-(2-phenylethyl)-4,5-dihydro-2H-pyridazin-3 on-6-yl, 2-(3-phenylpropyl)-4,5-dihydro-2H-pyridazin-3on-6-yl, 4-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 5methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 4,4-dimethyl4.5- dihydro-2H-pyridazin-3-on-6-yl, 5,5-dimethyl-4,5dihydro-2H-pyridazin-3-on-6-yl, 4,5-dimethyl-4,5dihydro-2H-pyridazin-3-on-6-yl, 2,4-dimethyl-4,5dihydro-2H-pyridazin-3-on-6-yl, 2,5-dimethyl-4,5dihydro-2H-pyridazin-3-on-6-yl, 2,4,5-trimethyl-4,5dihydro-2H-pyridazin-3-on-6-yl, 2,4,4-trimethyl-4,5dihydro-2H-pyridazin-3-on-6-yl, 2,5,5-trimethyl-4,5dihydro-2H-pyridazin-3-on-6-yl, 2H-pyridazin-3-on-6-yl, 2-methyl-2H-pyridazin-3-on-6-yl, 2-ethyl-2H-pyridazin-3on-6-yl, 2-n-propyl-2H-pyridazin-3-on-6-yl, 2-isopropyl2H-pyridazin-3-on-6-yl, 2-benzyl-2H-pyridazin-3-on-6-yl, 2-(2-phenylethyl)-2H-pyridazin-3-on-6-yl, 2-(3phenylpropyl)-2H-pyridazin-3-on-6-yl, 4-methyl-2Hpyridazin-3-on-6-yl, 5-methyl-2H-pyridazin-3-on-6-yl, 4.5- dimethyl-2H-pyridazin-3-on-6-yl, 2,4-dimethyl-2Hpyridazin-3-on-6-yl, 2,5-dimethyl-2H-pyridazin-3-on-6yl, 2,4,5-trimethyl-2H-pyridazin-3-on-6-yl, 3,3dimethyl-pyrrolidino, 3,4-dimethyl-pyrrolidino, 3,3dimethyl-piperidino, 3,4-dimethylpiperidino, 4,4dimethyl-piperidino, 3,3-dimethyl-hexamethyleneimino, 3,4-dimethyl-hexamethyleneimino, 4,4-dimethylhexamethyleneimino, 3,5-dimethyl-hexamethyleneimino, phenylsulphonylamino, cyclohexylmethylaminocarbonylamino, 2-methylamino-benzoylamino, 2-carboxy-cyclohexylmethylcarbonylamino, 2-tert.butoxycarbonylcyclohexylmethylcarbonylamino, 2-carboxy-3,4,5,6tetrahydrobenzoylamino, 3-cyclohexylpropylamino, Npropylsulphonyl-methylamino, N-phenylsulphonylmethylamino, N-(4-methylphenylsulphonyl)-methylamino, N(4-chlorophenylsulphonyl)-methylamino, N-phenylsulphonyl-n-pentylamino, N-(4-methoxyphenylsulphonyl)-npentylamino, N-(4-methylphenylsulphonyl)-n-propylamino, N- (4-methoxyphenylsulphonyl)-n-propylamino, N-benzoylisopropylamino, N-(4-chlorophenylsulphonyl)-isopropylIE 912563 - 9 amino, N-acetyl-cyclohexylmethylamino, 3,4,5,6tetrahydrophthalimido, hexahydrophthalimido, N-methanesulphonyl-2-phenylethylamino, N-chlorophenylsulphonylbenzylamino, piperidino, 4-methyl-piperidino, hexamethyleneimino, 3-carboxy-propionyl, 3-carboxy-2methyl-propionyl, pyrrolidinocarbonylamino, Nmethylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbonyl-n-pentylamino, 3,3-dimethyl-glutaric acid imido, 4,4—tetramethylene—glutaric acid imido, 2carboxy-cyclohexylmethylcarbonylamino, 1-n-butylimidazolin-2-yl, l-n-pentyl-imidazolin-2-yl, 1-n-hexylimidazolin-2-yl, l-cyclopropyl-imidazolin-2-yl, lcyclobutyl-imidazolin-2-yl, l-cyclohexyl-imidazolin-2yl, l-cycloheptyl-imidazolin-2-yl, imidazol-2-yl, 1methyl-imidazol-2-yl, l-ethyl-imidazol-2-yl, 1-propylimidazol-2-yl, l-n-butyl-imidazol-2-yl, 1-n-pentylimidazol-2-yl, l-n-hexyl-imidazol-2-yl, 1-cyclopropylimidazol-2-yl, l-cyclobutyl-imidazol-2-yl, 1-cyclohexyl imidazol-2-yl or l-cycloheptyl-imidazol-2-yl group; and 1*2 may represent a hydrogen atom, a methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tert.-butyl, npentyl, l-methylpropyl, 1-methylbutyl, 2-methylbutyl, 3 methylbutyl, 1-ethylpropyl, 1,1-diethylethyl, methylmercaptomethyl, 2-methylmercapto-ethyl, 3methylmercaptopropyl or 4-methylmercaptobutyl group.
Preferred compounds according to the invention include those of formula I wherein R1 represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, a benzimidazolyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom or by a methyl, methoxy or trifluoromethyl group, and in which the NHgroup of the above-mentioned imidazole rings may additionally be substituted by a CV6-alkyl group or by - 10 Cj^-cycloalkyl group, a benzoxazol-2-yl group optionally substituted by a methyl group, an amino group substituted by a bicyclohexylcarbonyl, biphenylcarbonyl or benzofuryl-2-carbonyl group, an aminocarbonylamino group substituted in the 3-position by a bicyclohexyl or biphenyl group, a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two methyl groups or by a tetramethylene or pentamethylene group wherein a methylene group is replaced by a carbonyl or sulphonyl group, a 3,4,5,6tetrahydro-2(1H)-pyrimidinone group optionally substituted by a methyl or benzyl group, a hydroxy(C4alkyl)aminocarbonyl group, a maleic acid amido or maleic acid imido group optionally substituted by one or two substituents which may be the same or different selected from methyl and phenyl groups, an imidazolin-2-yl or imidazol-2-yl group substituted in the 1-position by a C^-alkyl group or by a C3.7~cycloalkyl group, an imidazolidinedione group optionally substituted by a methyl, benzyl, tetramethylene or pentamethylene group, a methylamino or benzylamino group substituted by a butanesulphonyl group or by a phenylmethanesulphonyl group, an amino or methylamino group substituted by a naphthalenesulphonyl group in which the naphthalene ring may be substituted by a dimethylamino group or by 2 methoxy groups, a pyridazin-3-one or dihydro-pyridazin3-one group optionally substituted by a methyl or benzyl group, a pyrrolidino, piperidino or hexamethyleneimino group substituted by two methyl groups, a heptamethyleneimino, 1H,3H-quinazolin-2,4-dion-3-yl, hydroxycyclohexylamino-carbonyl, 4,5-pentamethyleneoxazolin-2-yl, 7-nitro-benzofurazan-4-yl-amino or 7nitro-benzofurazan-4-yl-aminopropionylamino group, and where R3 represents a carboxy group and R2 represents an n-butyl group, R1 in the 6-position may also represent an amino group substituted by a phenylsulphonyl, - 11 cyclohexylmethylaminocarbonyl, 2-carboxycyclohexylmethylcarbonyl, 2-tert.-butoxycarbonyl-cyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6-tetrahydrobenzoyl, Nmethyl-phenylaminocarbonyl or 3-cyclohexylpropyl group, a methylamino group substituted by a propylsulphonyl, phenylsulphonyl, 4-methylphenylsulphonyl or 4chlorophenylsulphonyl group, an n-pentylamino group substituted by a phenylsulphonyl or 4-methoxyphenylsulphonyl group, an n-propylamino group substituted by a 4-methylphenylsulphonyl or 4-methoxyphenylsulphonyl group, an isopropylamino group substituted by a benzoyl or 4-chlorophenylsulphonyl group, an N-acetylcyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido, hexahydrohomophthalimido, N-methanesulphonyl-2phenylethylamino, N-(4-chlorophenylsulphonyl)benzylamino, piperidino, 4-methyl-piperidino or hexamethyleneimino group, and where R3 represents a carboxy group and R2 represents an n-butyl group, R1 in the 5- or 6-position may also represent a 2-oxo-l,2-dihydro-3,4-tetramethylenepyrrolidin-l-yl, 3-carboxy-propionyl or 3-carboxy-2methyl-propionyl group, and where R3 represents a carboxy group and R? represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R1 in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R3 represents a tetrazolyl group and R2 represents an n-butyl group, R1 in the 5- or 6-position may also represent an n-pentylamino group substituted by a methylaminocarbonyl or cyclohexylaminocarbonyl group and R, in the 6-position may also represent a 3,3-dimethylglutaric acid imido or 4,4-tetramethylene-glutaric acid imido group, and - 12 where R3 represents a tetrazolyl group and R2 represents an ethyl or n-propyl group, R, in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and where R3 represents a tert.butoxycarbonyl group and R2 represents an n-butyl group, R, in the 6-position may also represent a 2-carboxy-cyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group; R2 represents a hydrogen atom or a straight-chained or branched C1.4-alkyl group in which a methylene group may be replaced by a sulphur atom; R3 represents a carboxy, cyano, ΙΗ-tetrazolyl or 1triphenylmethyl-tetrazolyl group or a (CV4-alkoxy)carbonyl group; and R4 represents a hydrogen, fluorine, chlorine or bromine atom; and isomers and salts thereof, especially the 1-, 3isomer mixtures thereof, and particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
Particularly preferred compounds according to the invention include those of formula I wherein R1 in the 6-position represents a l-methylbenzimidazol-2yl, 3,4,5,6-tetrahydro-phthalimino, 2,3-diphenyl-maleic acid imido, 2,3-dimethyl-maleic acid imido, N-phenylmethanesulphonyl-methylamino, 2-oxo-pyrrolidin-l-yl, 2oxo-piperidin-l-yl, 2-oxo-hexamethyleneimino, 2-oxo-3,4tetramethylene-pyrrolidin-2-yl, 3,3-dimethylglutarimido, N-methylaminocarbonyl-n-pentylamino, propanesultam-l-yl or butanesultam-l-yl group; - 13 1*2 represents a methyl, ethyl, n-propyl or n-butyl group R3 represents a carboxy or ΙΗ-tetrazolyl group; and R4 represents a hydrogen atom; and the isomers and salts, especially the 1-,3- isomer mixtures thereof and particularly the physiologically acceptable addition salts thereof with organic or inorganic acids or bases.
Although the present invention relates to new compounds of formula I, the corresponding cyano, tert.butoxycarbonyl and triphenylmethyl compounds, in particular, represent valuable intermediates which can readily be converted to one of the pharmacologically active compounds.
According to a further aspect the invention also provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps: a) cyclising a compound of formula II (wherein R1 is as hereinbefore defined; one of the groups X1 or Y, represents a group of formula R and the other group X1 or Y1 represents a group of formula / NH - XCZ - R. '2 R2, R3 and R4 are as hereinbefore defined; Rj represents a hydrogen atom or an R2CO group; Z1 and Z2, which may be the same or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl (e.g. C1.6-alkyl) groups, or Z, and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C13~alkyl group, or a C2.3-alkylenedioxy or C2.3alkylenedithio group, with the proviso that one of the groups X, or Y1 must represent a group of formula cor2 or NH - C - R2 ) or an N-oxide thereof - 15 and subsequently if necessary reducing the cyclized N oxide product; b) reacting a benzimidazole of formula III (wherein Rj and R? are as hereinbefore defined) with a biphenyl compound of formula IV (wherein R3 and R4 are as hereinbefore defined; and Z3 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or ptoluenesulphonyloxy group); c) (to prepare a compound of formula I wherein R3 represents a carboxy group) converting a compound of formula V (wherein 1*2 and R4 are as hereinbefore defined; R,1 is a group R1 as hereinbefore defined or a 3-((C.,_3alkoxy)carbonyl)propionyl or 3-((C13-alkoxy)carbonyl)-2methylpropionyl group; and R3' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound; d) (to prepare a compound of formula I wherein R3 represents a ΙΗ-tetrazolyl group) cleaving a protecting group from a compound of formula VI R (VI ) (wherein R,, R2 and R4 are as hereinbefore defined; and R3 represents a ΙΗ-tetrazolyl group protected in the 1or 3-position by a protecting group); e) (to prepare a compound of formula I wherein R3 represents a ΙΗ-tetrazolyl group) reacting a compound of formula VII - 17 (wherein R1, R2 and R4 are as hereinbefore defined) with hydrazoic acid or a salt thereof; f) (to prepare compounds of formula I wherein R1 represents a pentamethylene-oxazolin-2-yl group) reacting a compound of formula VIII (wherein R2, R3 and R4 are as hereinbefore defined) with 1aminomethyl-cyclohexanol in the presence of an acidactivating agent; g) (to prepare a compound of formula I wherein R1 represents a 2-oxo-3,4-tetramethylene-pyrrolidin-l-yl group) hydrogenating a compound of formula IX (wherein R2, R3 and R4 are as hereinbefore defined) ; h) (to prepare compounds of formula I wherein R1 represents an amino group substituted by a bicyclohexylcarbonyl or biphenylcarbonyl group, which - 18 may additionally be substituted at the N-atom by a CV3alkyl group, an aminocarbonylamino group substituted by a bicyclohexyl or biphenyl group and optionally additionally substituted by one or two C.,_3alkyl groups at the N-atom, a maleic acid amido or maleic acid imido group optionally mono- or disubstituted by substituents selected from C13-alkyl and phenyl groups, a (C13~ alkyl) amino or phenyl (C1.3-alkyl) amino group substituted by a C4.6-alkylsulphonyl group or by a phenyl (Chalky 1) sulphonyl group, an amino or C.,_3-alkylamino group substituted by a naphthalenesulphonyl group and optionally substituted in the naphthalene ring by a di (Cv3-alkyl) amino group or by one or two CV3-alkoxy groups, a 7-nitro-benzofurazan-4-yl-amino(C2.3alkanoyl)amino group, a benzofurancarbonyl-amino or 7nitro-benzofurazan-4-yl-amino group, and where R3 represents a carboxy group and R£ represents an n-butyl group, R1 in the 6-position may also represent an amino group substituted by a phenylsulphonyl, cyclohexylmethylamino-carbonyl, 2carboxycyclohexylmethylcarbonyl, 2-tert.-butoxycarbonylcyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6tetrahydrobenzoyl, N-methyl-phenylaminocarbonyl or 3cyclohexylpropyl group, a methylamino group substituted by a propylsulphonyl, phenylsulphonyl, methylphenylsulphonyl or chlorophenylsulphonyl group, an n-pentylamino group substituted by a phenylsulphonyl or methoxyphenylsulphonyl group, an n-propylamino group substituted by a methylphenylsulphonyl or methoxyphenylsulphonyl group, an isopropylamino group substituted by a benzoyl or chlorophenylsulphonyl group, an N-acetylcyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido, hexahydrohomophthalimido, N-methanesulphony1-2phenylethylamino or N-chlorophenylsulphonyl-benzylamino group, and - 19 where R3 represents a carboxy group and R2 represents an n-butyl group, R1 in the 5- or 6-position may also represent a 2-oxo-l,2-dihydro-3,4-tetramethylenepyrrol idin-l-yl group, and where R3 represents a carboxy group and R2 represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R1 in the 6-position may also represent a pyrrolidino-carbonylaraino group, and where R3 represents a tetrazolyl group and R2 represents an n-butyl group, R, in the 5- or 6-position may also represent an n-pentylamino group substituted by a methylamino-carbonyl or cyclohexylaminocarbonyl group and R, in the 6-position may also represent a 3,3dimethyl-glutaric acid imido or 4,4-tetramethyleneglutaric acid imido group, and where R3 represents a tetrazolyl group and R2 represents an ethyl or n-propyl group, R, in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and where R3 represents a tert.-butoxycarbonyl group and R2 represents an n-butyl group, R, in the 6-position may also represent a 2-carboxy-cyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group) reacting a compound of formula X (wherein - 20 R2, R3 and R4 are as hereinbefore defined; and R6 represents a hydrogen atom, an n-pentyl, cyclohexylmethyl, Cv3-alkyl or phenyl (C.,_3-alkyl) group) with a compound of formula XI Z4 - W - R? (XI) (wherein Z4 represents a nucleophilic leaving group; W represents a -CO- or -SO2~ group; and R? represents a 2-hydroxycarbonyl-ethenyl group wherein the ethenyl moiety is mono- or disubstituted by substituents selected from Cv3-alkyl and phenyl groups, a C3.6-alkyl group, a phenyl (C1.3-alkyl) group, a naphthalene group optionally substituted by a difC^jalkyl)amino group or by one or two C1.3-alkoxy groups, a methyl, phenyl, methylphenyl, methoxyphenyl, chlorophenyl, biphenyl, bicyclohexyl, 2-carboxycyclohexylmethyl, 2-carboxy-3,4,5,6-tetrahydrophenyl, 3carboxy-1,1-dimethyl-propyl, 3-carboxy-2,2tetramethylenepropyl, 7-nitro-benzofurazan-4-ylaminomethyl or 7-nitro-benzofurazan-4-yl-aminoethyl group, and where W represents a -CO- group, R? may also represent an R8NR9 group wherein R8 represents a hydrogen atom or a C.,_3-alkyl group, R9 represents a methyl, cyclohexyl, cyclohexylmethyl, phenyl, biphenyl or bicyclohexyl group, or R8 and R? together with the nitrogen atom between them represent a pyrrolidino group, or Z4 together with R<-> represents another carbonIE 912563 - 21 nitrogen bond, and R? together with W may also represent a 7-nitrobenzofurazan-4-yl-amino group) or a reactive derivative of a carboxylic acid of formula XI; i) (to prepare compounds of formula I wherein R, represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, or a benzimidazolyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a C1.3-alkyl group, by a Cj.j-alkoxy group or by a trifluoromethyl group, and in which the NH-group of the above-mentioned imidazole rings may additionally be substituted by a CV6-alkyl group or by a C3 7-cycloalkyl group, a hydroxy(CS7~cycloaIky1)aminocarbonyl group, which may additionally be substituted at the N-atom by a C.,_3-alkyl group, or a straight-chained or branched hydroxy(C4.6alkyl)aminocarbonyl group) reacting a compound of formula XII (wherein Rj, R3 and R4 are as hereinbefore defined) or a reactive derivative thereof, for example an acid halide, ester, amide, anhydride or nitrile, with an amine of formula XIII H (XIII) - 22 (wherein Rlo represents a hydrogen atom, a cycloalkyl group or a CV6-alkyl group; and Rn represents a C4.6-hydroxyalkyl group, a C5.?-hydroxycycloalkyl group or a 2-aminophenyl group which may be substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a CV3-alkyl group, by a alkoxy group or by a trifluoromethyl group, a 2aminocyclohexyl or 2-aminopyridyl group) optionally with simultaneous decarboxylation; j) (to prepare compounds of formula I wherein R1 represents a dihydro-pyridazin-3-one or a pyridazin-3one group which may be substituted in the 2-position by an optionally phenyl-substituted C1.3~alkyl group or at a carbon atom by one or two CV3-alkyl groups) reacting a carboxylic acid of formula XIV (wherein R1, Rz, R3 and R4 are as hereinbefore defined; and A represents an ethylene or ethenylene group optionally substituted by one or two C1.3-alkyl groups) or a reactive acid derivative thereof, for example an ester, amide or halide thereof, with a hydrazine of formula XV H2N - NHR12 (XV) (wherein R12 represents a hydrogen atom or an optionally phenylsubstituted C13-alkyl group) ; - 23 k) resolving a 1-,3- isomer mixture of a compound of formula I by isomer separation into the 1- and 3isomers thereof; l) converting a compound of formula I into an addition salt thereof, more particularly, for pharmaceutical use into a physiologically acceptable salt thereof with an organic or inorganic acid or base or converting a salt of a compound of formula I into the free compound; and m) carrying out a reaction according to any one of steps (a) to (1) above in which one or more groups are protected by a protecting group and subsequently removing any protecting group used.
In the reactions described above, any reactive groups present such as hydroxy, amino or alkylamino groups may optionally be protected during the reaction by conventional protecting groups which are split off again after the reaction.
Examples of suitable protecting groups for a hydroxy group are trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.-butyl, benzyl or tetrahydropyranyl groups and suitable protecting groups for an amino, alkylamino or imino group include 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, conveniently at temperatures between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, a - 24 benzyl group is preferably removed 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, conveniently 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.
The cyclisation of step (a) may conveniently be carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide. The reaction is conveniently effected at temperatures between 0 and 250°C, preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionyIchloride, sulphurylchloride, sulphuric acid, ptoluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid anhydride, or optionally in the presence of a as potassium ethoxide or potassium tert.However, cyclisation may also be carried out solvent and/or condensing agent. or acetic base such butoxide. without a It is particularly advantageous to carry out the reaction of step (a) by preparing a compound of formula II in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of general formula R2COOH, or by acylating a corresponding o-diamino compound. When the - 25 reduction of the nitro group is broken off at the hydroxylamine stage, the N-oxide of a compound of formula I is obtained in the subsequent cyclisation.
The resulting N-oxide is then converted by reduction into a corresponding compound of formula I. The subsequent reduction of the N-oxide of formula I obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50 °C, preferably at ambient temperature.
The reaction of step (b) may conveniently be 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, conveniently at temperatures between 0 and 100°C, preferably at temperatures between ambient temperature and 50°C. A mixture of the 1- and 3isomers is preferably obtained.
In step (c) functional derivatives of the carboxy group such as optionally substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines and anhydrides, and nitrile and tetrazolyl groups may be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. tert.butylesters, may be - 26 converted by thermolysis into a carboxy group and esters with aralkanols, e.g. benzyl esters, may be converted by hydrogenolysis into a carboxy group.
The hydrolysis of step (c) is conveniently carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10°C and 120°C, preferably at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic or trifluoroacetic acid, any alcoholic hydroxy groups present may simultaneously be converted into a corresponding acyloxy group such as a trifluoroacetoxy group.
If Rj' in a compound of formula V represents a cyano or aminocarbonyl group, such a group may also be converted into a carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which may simultaneously also be used as solvent, at temperatures between 0 and 50 °C.
If R/ in a compound of formula V represents for example a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as ptoluenesulphonic, sulphuric, phosphoric or polyphosphoric acid, conveniently at temperatures between 40°C and 100°C, preferably at the boiling temperature of the solvent used. - 27 If Rj' in a compound of formula V represents for example a benzyloxycarbonyl group, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50’C, more preferably 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 the amino group, a benzyloxy group to the hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenylpropionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen may be replaced by a hydrogen atom.
If R1 in a compound of formula V represents one of the above mentioned hydrolysable groups, it may be converted during the reaction into a corresponding carboxy or amino compound.
Suitable protecting groups for use in step (d) include, for example, triphenylmethyl, tributyl tin and triphenyl tin groups.
The cleaving of a protecting group is preferably carried out in the presence of a hydrohalic acid, more preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, conveniently at temperatures between 0 and 100’C, preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and - 28 150’C, preferably at temperatures between 120 and 140’C.
The reaction of step (e) is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150°C, preferably at 125’C. Appropriately, 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 the tetrazolide salt obtained in the reaction mixture from the reaction with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which is also preferably produced in the reaction mixture by reacting aluminium chloride or tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric or 2N sulphuric acid.
The reaction of step (f) is preferably carried out in a solvent such as tetrahydrofuran or dioxane in the presence of an acid activating agent such as carbonylimidazole at temperatures between 0 and 50°C, preferably at ambient temperature.
The catalytic hydrogenation of step (g) is conveniently carried out 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 at temperatures between 0 and 50°C, preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.
Examples of nucleophilic leaving groups for Z4 in step (h) include chlorine or bromine atoms, alkoxy or phenylalkoxy groups such as methoxy, ethoxy or benzyloxy groups or, if R? represents a hydrocarbon group, a hydroxy group. - 29 The reaction of step (h) may conveniently be carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N·-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Ν'-carbonyldiimidazole, N,N'-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously be used as solvents, conveniently at temperatures between -25 and 150°C, preferably at temperatures between -10°C and the boiling temperature of the solvent used.
If Z4 represents a hydroxy group, however, it is particularly advantageous to carry out the reaction of step (h) with the reactive derivatives of a carboxylic acid of general formula XI, e.g. with the esters, thioesters, halides, anhydrides or imidazolides.
The reaction of step (i) may conveniently be carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N1-dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N1-carbonyldiimidazole, N,N1-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an agent - 30 which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously be used as solvents, conveniently at temperatures between -25 and 150°C, but preferably at temperatures between -10°C and the boiling temperature of the solvent used.
An ortho-benzamido compound optionally obtained in this way can then, if necessary, be converted into the desired benzimidazole compound by heating, preferably in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, sulpholane, dimethylformamide or tetraline, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulphuryl chloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid anhydride or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide. However, this cyclisation may also be carried out without a solvent and/or condensing agent.
The reaction of step (j) may conveniently be carried out in a solvent such as methanol, ethanol, isopropanol, glacial acetic acid or propionic acid and/or in an excess of the hydrazine or hydrazine hydrate used, at temperatures between 0 and 200’C, preferably at temperatures between 20 and 150°C, more preferably at the boiling temperature of the reaction mixture, and optionally in the presence of an acid such as sulphuric or p-toluenesulphonic acid as a condensing agent. The reaction may, however, also be carried out without a - 31 solvent.
The isomer separation of step (k) is preferably carried out by chromatography using a substrate such as silica gel or aluminium oxide.
The compounds of formula I obtained may, if desired, be converted into the acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable salts thereof with inorganic or organic acids. Suitable acids for this purpose include hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric and maleic acid.
Furthermore, the new compounds of 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 salts thereof. Suitable bases for this purpose include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Some of the compounds of general formulae II to XV used as starting materials are known from the literature. Otherwise these compounds may be obtained by methods known from the literature.
Thus, for example, a compound of general formula II may be obtained by alkylation of a corresponding o-aminonitro compound and subsequent reduction of the nitro group.
Compounds of general formulae III, V, VI, VII, VIII, IX, X, XII or XIV used as starting materials may be obtained - 32 by alkylation of a corresponding o-phenylenediamine or a corresponding o-amino-nitro compound, followed by reduction of the nitro group and subsequent cyclisation of an o-diamino-phenyl compound thus obtained, optionally followed by cleaving any protecting group used or by NH-alkylation of a corresponding 1Hbenzimidazole, whilst the isomer mixture thus obtained may subsequently be resolved by conventional methods, e.g. chromatography. Some of the starting compounds mentioned above are described in EP-A-392317.
The new compounds of general formula I and the physiologically acceptable salts thereof have valuable pharmacological properties. They are angiotensin antagonists, in particular, angiotensin-II-antagonists.
Thus in a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.
In a still further aspect the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of cardiac insufficiency progression after myocardial infarct, or for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
In a still yet further aspect the present invention provides a method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory - 33 disorders, myocardial ischaemia (angina), cardiac insufficiency progression following myocardial infarction, diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
By way of example, the following compounds: A = 4’-[[2-n-propyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]methylJbiphenyl-2-carboxylic acid ? B = 4'-[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic aciddihydrate; C = 4'-[[2-n-butyl-6-(2,3-diphenyl-maleic acid imido)benzimidazol-1-ylJmethyl]biphenyl-2-carboxylic acid; D = 4'-[[2-n-butyl-6-(2,3-dimethyl-maleic acid imido)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid; E = 4'-[[2-n-butyl-6-(N-phenylmethanesulphonylmethylamino)-benzimidazol-l-ylJmethylJbiphenyl-2carboxylic acid; F = 4'-[[2-n-butyl-6-(2-oxo-piperidin-l-yl)benzimidazol-1-ylJmethylJ-2-(lH-tetrazol-5-yl) biphenyl? G = 4’-[[2-n-butyl-6-(2-oxo-pyrrolidin-l-yl)benzimidazol-l-ylJmethylJ-2-(lH-tetrazol-5-yl)biphenyl; H = 4'-[[2-n-butyl-6-(2-oxo-hexamethyleneimino)benzimidazol-1-ylJmethylJ-2-(lH-tetrazol-5-yl)IE 912563 - 34 biphenyl; 1 = 4'-[[2-n-butyl-6-(3,3-dimethylglutarimido)benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)biphenyl; J = 4’-[[2-n-butyl-6-(N-methylaminocarbonyl-npentylamino)-benzimidazol-l-yl]methyl]-2-(1Htetrazol-5-yl)-biphenyl; K = 4·-[[2-n-butyl-6-(cyclohexylaminocarbonyl-npentylamino)-benzimidazol-l-ylJmethyl]-2-(1Htetrazol-5-yl)-biphenyl hydrate; and L = 41—[[2—n-butyl—6—(2—oxo—3,4—tetramethylene— pyrrolidin-l-yl)-benzimidazol-l-yl]methyl]biphenyl2-carboxylic acid were tested for their biological effects as follows: Rats (male, 180-220 g) are anaesthetised with sodium hexobarbital (150 mg/kg i.p.). After they have become unconscious, a tracheal cannula is inserted, the animals are pithed and then immediately artificially respirated with a ventilator pump. The arterial blood pressure is recorded by means of a cannula in the carotid artery using a Bell & Howell pressure recorder. The substances are administered in the jugular vein through a cannula.
Test substances are administered in three doses (10, 20 and 30 mg/kg i.v.), with one dose of substance being tested on each animal. Three minutes after the intravenous administration of the test substance, angiotensin-II is administered intravenously in increasing doses and in this way a cumulative doseactivity relationship is achieved for angiotensin-II in the presence of the test substances. The increase in - 35 arterial blood pressure is measured.
These dose-activity curves are compared with standard curves for angiotensin-II without the use of any test substances. Using a computer program, the shift to the right in the dose-activity curves for angiotensin-II as a result of the administration of the test substances are determined and corresponding pA2-values are calculated for the test substances.
The pA2 values of the above-mentioned test compounds A to L are between 6.0 and 7.5.
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 heart rhythm disorders, were observed. Accordingly, the compounds are well tolerated.
The new compounds and their physiologically acceptable salts 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 infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
The new compounds and the physiologically acceptable salts thereof are also suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl choline and dopamine in the brain, the new angiotensin antagonists - 36 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 is conveniently, 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 formula I and salts thereof, optionally in conjunction with other active substances such as antihypertensives, diuretics and/or calcium channel blockers, may be incorporated together with one or more inert conventional carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene-glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
Suitable active ingredients for the above-mentioned combinations include for example atenolol, bendroflumethiazide, chlorothiazide, (di)hydralazine hydrochloride, hydrochlorothiazide, metoprolol, prazosin, propranolol, spironolactone, benzthiazide, cyclothiazide, ethacrinic acid, furosemide, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine and nitrendipine. The individual dosages for these ingredients can range from about one-fifth of the usually minimal recommended dosage up to the maximum recommended dosage, for example from 15 to 200 mg of - 37 hydrochlorothiazide, from 125 to 2000 mg of chlorothiazide, from 15 to 200 mg of ethacrinic acid, from 5 to 80 mg of furosemide, from 20 to 480 mg of propranolol, from 5 to 60 mg of felodipine, from 5 to 60 mg of nifedipine or from 5 to 60 mg of nitrendipine.
The following non-limiting Examples are provided to illustrate the invention. Unless otherwise specified all percentages and ratios given are by weight: - 38 Example 1 4'-[[2-n-Propyl-5-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid and 4’-[[2-n-Propyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid a) Methvl-2-n-propyl-benzimidazole-5-carboxvlate A solution of 23.9 g (100 mMol) of methyl 3,4-diaminobenzoate dihydrochloride and 11.7 g (110 mMol) of butyric acid chloride in 100 ml of phosphorus oxychloride is refluxed for 2 hours. Then about 80 ml of phosphorus oxychloride are distilled off and the residue is mixed with about 150 ml of water. The oily crude product precipitated is extracted three times with 50 ml of ethyl acetate and after evaporation purified by column chromatography (600 g of silica gel; eluant: methylene chloride/methanol (30:1 by volume)).
Yield: 15.0 g of oil (69% of theory) b) 2-n-Propyl-benzimidazole-5-carboxylic acidhemisulphate A solution of 15.0 g (73 mMol) of methyl 2-n-propylbenzimidazole-5-carboxylate and 8 g (200 mMol) of sodium hydroxide in 200 ml of water and 400 ml of ethanol is refluxed for 2 hours. Then the alcohol is distilled off, the aqueous solution is acidified with dilute sulphuric acid (pH 4-5) and evaporated using a rotary evaporator. The product crystallising out is suction filtered, washed with 50 ml of acetone and 50 ml of diethylether and dried.
Yield: 9.1 g (61% of theory), Melting point: '> 220°C.
C^H^Oj x 1/2 H2SO4 (253.26) Calculated: C 52.17 H 5.17 N 11.06 S 6.33 - 39 Found: 51.87 5.23 11.11 6.41 c) 2-n-Propyl-5-(l-methvlbenzimidazol-2-vl)benzimidazole A solution of 6.7 g (25 mMol) of 2-n-propylbenzimidazole-5-carboxylic acid-hemisulphate and 4.9 g (25 mMol) of 2-methylaminoaniline-dihydrochloride in 200 g of polyphosphoric acid is stirred for 5 hours at 150’C, then poured onto 600 ml of water and made alkaline with concentrated ammonia whilst cooling with ice. The resulting solution is extracted three times with 200 ml of ethyl acetate, the crude product thus obtained is purified by column chromatography (300 g of silica gel; eluant: methylene chloride/methanol = 15:1 by volume).
Yield: 2.8 g of oil (39% of theory), C18H18N4 (290.37) Calculated: C 74.46 H 6.25 N 9.29 Found: 73.92 6.32 18.96 d) Tert.-butyl 4’-[[2-n-propyl-5-(1-methylbenzimidazol2-yl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid and tert.-butyl 4'-[[2-n-propyl-6-(1-methylbenzimidazol2-yl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid A solution of 2.0 g (6.9 mMol) of 2-n-propyl-5-(1methylbenzimidazol-2-yl)-benzimidazole and 0.91 g (7.5 mMol) of potassium tert.-butoxide in 50 ml of dimethylsulphoxide is stirred for 90 minutes at ambient temperature, then 2.6 g (7.5 mMol) of tert.-butyl 4'bromomethyl-biphenyl-2-carboxylate are added and the mixture is stirred for a further 15 hours at ambient temperature. The mixture is then poured onto 300 ml of water and extracted three times with 50 ml of ethyl acetate. The crude product obtained after evaporation - 40 of the organic phase is purified by column chromatography (300 g silica gel; eluant: methylene chloride/methanol = 30:1 by volume). In this way, 2.7 g (70% of theory) of an isomer mixture are obtained, which when analysed by NMR spectroscopy, contains about 1.18 g of tert.-butyl 4'-[(2-n-propyl-5-(1-methylbenzimidazol2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and about 1.52 g of tert.-butyl 4'-[(2-n-propyl-6-(1methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate.
Rf value: 0.43 (methylene chloride/methanol = 19:1 by volume) e) 4'-[[2-n-Propyl-5-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid and 41 -[[2-n-propyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-vllmethyl!biphenvl-2-carboxylic acid 2.70 g of the isomer mixture obtained in Example Id are dissolved in 100 ml of methylene chloride, mixed with 40 ml of trifluoroacetic acid and stirred for 4 hours at ambient temperature. The mixture is then evaporated to dryness in vacuo. the residue is dissolved in 100 ml of 2N sodium hydroxide solution, the solution is washed with 50 ml of diethylether and the product mixture is precipitated by acidifying the aqueous phase with acetic acid. By column chromatography (400 g of silica gel, eluant: methylene chloride/methanol = 15:1 by volume) of the solid thus obtained, 0.7 g (58% of theory) of 4’[ [2-n-propyl-5-(l-methylbenziraidazol-2-yl)-benzimidazoll-yl] methyl]-biphenyl-2-carboxylate are obtained, melting point 219-220°C C32H28N4°2 (500.60) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.54 5.57 11.01 Rf value: 0.15 (methylene chloride/methanol = 9:1 by volume) and 0.9 g (74% of theory) of 4'-[[2-n-propyl-6-(1IE 912563 - 41 methylbenzimidazol-2-yl)-benzimidazol-1ylJmethyl]biphenyl-2-carboxylate are obtained, melting point 217-218’C C32H28N«°2 (500.60) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.63 5.55 11.29 Rf value: 0.40 (methylene chloride/methanol = 9:1) The following compounds are obtained analogously: 4’—[[2-n-propyl-6-(1,6-dimethyl-benzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylie acid 4’-[[2-n-butyl-6-(l-methyl-5-bromo-benzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 4·-[[2-n-butyl-6-(l-methyl-5-methoxy-benzimidazol-2-yl) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 41-[[2-n-butyl-6-(l-n-butyl-5-trifluoromethylbenzimidazol-2-yl)-benzimidazol-l-ylJmethyl]biphenyl-2carboxylic acid 4'-[[2-n-butyl-6-(l-n-hexyl-5-methyl-benzimidazol-2-yl) benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid · -[[2-n-propyl-6-(l-methyl-5-fluoro-benzimidazol-2-yl) benzimidazol-l-ylJmethyl]biphenyl-2-carboxylie acid 4'-[[2-n-propyl-6-(l-methyl-5-chloro-benzimidazol-2-yl) benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid - 42 Example 2 4[2-n-Butyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[(2-n-butyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 43% of theory, Melting point: amorphous c33h30n4o2 (514.60) Calculated: C 77.02 H 5.88 N 10.89 Found: 76.88 5.83 10.55 Rf value: 0.42 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: (M + H)+ = 515 Example 3 4'-[[6-(Biphenyl-4-carbonylamino)-2-n-butylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid x 0.25 H20 Prepared analogously to Example 1 from tert.-butyl 4'[[6-(biphenyl-4-carbonylamino)-2-n-butyl-benzimidazol-l yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 70.6% of theory, Melting point: 316-317’C C38H33N3°3 X °·25 H2° (584.20) Calculated: C 78.13 H 5.78 N 7.19 Found: 78.12 5.79 7.08 Rf value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 43 Example 4 4'-[[6-(Biphenylyl-4-aminocarbonylamino)-2-n-butylbenzimidazol-l-y1]methyl]bipheny1-2-carboxylic acid trifluoroacetate-semihydrate Prepared analogously to Example 1 from tert.-butyl 4'[(6-(biphenylyl-4-aminocarbonylamino)-2-n-butylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 97.0% of theory, Melting point: 171-172 °C C38H5ZN4O3 x CF3COOH X 1/2 H2O (717.74) Calculated: C 66.94 H 5.06 N 7.81 Found: 67.13 4.99 7.76 Rf value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) Example 5 4·—[(6-Benzenesulphonamido-2-n-butyl-benzimidazol-l-yl) methyl]bipheny1-2-carboxy1ic acid Prepared analogously to Example 1 from tert.-butyl 4’[(6-benzenesulphonamido-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 75.0% of theory, Melting point: 251-252 °C C^H-^N^S (539.65) Calculated: C 69.00 H 5.42 N 7.79 S 5.94 Found: 68.96 5.52 7.82 5.86 Rf value: 0.50 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 50:45:5) - 44 Example 6 4·-[[6-(N-Benzenesulphonyl-methylamino)-2-n-butylbenzimidazol-l-y1]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4' [ [6-(N-benzenesulphonyl-methylamino)-2-n-butylbenzimidazol-l-yl]methyl)biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 70.0% of theory, Melting point: 211-212 °C C32H31N3°4S (553.68) Calculated: C 69.42 H 5.64 N 7.59 S 5.79 Found: 69.24 5.66 7.53 6.02 Rf value: 0.55 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 50:45:5 by volume) Example 7 '-[ [2-n-Butyl-6-(cyclohexylmethylaminocarbonylamino) benz imidazol-l-yl]methyl]biphenyl-2-carboxylic acidtrifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4' [ [2-n-butyl-6-(cyclohexylmethylaminocarbonylamino)benz imidazol-l-yl]methyl]bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 91.1% of theory, Melting point: 149-150°C C33H38N4°3 x CF3COOH (652.71) Calculated: C 64.41P H 6.02 N 8.58 Found: 64.23 6.09 8.73 Rf value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 45 Example 8 '-[ [2-n-Butyl-6-(N-cyclohexylmethyl-acetamido)benz imidazol-l-yl ] methyl] biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’ [ [2-n-butyl-6-(N-cyclohexylmethyl-acetamido) benzimidazol-l-yl]methyl]bipheny 1-2-carboxy 1 ate and trifluoroacetic acid in methylene chloride.
Yield: 78.6% of theory, Melting point: 185-187°C Cj4H39N3O3 (537.70) Calculated: C 75.95 H 7.31 N 7.81 Found: 75.75 7.40 7.65 Rf value: 0.45 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 50:45:5 by volume) Example 9 '-[ [6-(Bicyclohexyl-4-carbonylamino)-2-n-butylbenzimidazol-l-yl]methy 1 ]bipheny 1-2-carboxylic acid trifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4’ [ [6-(bicyclohexyl-4-carbonylamino) -2-n-butylbenzimidazol-l-yl ]methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 93.3% of theory, Melting point: 104-106°C C38H45N3°3 x CFjCOOH (705.82) Calculated: C 68.07 H 6.57 Ν 5.95 Found: 68.38 6.64 5.80 Rf value: 0.30 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 46 Example 10 ’-[[6-(Bicyclohexyl-4-aminocarbonylamino)-2-n-butyl benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid semitrifluoroacetate-monohydrate Prepared analogously to Example 1 from tert.-butyl 4 [[6-(bicyclohexyl-4-aminocarbonylamino)-2-n-butylbenzimidazol-l-ylJmethyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 94.9% of theory, Melting point: 119-120’C C38H46N4°3 x V2 CF3 COOH X H2O (681.83) Calculated: C 68.70 H 7.17 N 8.22 Found: 68.32 6.91 7.81 Rf value: 0.30 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) Example 11 4'-[[2-n-Butyl-6-(3,4,5,6-tetrahydro-phthalimino)benzimidazol-l-ylJmethylJbiphenyl-2-carboxylic acid dihydrate Prepared analogously to Example 1 from tert.-butyl 4 [[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 14.7% of theory, Melting point: 119-122’C C33H31N3°4 x 2 H2° (533.63) Calculated: C 69.58 H 6.19 N 7.38 Found: 69.77 6.34 7.65 Rf value: 0.45 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 47 Example 12 4'-[[2-n-Butyl-6-(5-dimethylamino-naphthalen-lsulphonamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid-semitrifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4' [[2-n-butyl-6-(5-dimethylamino-naphthalen-lsulphonamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 92.3% of theory, Melting point: 148-150°C x V2 CF3COOH (689.78) Calculated: C 66.17 H 5.33 N 8.12 S 4.64 Found: 65.40 5.33 7.92 5.19 Example 13 4'—[[2—n—Butyl—6—(2,3—diphenyl—maleic acid imido)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4' [[2-n-butyl-6-(2,3-diphenyl-maleic acid imido)benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 82.6% of theory, Melting point: 236-237 °C C41H33N3°4 (631.73) Calculated: C 77.95 H 5.27 N 6.65 Found: 77.66 5.24 6.56 Rf value: 0.65 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 50:45:5 by volume) - 48 Example 14 4[2-n-Butyl-6-(N-methanesulphonyl-2-phenylethylamino)-benzimidazol-1-ylJmethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4' [ [2-n-butyl-6-(N-methanesulphonyl-2-phenylethylamino) benzimidazol-l-ylJmethylJbiphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 71.4% of theory, Melting point: 215-216°C C34H35N3°4 (581.73) Calculated: C 70.20 H 6.06 N 7.22 S 5.51 Found: 69.99 6.14 7.23 5.55 Rf value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) Example 15 4'-[[2-n-Butyl-6-(2,3-dimethyl-maleic acid imido)benzimidazol-l-ylJmethylJbiphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4' [[2-n-butyl-6-(2,3-dimethyl-maleic acid imido)benzimidazol-1-ylJmethyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 69.6% of theory, Melting point: 289-290°C C31H29N3O4 (507.59) Calculated: C 73.35 H 5.76 N 8.28 Found: 73.14 5.90 8.20 Rf value: 0.55 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 50:45:5 by volume) - 49 Example 16 4'-[[6-(N-Benzenesulphonyl-n-pentylamino)-2-n-butylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4' [[6-(N-benzenesulphonyl-n-pentylamino)-2-n-butylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 83.9% of theory, Melting point: 243-244°C (609.78) Calculated: C 70.91 H 6.45 N 6.89 S 5.26 Found: 70.92 6.21 6.98 5.19 Rf value: 0.45 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) Example 17 4'-[[2-n-Butyl-6-(N-4-methoxybenzenesulphonyl-npentylamino)-benz imidazol-1-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’ [[2-n-butyl-6-(N-4-methoxybenzenesulphonyl-npentylamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 84.6% of theory, Melting point: 207-208°C C37H41N3O5S (639.81) Calculated: C 69.46 H 6.46 N 6.57 S 5.01 Found: 69.31 6.50 6.77 5.21 Rf value: 0.50 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 50 Example 18 4'-[[2-n-Butyl-6-(N-4-chlorobenzenesulphonylmethylamino)-benzimidazol-l-ylJmethylJbiphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[[2-n-butyl-6-(N-4-chlorobenzenesulphonyl-methylamino)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 84.8% of theory, Melting point: 240-241’C C32H30ClN3O4S (588.12) Calculated: C 65.35 H 5.14 N 7.14 Cl 6.03 S 5.45 Found: 65.02 5.30 7.17 6.21 5.46 Example 19 1 - [[2-n-Butyl-6-(N-phenylmethanesulphonyl-methylamino) benzimidazol-l-y1Jmethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-(N-phenylmethanesulphonyl-methylamino)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 54.9% of theory, Melting point: 208-209 °C C33H33N3°4S (567.70) Calculated: C 69.82 H 5.86 N 7.40 S 5.65 Found: 69.54 5.79 7.47 5.59 - 51 Example 20 4'-[[2-n-Butyl-6-(N-4-methylbenzenesulphonylmethylamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[ [2-n-butyl-6- (N-4-methylbenzenesulphonyl-methylamino) benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 92.5% of theory, Melting point: 259-260°C C33H33N3°4S (567.70) Calculated: C 69.82 H 5.86 N 7.40 S 5.65 Found: 69.70 5.90 7.44 5.68 Rf value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) Example 21 ' -([2-n-Butyl-6-(N-n-propylsulphonyl-methylamino)benzimidazol-l-yl]methyl)biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-(N-n-propylsulphonyl-methylamino)benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 67.3% of theory, Melting point: 222-223"C C29H33N3O4S (519.66) Calculated: C 67.03 H 6.40 N 8.09 S 6.17 Found: 67.02 6.49 8.04 6.18 Rf value: 0.20 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 52 Example 22 ' -[[2-n-Butyl-6-(N-4-methoxybenzenesulphonyl-npropylamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4' [ [2-n-butyl-6-(N-4-methoxybenzenesulphonyl-npropylamino) -benz imidazol-l-yl] methyl] biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 86.4% of theory, Melting point: 227-228 °C C35H37N3O5S (611.75) Calculated: C 68.72 H 6.10 N 6.87 S 5.24 Found: 68.54 6.20 6.88 5.25 Rf value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) Example 23 4[2-n-Butyl-6-(N-4-methylbenzenesulphonyl-npropylamino) -benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’ [ [2-n-butyl-6- (N-4-methylbenzenesulphonyl-npropylamino)-benzimidazol-l-yl]methyl]bipheny1-2carboxylic acid and trifluoroacetic acid in methylene chloride.
Yield: 82.8% of theory, Melting point: 223-224"C C35h37n3°4S (595.76) Calculated: C 70.56 H 6.26 N 7.05 S 5.38 Found: 70.25 6.20 7.24 5.61 Rf value: 0.28 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 53 Example 24 4'-[[2-n-Butyl-6-(N-4-chlorobenzenesulphonylisopropylamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-(N-4-chlorobenzenesulphonylisopropylamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 82.1% of theory, Melting point: 260-261’C C^H^ClNjO^S (616.17) Calculated: C 66.28 H 5.56 N 6.82 Cl 5.75 S 5.20 Found: 66.05 5.77 7.05 5.87 5.34 Rf value: 0.30 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) Example 25 4[6-(N-Benzoyl-isopropylamino)-2-n-butylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4*[[6-(N-benzoyl-isopropylamino)-2-n-butyl-benzimidazol-l yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 58.3% of theory, Melting point: 209-210’C C35H35N3°3 (545.68) Calculated: C 77.04 H 6.46 N 7.70 Found: 76.66 6.57 7.65 Rf value: 0.20 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 54 Example 26 1 -[[2-n-Butyl-6-(1H, 3H-quinazolin-2,4-dion-3-yl) benz imidazol-l-yl ] methyl] biphenyl-2-carboxylic acid hemihydrate Prepared analogously to Example 1 from tert.-butyl 4'[ [2-n-butyl-6- (1H, 3H-quinazolin-2,4-dion-3-yl) benzimidazol-l-yl ] methyl ] biphenyl-2 -carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 53.1% of theory, Melting point: 338-340°C C33H28N4°4 x V2 H20 (553.61) Calculated: C’71.59 H 5.28 N 10.12 Found: 71.19 5.33 10.22 Example 27 4’-[[2-n-Butyl-6-(N-4-chlorobenzenesulphonylbenzylamino) -benzimidazol-l-yl Jmethyl'J biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[ [2-n-butyl-6- (N-4-chlorobenzenesulphonyl-benzylamino) benz imidazol-l-yl Jmethyl J biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 64.5% of theory, Melting point: 212-213 °C C38H34C1N3O4S (664.22) Calculated: C 68.72 H 5.16 N 6.33 Cl 5.34 S 4.83 Found: 68.76 5.27 6.39 5.62 4.81 Rf value: 0.28 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 55 Example 28 ’ — [[2-n-Butyl-6-(N-n-butanesulphonyl-benzylamino)benz imidazol-l-yl]methyl]bipheny1-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[[2-n-butyl-6-(N-n-butanesulphonyl-benzylamino)benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 66.4% of theory, Melting point: 193-194°C C^H^N^S (609.78) Calculated: C 70.91 H 6.45 N 6.89 S 5.26 Found: 70.76 6.54 6.94 5.40 Rf value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) Example 29 4’-[[2-n-Butyl-6-(N-6,7-dimethoxynaphthalen-2-sulphonyl methylamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4·[[2-n-butyl-6-(N-6,7-dimethoxynaphthalen-2-sulphonylmethylamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87.0% of theory, Melting point: 261-262 °C C38H37N3°6S (663.79) Calculated: C 68.76 H 5.62 N 6.33 S 4.83 Found: 69.00 6.00 6.15 5.07 Rf value: 0.23 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 56 Example 30 ’ - [[2-n-Butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-lyl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[[2-n-butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-lyl) -benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 38.0% of theory, Melting point: 146-148°C (519.65) Rf value: 0.30 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Example 31 4'-[[2-n-Butyl-5-(2-oxo-3,4-tetramethylene-pyrrolidin-lyl) -benz imidazol-l-yl Jmethyl] biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[[2-n-butyl-5-(2-oxo-3,4-tetramethylene-pyrrolidin-lyl) -benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 15.5% of theory, Melting point: amorphous °33Η33Ν3°3 (519.65) Rf value: 0.20 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) - 57 Example 32 4'-[[2-n-Butyl-6-(3,3-dimethylpiperidin-l-yl)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[[2-n-butyl-6-(3,3-dimethylpiperidin-l-yl)-benzimidazol l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 86% of theory, Melting point: from 120°C (sintering) c32H37N3°2 (495.70) Calculated: C 77.54 H 7.52 N 8.48 Found: 77.54 7.24 8.19 Rf value: 0.35 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Example 33 '-[[2-n-Butyl-6-heptamethyleneimino-benzimidazol-l-ylJ methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-heptamethyleneimino-benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 71% of theory, Melting point: 195-198’C C32H37N3°2 (495.60) Calculated: C 77.55 H 7.52 N 8.48 Found: 77.40 7.66 8.23 Rf value: 0.40 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) - 58 Example 34 4'-[[2-n-Butyl-6-(piperidin-l-yl)-benzimidazol-1yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-(piperidin-l-yl)-benzimidazol-1yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 84% of theory, Melting point: 199-200’C C30H33N3°2 (467.60) Calculated: C 77.06 H 7.11 N 8.99 Found: 76.85 7.28 9.02 Rf value: 0.40 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Example 35 4'-[[2-n-Butyl-6-(4-methylpiperidin-l-yl)-benzimidazol l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-(4-methyl-piperidin-l-yl)-benzimidazol-1 yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 82% of theory, Melting point: 162-165°C C31H35N3°2 (481.60) Calculated: C 77.31 H 7.33 N 8.73 Found: 77.20 7.19 8.63 Rf value: 0.40 (silica gel; eluant: methylene chloride/ethanol - 9:1 by volume) - 59 Example 36 ’ - [[2-n-Butyl-6-hexamethyleneimino-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[(2-n-butyl-6-hexamethyleneimino-benzimidazol-l-yl)methylJ-biphenyl-2-carboxylate and trifluoroacetic acid Yield: 34% of theory, Melting point: 197-199°C C31H35N3°2 (481.60) Calculated: C 77.31 H 7.33 N 8.73 Found: 76.99 7.35 8.62 Rf value: 0.40 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Example 37 4’-[[2-n-Propyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-1 yl]methylJbiphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-propyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-lyl Jmethyl ]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 60% of theory, Melting point: 208-210°C C29H29N3°3 (4 67.60) Calculated: C 74.49 H 6.25 N 8.99 Found: 74.00 6.29 8.90 Rf value: 0.50 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) - 60 Example 38 * — [[2-n-Propyl-6-(propanesultam-l-yl)-benzimidazol-l yl]methyl]bipheny1-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4' [[2-n-propyl-6-(propanesultam-l-yl)-benzimidazol-lyl] methyl ]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 49% of theory, Melting point: amorphous C27H27N3°4S (489.58) Calculated: C 66.23 H 5.56 N 8.56 S 6.55 Found: 66.08 5.50 8.37 6.51 Rf value: 0.47 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: (M + H)+ = 490 Example 39 4’-[[2-n-Propyl-6-(butanesultam-l-yl)-benzimidazol-lyl ]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’ [[2-n-propyl-6-(butanesultam-l-yl)-benzimidazol-lyl] methyl]bipheny1-2-carboxylate and trifluoroacetic acid.
Yield: 57% of theory, Melting point: amorphous C28H29N3°4S (503.63) Calculated: C 66.77 H 5.80 N 8.34 S 6.37 Found: 66.59 5.77 8.18 6.33 Rf value: 0.51 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: (M + H)+ = 504 - 61 Example 40 [2-n-Butyl-6-(butanesultam-l-yl)-benzimidazol-lyl ]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-(butanesultam-l-yl)-benzimidazol-1yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 51% of theory, Melting point: 203-205°C C29H31N3°4S (517.63).
Calculated: C 67.29 H 6.04 N 8.12 S 6.19 Found: 67.22 5.97 7.97 6.10 Rf value: 0.52 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: (M + H)+ = 518 Example 41 '-[[2-n-Butyl-6-(benzoxazol-2-yl)-benzimidazol-1yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl a) 2-n-Butyl-5-(benzoxazol-2-yl)-benzimidazole 1.43 g (12 mMol) of thionyl chloride are added dropwise at 10°C with stirring to a suspension of 2.52 g (10 mMol) of 2-n-butyl-benzimidazole-5-carboxylic acid in 15 ml of N-methylpyrrolidinone. The mixture is stirred for a further 15 minutes at ambient temperature, then 1.31 g (11 mMol) of 2-aminophenol are added and the mixture is heated to 140°C for 2 hours. The mixture is then poured onto about 50 g of ice and 5 ml of 30% sodium hydroxide solution are added with stirring. The crude product precipitated is suction filtered and purified by column chromatography (300 g of silica gel; eluant: methylene chloride + 3% ethanol). - 62 Yield: 1.2 g (41% of theory), Melting point: 118-120’C C18H17N3O (291.36) Calculated: C 74.20 H 5.88 N 14.42 Found: 73.98 5.97 14.20 b) Isomer mixture of '-[[2-n-butyl-6-(benzoxazol-2-yl)-benzimidazol-lyl ]methyl]biphenyl-2-carboxylic acid nitrile and 4 [2-n-butyl-5-(benzoxazol-2-yl)-benzimidazol-lyl 1 methyl 1biphenvl-2-carboxvlic acid nitrile A solution of 1 g (3.43 mMol) of 2-n-butyl-5(benzoxazol-2-yl)-benzimidazole and 0.98 g (3.60 mMol) of 4'-bromomethyl-biphenyl-2-carboxylic acid nitrile in 20 ml dimethylsulphoxide is mixed with 0.41 g (3.6 mMol) of potassium tert.-butoxide and stirred for 48 hours at ambient temperature. The mixture is then poured onto 100 ml of water, saturated with sodium chloride and extracted three times with 30 ml of ethyl acetate. By column chromatography (200 g of silica gel; eluant: ethyl acetate/petroleum ether (1:1 by volume)) 1.4 g (85% of theory) of a mixture of the isomers is obtained in the ratio 1:1 and this mixture begins to sinter from 130’C.
C32H26N4° (482.59) Calculated: C 79.64 H 5.43 N 11.61 Found: 79.64 5.36 11.59 c) 4'-[[2-n-Butyl-6-(benzoxazol-2-yl)-benzimidazol-1yl1methyl1-2-(lH-tetrazol-5-yl)-biphenyl A solution of the (1:1) isomer mixture of 4’-[[2-nbutyl-6- (benzoxazol-2-yl) -benzimidazol-l-yl] methyl] biphenyl-2-carboxylic acid nitrile and 4·-[[2-n-butyl-5(benzoxazol-2-yl) -benzimidazol-l-yl]methyl]bipheny1-2carboxylic acid nitrile in 20 ml of dimethyl formamide is mixed with 2 g of ammonium chloride and 2 g of sodium azide and heated to 120-130°C for 4 hours. After a further 2 g of ammonium chloride and 2 g of sodium azide have been added and the mixture has been heated to - 63 120-130°C for a further 18 hours, it is poured onto 100 ml of water. The product mixture precipitated is suction filtered and separated by column chromatography (300 g of silica gel, eluant: methylene chloride + 3% ethanol).
Yield: 100 mg (20% of theory) in amorphous form.
C^H^/) (525.62) Calculated: C 73.12 H 5.18 N 18.66 Found: 73.10 5.50 18.42 Rf value: 0.75 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) The following compounds are obtained analogously to Example 41: 4'-[[2-n-butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl) benz imidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl [2-n-propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl ' - [[2-ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)benzimidazol-l-yl ] methyl]-2-(lH-tetrazol-5-yl)-biphenyl * -[ [2-n-butyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazoll-yl] methyl ]—2 —(lH-tetrazol-5-yl)-biphenyl ’-[[2-n-propyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol 1-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl ' -[ [2-ethyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-lyl ] methyl]-2-(lH-tetrazol-5-y1)-biphenyl ’ — [ [2-n-propyl-6-(2-methyl-4,5-dihydro-pyridazin-3-on6-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)biphenyl 4[2-n-propyl-6-(2-benzyl-4,5-dihydro-pyridazin-3-on6-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl) IE 912563 - 64 biphenyl 4'-[[2-n-butyl-6-(l-methyl-imidazolin-2-yl)benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-6-(l-n-hexyl-imidazolin-2-yl)benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-6-(l-n-butyl-imidazolin-2-yl)benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-6-(l-cyclopropyl-imidazolin-2-yl)benzimidazol-1-yl]methyl]-2r(lH-tetrazol-5-yl)-biphenyl ·-[[2-n-propyl-6-(l-cyclohexyl-imidazolin-2-yl)benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl ’ -[[2-n-propyl-6-(1-methyl-imidazol-2-yl)-benzimidazol 1-y1]methyl]-2-(lH-tetrazol-5-yl)-biphenyl [2-n-butyl-6-(l-methyl-imidazol-2-yl)-benzimidazoll-yl ]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-6-(l-n-propyl-imidazol-2-yl)benz imidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl ' -[[2-n-propyl-6-(l-n-hexyl-imidazol-2-yl) benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 1 - [ [2-n-butyl-6-(l-n-butyl-imidazol-2-yl)-benzimidazol 1-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-6-(l-cyclopropyl-imidazol-2-yl) benzimidazol-l-yl ]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 41-[[2-n-propyl-6-(l-cyclohexyl-imidazol-2-yl) benzimidazol-l-yljmethyl]-2-(lH-tetrazol-5-yl)-biphenyl - 65 Example 42 '-[[2-n-Propyl-5-(l-methylbenziraidazol-2-yl)benzimidazol-l-ylJmethyl]-2-(lH-tetrazol-5-yl)-biphenyl and 4'-[[2-n-propyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-ylJmethyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from a mixture of 4' [ [2-n-propyl-5- (l-methylbenzimidazol-2-yl) -benzimidazol l-yl]-methyl]biphenyl-2-carboxylic acid nitrile and 4·[ [2-n-propyl-6- (l-methylbenzimidazol-2-yl) -benzimidazol l-yl]-methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide. -isomer: Yield: 29% of theory, Melting point: amorphous Wi (524.61) Calculated: C 73.26 H 5.38 N 21.36 Found: 73.03 5.22 21.26 Mass spectrum: (M + H)+ = 525 6-isomer: Yield: 34% of theory, Melting point: 198-200°C C32H28N8 (524.61) Calculated: C 73 Found: 73 Mass spectrum: (M 26 H 5.38 N 21.36 11 5.27 21.19 + H) + = 525 - 66 Example 43 4’-[[2-n-Butyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]methyl)-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-yl]methyl]bipheny1-2-carboxylie acid nitrile and sodium azide in dimethylformamide.
Yield: 28% of theory, Melting point: 224-226°C C33H30N8 (538.63) Calculated: C 73.58 H 5.61 N 20.81 Found: 73.31 5.73 19.99 Rf value: 0.76 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: (M + H)+ = 539 Example 44 ' -[[2-n-Butyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-lyl ]methyl)-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl6-(2-oxo-piperidin-l-yl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 20% of theory, Melting point: amorphous C30H31N7O (505.63) Calculated: C 67.94 H 6.23 N 17.33 Found: 67.67 6.13 17.52 Rf value: 0.30 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) - 67 Example 45 · — [[2-n-Butyl-6-(3,3-dimethylpiperidin-l-yl)benzimidazol-l-yl] -methyl] -2- (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl6-(3,3-dimethylpiperidin-l-yl)-benz imidazol-l-yl]methyl]-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 8% of theory, Melting point: sintering from 148°C C32H37N? x HC1 (519.70) Mass spectrum: (M + H)+ = 520 Example 46 ’ -[[2-n-Butyl-6-(4,4-tetramethyleneglutarimido)benzimidazol-l-yl]-methyl]-4-chloro-2-(lH-tetrazol-5yl)-biphenyl Prepared analogously to Example 41 from 4’-[[2-n-butyl6-(4,4-tetramethyleneglutarimido)-benzimidazol-l-yl]methyl]-4-chloro-biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 40% of theory, Melting point: sintering from 160°C C34H34N7O2C1 (608.16) calculated: C 67.15 H 5.64 N 16.12 Found: 66.90 5.86 15.86 Rf value: 0.50 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Example 47 ’ - [[2-n-Butyl-6-(propanesultam-l-yl)-benzimidazol-lyl ]-methyl]-2- (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl6-(propanesultam-l-yl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid nitrile and — 68 — dimethyIformamide.
Yield: 46% of theory, Melting point: 203-205’C c28H29n7°2S (527.70) Calculated: C 63.73 H 5.54 N 18.58 S 6.08 Found: 62.52 5.56 18.40 6.00 Rf value: 0.35 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Example 48 · - [[2-n-Butyl-6-(butanesultam-l-yl)-benzimidazol-l-yl] methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl6-(butanesultam-l-yl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 30% of theory, Melting point: 189-191°C C^^N/^S (541.70) Calculated: C 64.30 H 5.95 N 18.10 S 5.92 Found: 64.40 5.75 17.90 5.85 Rf value: 0.37 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Example 49 4’-[[2-n-Propyl-6-(butanesultam-l-yl)-benzimidazol-lyl ]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4'-[[2-n-propyl 6-(butanesultam-l-yl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 37% of theory, Melting point: 204-206°C C28H29N7°2S (527.63) Calculated: C 63.73 H 5.54 N 18.58 S 6.08 - 69 Found: 63.70 5.49 18.37 6.19 Rf value: 0.36 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: m/e = 527 Example 50 Mixture of 4[2-n-butyl-6-(2-hydroxy-cyclohexylaminocarbonyl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl and [2-n-butyl-5-(2-hydroxy-cyclohexylaminocarbonyl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from a mixture of 4'[[2-n-butyl-6-(2-hydroxy-cyclohexylaminocarbonyl)benzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid nitrile and 4·-[[2-n-butyl-5-(2-hydroxy-cyclohexylaminocarbonyl)-benzimidazol-l-yl]-methyl]biphenyl-2carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 8% of theory, Melting point: 198-200’C C32H35N7°2 (549.70) Rf value: 0.30 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: (M + H)+ = 550 Example 51 ’-[[2-n-Butyl-6-(2-oxo-pyrrolidin-l-yl)-benzimidazol-lyl ] -methyl ] -7.-(lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4[2-n-butyl6-(2-oxo-pyrrolidin-l-yl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 15% of theory, Melting point: 153-155’C - 70 C^H^O (491.60) Calculated: C 70.85 H 5.95 N 19.95 Found: 70.79 6.17 19.71 Rf value: 0.45 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: (M + H)* = 492 Example 52 Mixture of 1 -[[2-n-butyl-6-(1,1-dimethyl-2-hydroxy-ethylaminocarbonyl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5yl)-biphenyl and 4'-[[2-n-butyl-5-(1,l-dimethyl-2-hydroxy-ethylaminocarbonyl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5yl)-biphenyl Prepared analogously to Example 41 from a mixture of 4'[[2-n-butyl-6-(1,l-dimethyl-2-hydroxy-ethylaminocarbony1)-benz imidazol-l-yl]-methyl]biphenyl-2carboxylic acid nitrile and 41-[[2-n-butyl-5-(l,1dimethyl-2-hydroxy-ethylamino-carbonyl)-benzimidazol-lyl] -methyl] biphenyl-2 -carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 14% of theory, Melting point: amorphous C30H33N7°2 (523.60) Rf value: 0.30 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: (M + H)+ = 524 - 71 Example 53 4'-[[2-n-Butyl-6-(2-oxo-hexamethyleneimino)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl6- (2-oxo-hexamethyleneimino) -benzimidazol-l-yl ] methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 34% of theory, Melting point: amorphous C31H33N7O (519.70) Calculated: C 71.65 H 6.40 N 18.87 Found: 70.99 6.32 18.75 Rf value: 0.15 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Example 54 4'-[[2-n-Propyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-lyl ]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4’-[[2-n-propyl6-(2-oxo-piperidin-l-yl) -benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 14.5% of theory, Melting point: sintering from 125°C C^H-^O (491.60) Rf value: 0.25 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Mass spectrum: (M + H)+ - 492 - 72 Example 55 4'-[[2-n-Butyl-6-(3,3-dimethylglutarimido)-benzimidazoll-yl ]methyl ]-2-(lH-tetrazol-5-yl)-biphenyl a) 4’ [[2-n-Butyl-6-(3,3-dimethylglutarimido)benzimidazol-l-yl]methyl]-2-(1-triphenylmethyltetrazol-5-vl)-biphenyl 1.8 g (3.3 mMol) of 4'-bromomethyl-2-(1-triphenylmethyltetrazol-5-yl)-biphenyl are added to a solution of 1.04 g (3.3 mMol) of 2-n-butyl-5-(3,3-dimethylglutarimido)-benzimidazole and 425 mg (3.8 mMol) of potassium tert.-butoxide in 25 ml of dimethylsulphoxide. The mixture is stirred for 3 hours at ambient temperature, then stirred into 150 ml of water, extracted three times with 30 ml of ethyl acetate, then the organic extracts are dried and concentrated by evaporation. The residue obtained is purified by column chromatography (300 g of silica gel; eluant: ethyl acetate/petroleum ether (2:1 by volume)).
Yield: 400 mg (15% of theory), Rf value: 0.38 (ethyl acetate/petroleum ether = 6:1) b) 4' — [[2-n-Butyl-6-(3,3-dimethylglutarimido)benz imidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl) biphenyl A solution of 400 mg (0.5 mMol) of 4·-[[2-n-butyl-6(3,3-dimethylglutarimido)-benzimidazol-l-yl]-methyl)-2(l-triphenylmethyl-tetrazol-5-yl)-biphenyl in 10 ml of methanol is mixed with 1.5 ml of methanolic hydrochloric acid and stirred for 2 hours at ambient temperature, then concentrated by evaporation, the residue is mixed with 15 ml of water and made alkaline with concentrated ammonia, whereupon the product goes into solution. By acidification with glacial acetic acid, the crude product is precipitated and then purified by column chromatography (150 g of silica gel; eluant: methylene - 73 chloride + 5% ethanol).
Yield: 150 mg (55% of theory), Melting point: 184-186’C °32Η33Ν7°2 (547.70) Calculated: C 70.18 H 6.07 N 17.90 Found: 69.98 6.20 17.67 Example 56 ' -[[2-n-Butyl-6-(N-methylaminocarbonyl-n-pentylamino)benz imidazol-l-yl] methyl] -2- (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 55 from 4’-[[2-n-butyl6- (N-methylaminocarbonyl-n-pentylamino) -benzimidazol-lyl] methyl ] -2-(l-triphenylmethyl-tetrazol-5-yl)-biphenyl and hydrochloric acid in ethanol.
Yield: 53.8% of theory, Melting point: 124-126’C C33H38N8° (550.71) Rf value: 0.25 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Calculated: C 69.79 H 6.95 N 20.35 Found: 69.78 7.05 20.31 Mass spectrum: (M + H)* = 492 Example 57 '-[ [2-n-Butyl-5-(N-methylaminocarbonyl-n-pentylamino) benzimidazol-l-yl]methyl] -2- (lH-tetrazol-5-yl) -biphenyl dihydrate Prepared analogously to Example 55 from 4'-[[2-n-butyl5- (N-methylaminocarbonyl-n-pentylamino) -benzimidazol-lyl ]methyl]-2- (1-tr ipheny lmethy l-tetrazol-5-yl) -biphenyl and hydrochloric acid in ethanol.
Yield: 76.2% of theory, Melting point: 201-203 °C C32H38N8° x 2 H2° (586.74) - 74 Calculated: C 65.50 H 7.21 N 19.09 Found: 65.43 7.07 19.12 Example 58 ' -[[2-n-Butyl-6-(N-cyclohexylaminocarbonyl-npentylamino)-benzimidazol-l-ylJmethyl]-2-(lH-tetrazol-5 yl)-biphenyl-hydrate Prepared analogously to Example 55 from 4'-[[2-n-butyl6-(N-cyclohexylaminocarbonyl-n-pentylamino)benzimidazol-l-ylJmethylJ-2-(1-triphenylmethyl-tetrazol -yl)-biphenyl and hydrochloric acid in ethanol.
Yield: 95.2% of theory, Melting point: 128-132 °C C37H46N8° x H2° (636.84) Calculated: C 69.78 H 7.59 N 17.59 Found: 69.61 7.71 17.41 Rf value: 0.45 (silica gel; eluant: ethanol/ammonia = 80:40:2 by volume) Example 59 1 -[[2-n-Butyl-5-(N-cyclohexylaminocarbonyl-npentylamino) -benzimidazol-l-yl Jmethyl J -2- (lH-tetrazol-5 yl)-biphenyl-hydrate Prepared analogously to Example 55 from 4 * -[[2-n-butyl5-(N-cyclohexylaminocarbonyl-n-pentylamino)benzimidazol-l-yl]methyl J-2-(1-triphenylmethyl-tetrazol -yl)-biphenyl and hydrochloric acid in ethanol.
Yield: 88.6% of theory, Melting point: 117-120°C C37H46N8O x H2O (63 6.84) Calculated: C 69.78 H 7.59 N 17.59 Found: 70.06 7.58 17.56 Rf value: 0.45 (silica gel; eluant: ethanol/ammonia = 80:40:2 by volume) - 75 Example 60 4·-[[2-n-Butyl-6-(5-dimethylaminonaphthalen-lsulphonamino)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol5- yl)-biphenyl-hydrate Prepared analogously to Example 55 from 4'-[[2-n-butyl6- (5-dimethylaminonaphthalen-l-sulphonamino)benzimidazol-l-yl]methyl)-2-(1-triphenylmethyl-tetrazol5-yl)-biphenyl and hydrochloric acid in ethanol.
Yield: 44.7% of theory, C37H36N8°2S X H2° (674.81) Calculated: C 65.85 H 5.67 N 16.60 S 4.75 Found: 65.80 5.46 16.42 4.90 Example 61 4’-[[2-n-Butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-lyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid 420 mg (0.81 mMol) of 4'-[[2-n-butyl-6-(2-oxo-l,2dihydro-3,4-tetramethylene-pyrrol-l-yl)-benzimidazol-lyl] methyl]biphenyl-2-carboxylic acid are dissolved in 60 ml of methanol and 60 ml of ethyl acetate and hydrogenated with the addition of 200 mg of palladium on charcoal (10%) under 5 bar of hydrogen pressure and at 40’C. The catalyst is removed by suction filtering, the solvent is evaporated off and the crude product is purified by column chromatography (200 g of silica gel; eluant: methylene chloride + 3% ethanol).
Yield: 260 mg (62% of theory), Melting point: amorphous °33Η35Ν3°3 (521.67) Calculated: C 75.98 H 6.76 N 8.06 Found: 75.75 6.62 8.24 - 76 Example 62 Mixture of 4’-[[2-n-butyl-6-(5,5-pentamethylene-oxazolin-2-yl)benzimidazol-l-yl)-methyl)-2-(lH-tetrazol-5-yl)-biphenyl and 41 — [[2-n-butyl-5-(5,5-pentamethylene-oxazolin-2-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl A solution of 930 mg (2 mMol) of an isomer mixture of 4 ' -[[2-n-butyl-6-carboxy-benzimidazol-l-yl]-methyl]-2(lH-tetrazol-5-yl)-biphenyl and 4'-[[2-n-butyl-5carboxy-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl) biphenyl and 356 mg (2.2 mMol) of carbonyldiimidazole in 30 ml of tetrahydrofuran is stirred for 30 minutes at ambient temperature. Then 332 mg (2 mMol) of 1(aminomethyl)-cyclohexanol-dihydrochloride are added and the mixture is stirred for a further 15 hours at ambient temperature. The mixture is then concentrated by evaporation, 2 ml of thionyl chloride are slowly added dropwise, the mixture is stirred for one hour, the thionyl chloride is distilled off and the residue is mixed with 5 ml of ice water. The insoluble crude product is purified by column chromatography (150 g of silica gel; eluant: methylene chloride + 5% ethanol).
In this way, 25 mg (2% of theory) of a mixture of 4'[[2-n-buty1-6-(5,5-pentamethylene-oxazolin-2-yl) benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl and ’ - [[2-n-butyl-5-(5,5-pentamethylene-oxazolin-2-yl) benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl is obtained.
Melting point: from 215’C (decomp.) C33H35N7° (54 5.67) Mass spectrum: (M + H)+ = 546 - 77 Example 63 ' -[[2-n-Butyl-6-(N-methyl-phenylaminocarbonylamino)benzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid A solution of 0.8 g (2.00 mMol) of 41-[[2-n-butyl-6aminobenzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid and 0.9 g of N-methyl-isatoic acid anhydride in ml of pyridine is refluxed for 48 hours, then evaporated to dryness, the residue is suspended in about ml of methylene chloride, suction filtered, washed with a further 5 ml of methylene chloride and dried. Yield: 0.66 g (62% of theory), Melting point: 274-276°C °33Η32Ν4°3 (53 2.60) Calculated: C 74.41 H 6.06 N 10.57 Found: 74.23 5.94 10.66 Example 64 ’-[[2-n-Butyl-5-(3-carboxy-propionyl)-benzimidazol-lyl] -methyl ]biphenyl-2-carboxylic acid A solution of 200 mg (0.39 mMol) of methyl 4'-[[2-nbuty 1-5-(3-methoxycarbonyl-propionyl)-benzimidazol-lyl] -methyl]biphenyl-2-carboxylate and 0.75 ml of sodium hydroxide solution in 4 ml of ethanol is stirred for 2 hours at 75 °C, then mixed with 40 ml of water and acidified with glacial acetic acid. The alcohol is then distilled off, the resulting mixture is stirred for one hour at ambient temperature, the product precipitated is suction filtered, washed with 10 ml of water and dried. Yield: 120 mg (64% of theory), Melting point: 200-202°C C29h28n2°4 (4 84.60) Calculated: C 71.88 H 5.83 N 5.78 Found: 71.66 5.86 5.63 - 78 Example 65 41-[[2-n-Butyl-6-(3-carboxy-2-methyl-propionyl) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid x 0.25 H20 Prepared analogously to Example 64 from methyl 4'-[[2-nbuty1-6-(3-methoxycarbonyl-2-methyl-propionyl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Yield: 18% of theory, Melting point: 193-194 °C C30H30N2°5 X V4 H2° (498.60) Calculated: C 71.62 H 6.11 N 5.56 Found: 71.72 6.09 5.68 Rf value: 0.37 (silica gel; eluant: methylene chloride/ethanol/glacial acetic acid = 18:1:0.05 by volume) Example 66 ' - [ [2-n-Butyl-6-(3-carboxy-propionyl)-benzimidazol-lyl ]methyl]biphenyl-2-carboxy1ic acid Prepared analogously to Example 64 from methyl 4'-[[2-nbutyl-6-(3-methoxycarbonyl-propionyl)-benzimidazol-lyl ] methyl ]biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Yield: 97% of theory, Melting point: 240-242°C C^^Oj (484.60) Calculated: C 71.88 H 5.83 N 5.78 Found: 71.74 6.07 5.93 - 79 Example 67 4'-[[2-n-Butyl-6-(2,3-dimethylmaleic acid imino)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid 52.5 mg (0.1 mMol) of 4'-[[2-n-butyl-6-(2,3dimethylmaleic acid amino)-benzimidazol-l-yl]-methyl]biphenyl-2-carboxylate are heated to boiling for one hour in 2 ml of bis-(2-methoxy-ethyl)-ether. The solvent is removed by distillation and the oily residue is distributed in ethyl acetate/water. The organic phase is washed twice more with water, dried with magnesium sulphate and concentrated by rotary evaporation. The residue is triturated in 1 ml of acetone, suction filtered, washed with ether and dried in vacuo at 75°C.
Yield: 29.0 mg (57.2% of theory), Melting point: 289-291°C C^H^O* (507.59) Calculated: C 73.35 H 5.76 N 8.29 Found: 73.50 5.64 8.10 Example 68 4’-[[2-n-Butyl-6-(3,4,5,6-tetrahydro-phthalimino)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acidhydrate 0.275 g (0.5 mMol) of 4'-[[2-n-butyl-6-(2-carboxy3,4,5,6-tetrahydrobenzamino)-benzimidazol-l-ylJ methyl J biphenyl-2-carboxylate are refluxed for 4 hours in 5 ml of pyridine. The mixture is evaporated to dryness in vacuo by rotary evaporation and the crude product is recrystallised from acetone. It is suction filtered, washed with acetone and dried in vacuo at 70°C.
Yield: 0.2 g (72.4% of theory), Melting point: 226-228°C - 80 C30H31N3°4 X H2° (551.64) Calculated: C 71.85 H 6.03 N 7.62 Found: 71.83 5.90 7.61 Example 69 Tert.-butyl 4'-[[2-n-butyl-6-(pyrrolidinocarbonylamino)benzimidazol-l-yl] methyl] bipheny 1-2-carboxy late 2.0 g (15 mMol) of pyrrolidinocarbonyl chloride are placed in 50 ml of dry chloroform and 2.3 g (6 mMol) of tert.-butyl 4'-[(6-amino-2-n-butyl-benzimidazol-l-yl)methyl ]biphenyl-2-carboxylate dissolved in 50 ml of dry pyridine are added dropwise for one hour. The reaction solution is stirred for a further 24 hours and then concentrated by rotary evaporation. The oily residue is distributed in ethyl acetate and 10% sodium hydrogen carbonate solution, the organic phase is separated off and, after drying with magnesium sulphate, concentrated by rotary evaporation. Purification is carried out using a silica gel column (particle size: 0.063 0.2 mm), eluting with petroleum ether/ethyl acetate = 3:7. The corresponding column fractions are concentrated by rotary evaporation and dried in vacuo at 50°C.
Yield: 1.7 g (61.8% of theory), Melting point: 68-70’C (amorphous) (552.72) Rf value: 0.35 (silica gel; eluant: ethyl acetate/ethanol = 19:1 by volume) Example 70 ' -[[2-n-Butyl-6-(pyrrolidinocarbonylamino)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid trifluoroacetate-monohydrate Prepared analogously to Example 1 from tert.-butyl 4’IE 912563 - 81 [[2-n-butyl-6-(pyrrolidinocarbonylamino)-benzimidazol-lyl] methyl ]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 91.7% of theory, Melting point: 233-234 °C C30H32N4°3 x CF3COOH X H20 (628.25) Calculated: C 61.14 H 5.61 N 8.91 Found: 61.25 5.62 9.09 Rf value: 0.48 (silica gel; eluant: ethyl acetate:ethanol:ammonia = 50:45:5 by volume) Example 71 4’—[[2—n-Butyl—6—(2,3—dimethylmaleic acid imino)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 314 mg (0.5 mMol) of 4’-[(6-amino-2-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate are refluxed together with 76 mg (0.6 mMol) of 2,3-dimethylmaleic acid anhydride in 10 ml of pyridine for 18 hours. The solvent is then removed by rotary evaporation and the oily substance is distributed in ethyl acetate and 10% sodium hydrogen carbonate solution. The organic phase is separated off, dried with magnesium sulphate and concentrated by rotary evaporation after being filtered. By trituration with acetone and ether, a white crystalline product is obtained which is dried at 50°C in vacuo after suction filtering.
Yield: 165 mg (65.0% of theory), Melting point: 288-290°C C^H-^N^ (507.59) Calculated: C 73.35 H 5.76 N 8.29 Found: 73.14 5.94 8.32 - 82 Example 72 '-[ (2-n-Butyl-6-hexahydrohomophthalimino-benzimidazol1-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 71 from 4*-[(6-amino-2n-butyl-benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid and hexahydrohomophthalic acid anhydride in pyridine.
Yield: 15.3% of theory, Melting point: 183-185°C C34H35N3°4 (549.67) Calculated: C 74.29 H 6.49 N 7.64 Found: 74.09 6.47 7.80 Example 73 41-[[2-n-Butyl-6-(benzofuran-2-carbonylamino)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 71 from 4·-[(6-amino-2n-butyl-benz imidazol-l-yl) -methyl] biphenyl-2-carboxylic acid and benzofuran-2-carboxylic acid anhydride in pyridine.
Yield: 80.7% of theory, Melting point: 321-323 °C C34H39N3O4 (54 3.62) Calculated: C 75.12 H 5.38 N 7.73 Found: 74.92 5.45 7.87 Example 74 ' -[[2-n-Butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-benzimidazol-l-yl]methyl]bipheny1-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H) pyrimidinon-l-yl)-benzimidazol-l-yl]-methyl]biphenyl-2carboxylate and trifluoroacetic acid in methylene - 83 chloride.
Yield: 42.2% of theory, Melting point: 119-122’C C36H36N4°3 X H2° (590.72) Calculated: C 73.20 H 6.48 N 9.48 Found: 73.11 6.50 9.67 Example 75 4'-[[2-n-Butyl-6-(2-carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-l-ylJmethyl]biphenyl-2-carboxylie acid hydrate a) Tert.-butyl 4’-[[2-n-butyl-6-(2-carboxycyclohexylmethylcarbonylamino)-benzimidazol-l-yl]methyllbiphenyl-2-carboxvlate 1.3 g (2.86 mMol) of tert.-butyl 4·-[(6-amino-2-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate, 0.6 g (5.35 mMol) of hexahydrohomophthalic acid anhydride and 5 ml of pyridine are refluxed with stirring for 3 hours. Then the pyridine is removed by rotary evaporation in vacuo, the residue is crystallised from acetone, washed with acetone and dried in vacuo at 70°C.
Yield: 0.67 g (37.6% of theory), Melting point: 227-229°C C38H45N3°5 (62 3.79) Calculated: C 73.17 H 7.27 N 6.74 Found: 72.93 7.15 6.94 b) 4'-[[2-n-butyl-6-(2-carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid 0.6 g (0.06 mMol) of tert.-butyl 4'-[[2-n-butyl-6-(2carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-lyl Jmethyl ]biphenyl-2-carboxylate, 30 ml of methylene chloride and 10 ml of trifluoroacetic acid are stirred for 3 hours at ambient temperature. The mixture is diluted with 20 ml of methylene chloride, extracted with - 84 water, the organic phase is dried over sodium sulphate and evaporated to dryness. The residue is dissolved in ethanol and made alkaline by the addition of ammonia.
The solvent is distilled off in vacuo. The remaining agueous solution is acidified with acetic acid, the product which crystallises out is suction filtered, washed with water and dried in vacuo at 70°C.
Yield: 0.55 g (98.2% of theory), Melting point: 160-162 °C C34H37N3O5 x H20 (585.68) Calculated: C 69.72 H 6.71 N 7.17 Found: 69.63 6.64 7.33 Example 76 4'-[[2-n-Butyl-6-(2-carboxy-3,4,5,6-tetrahydrobenzamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid 0.4 g (1 mMol) of 4'-[(6-amino-2-n-butyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid, dissolved in 7 ml of pyridine, are mixed with 0.34 g (1.1 mMol) of 1cyclohexene-1,2-dicarboxylic acid anhydride at ambient temperature and stirred for 2¼ hours. The mixture is cooled with ice and the product which crystallises out is suction filtered, washed with cooled acetone and dried in vacuo at 70 °C.
Yield: 0.37 g (67.2% of theory), Melting point: 250-252 °C C33H33N3°5 (551.64) Calculated: C 71.85 H 6.03 N 7.62 Found: 71.70 5.99 7.60 - 85 Example 77 4·-[[2-n-Propyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 604 mg (1.0 mMol) of tert.-butyl 4'-[[2-nitro-5-(1methylbenz imidazol-2-yl)-N-n-butyry1-anilino]methyl]biphenyl-2-carboxylate are stirred in 50 ml of methylene chloride with the addition of 10 ml of trifluoroacetic acid at ambient temperature for 3 hours. The solvent is then distilled off, the residue is dissolved in 25 ml of glacial acetic acid and hydrogenated at 80°C with the addition of 500 mg of 10% palladium/charcoal. In order to work up the product, the solvent is distilled off in vacuo, the residue is dissolved in 30 ml of 2N sodium hydroxide solution and the solution is washed with 20 ml of diethyl ether. The crude product precipitated by the acidification of the aqueous phase is purified by subsequent column chromatography (80 g silica gel, eluant: methylene chloride/methanol = 15:1 by volume). Yield: 90 mg (18% of theory), Melting point: 214-216°C C32H28N4°2 (50θ·θθ) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.58 5.49 11.30 Example 78 4'-[[2-n-Propyl-6-(l-methylbenzimidazol-2-yl)~ benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid A suspension of 940 mg (2.0 mMol) of tert.-butyl 4*-[(2n-propyl-6-carboxy-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and 320 mg (2.0 mMol) of carbonyldiimidazole in a solution of 1.0 ml of triethylamine in 30 ml of tetrahydrofuran is stirred for 30 minutes at ambient temperature, then 250 mg (2.0 mMol) of 2-methylaminoaniline are added and the mixture is stirred for a - 86 further 16 hours. It is then evaporated to dryness and the residue is refluxed in 20 ml of phosphorus oxychloride, with stirring, for l hour. The majority of the phosphorus oxychloride is then distilled off, the dark, greasy residue is decomposed with 30 ml of water, the strongly acidic suspension thus obtained is refluxed for about 1 hour, adjusted to pH 6 after cooling and then concentrated by evaporation. The crude product obtained is purified by column chromatography (120 g of silica gel, eluant: methylene chloride/methanol = 15:1 by volume).
Yield: 73 mg (7.3% of theory), Melting point: 213-215°C C32H28N4°2 (500.60) calculated: C 76.78 H 5.64 N 11.19 Found: 76.61 5.64 10.94 Example 79 4’-[[2-n-Propyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-lyl ]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Within 10 minutes, 155 mg (1.0 mMol) of 5-chloro-valeric acid chloride, dissolved in 5 ml of tetrahydrofuran, are added dropwise to a solution of 650 mg (1.0 mMol) of 4’[(2-n-propyl-6-amino-benzimidazol-l-yl)-methyl]-2-(1Htriphenylmethyl-tetrazol-5-yl)-biphenyl in 30 ml of tetrahydrofuran and the mixture is stirred for a further hour at ambient temperature, then evaporated to dryness. The residue is stirred into 20 ml of ethanol, then a solution of 2.0 mMol of sodium ethoxide in 20 ml of ethanol is added and the resulting mixture is refluxed for one hour. After cooling, 10 ml of methanolic hydrochloric acid are added dropwise, the mixture is stirred for a further two hours at ambient temperature and then evaporated down. The residue is mixed with 10 ml of water and made alkaline with concentrated ammonia, whereupon the product goes into solution. By acidifying with glacial acetic acid the crude product is - 87 precipitated and then purified by column chromatography (70 g silica gel, eluant: methylene chloride + 5% ethanol).
Yield: 54 mg (11% of theory), Melting point: sintering from 117’C C2H29N7O (491.60) Calculated: C 70.85 H 5.95 N 19.95 Found: 70.69 5.94 19.99 The following compounds are obtained analogously: '-[[2-n-butyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-lyl ]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Yield: 16% of theory, Melting point: amorphous C3OH31N7° (505.63) Calculated: C 67.94 H 6.23 N 17.33 Found: 67.81 6.29 17.18 4·-[[2-n-butyl-6-(2-oxo-pyrrolidin-l-yl)-benzimidazol-1 yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Yield: 9% of theory, Melting point: 150-151 °C C29H29N7° (491.60) Calculated: C 70.85 H 5.95 N 19.95 Found: 70.61 6.08 19.80 Example 80 [2-n-Butyl-6-(propanesultam-l-yl)-benzimidazol-lyl ]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Within 10 minutes, a solution of 265 mg (1.5 mMol) of 3 chloro-propanesulphonic acid chloride in 5 ml of tetrahydrofuran is added dropwise to a solution of 665 mg (1.0 mMol) of 4’-[(2-n-butyl-6-aminobenzimidazol 1-yl)-methyl]-2-(l-triphenylmethyl-tetrazol-5-yl)biphenyl and 1 ml of triethylamine in 30 ml of tetrahydrofuran and the mixture is stirred for 1¾ hours - 88 at ambient temperature. The mixture is then evaporated to dryness, the residue is taken up in 20 ml of ethanol, a solution of 3.0 mMol of sodium ethoxide in 20 ml of ethanol is added and the resulting mixture is refluxed for two hours. After cooling, 10 ml of methanolic hydrochloric acid are added dropwise, the mixture is stirred for a further two hours at ambient temperature and finally concentrated by evaporation. The residue is mixed with 10 ml of water and brought into solution with concentrated ammonia. By acidifying with glacial acetic acid, the crude product is precipitated and then purified by column chromatography (70 g of silica gel, eluant: methylene chloride + 5% ethanol).
Yield: 68.5 mg (13% of theory), Melting point: 202-205°C C28H29N7°2S (527.70) Calculated: C 63.73 H 5.54 N 18.58 Found: 63.70 5.61 18.35 The following compounds are obtained analogously: ' -[[2-n-butyl-6-(butanesultam-l-yl)-benzimidazol-lyl Jmethyl ] -2- (lH-tetrazol-5-yl) -biphenyl Yield: 10% of theory, Melting point: 185-187°C C29H31N7O2S (541.70) Calculated: C 64.30 H 5.95 N 18.10 Found: 64.19 5.91 17.92 ·-[[2-n-propyl-6-(butanesultam-l-yl)-benzimidazol-1yljmethyl]-2-(lH-tetrazol-5-yl)-biphenyl Yield: 17% of theory, Melting point: 203-205°C C28H29N7°2S (527.63) Calculated: C 63.73 H 5.54 N 18.58 Found: 63.63 5.54 18.39 - 89 Example 81 ' -[[2-n-Butyl-6-(l-benzyl-imidazolidin-2,4-dion-3-yl) benz imidazol-l-yl]methyl]biphenyl-2-carboxylic acid trifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4·[[2-n-butyl-6-(l-benzyl-imidazolidin-2,4-dion-3-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 58% of theory, Melting point: amorphous C35H32N4°4 x CFjCOOH (686.71) Calculated: C 64.72 H 4.84 N 8.16 Found: 64.48 4.68 8.09 Example 82 ' -[[2-n-Propyl-6-(5,5-pentamethylene-imidazolidin-2,4 dion-3-yl) -benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[ [2-n-propyl-6-(5,5-pentamethylene-imidazolidin-2,4dion-3-yl)-benzimidazol-l-yl]methyl]bipheny1-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 27% of theory, Melting point: amorphous (550.63) Calculated: C 71.98 H 6.22 N 10.18 Found: 71.93 6.16 10.09 Rf value: 0.60 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) - 90 Example 83 4'-[[2-Ethyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-lyl ]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4'-[[2-ethyl-6(2-oxo-piperidin-l-yl)-benz imidazol-l-yl]methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 33% of theory, Melting point: sintering from 150°C C28H27N7° (4 77.58) Calculated: C 70.42 H 5.70 N 20.53 Found: 70.48 5.72 19.88 Example 84 1 - [[2-Ethyl-6-(butanesultam-l-yl)-benzimidazol-lyl ]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4’-[[2-ethyl-6(butanesultam-l-yl)-benzimidazol-l-yljmethyl]biphenyl-2 carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 36% of theory, Melting point: decomposition from 240°C C27H27N7O2S (513.64) Calculated: C 63.14 H 5.30 N 19.09 Found: 63.06 5.19 19.08 Example 85 4'-[[2-n-Propyl-6-(3-n-hexyl-imidazo[4,5-b]pyridin-2yl)-benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-propyl-6-(3-n-hexyl-imidazo[4,5-b]pyridin-2-yl)benz imidazol-l-yl]methyl]biphenyl-2-carboxylate and - 91 trifluoroacetic acid in methylene chloride.
Yield: 57% of theory, Melting point: amorphous θ36Η3Α°2 (571.74) Calculated: C 75.63 H 6.52 N 12.25 Found: 75.58 6.48 12.08 Example 86 4'-[[2-n-Propyl-6-(3-methyl-imidazo[4,5-b]pyridin-2-yl) benz imidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4·[ [2-n-propyl-6-(3-methyl-imidazo[4,5-b]pyridin-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 40% of theory, Melting point: 208-210°C Cj^jNjOj (501.60) Calculated: C 74.23 H 5.43 N 13.96 Found: 74.19 5.32 13.94 Example 87 4'-[[2-n-Propyl-6-(l-methyl-imidazolin-2-yl)benz imidazol-l-yl]methyl]bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.-butyl 4'[ [2-n-propyl-6-(l-methyl-imidazolin-2-yl) -benzimidazoll-yl] methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 53% of theory, Melting point: amorphous C28H28N4°2 (4 52.57) Calculated: C 74.31 H 6.24 N 12.38 Found: 74.31 6.11 12.27 - 92 The following compounds are obtained analogously to Example 87: 4'-[[2-n-butyl-6-(l-methyl-imidazolin-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-6-(l-n-hexyl-imidazolin-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylie acid 4'-[[2-n-butyl-6-(l-n-butyl-imidazolin-2-yl)benzimidazol-l-yl]methyl]bipheny1-2-carboxylie acid 4'-[[2-n-propyl-6-(l-cyclopropyl-imidazolin-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-6-(l-cyclohexyl-imidazolin-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 1 -[[2-n-propyl-6-(l-methyl-imidazol-2-yl)-benzimidazol l-yl]methyl]biphenyl-2-carboxylic acid '-[[2-n-butyl-6-(l-methyl-imidazol-2-yl)-benzimidazoll-yl] methyl] bipheny 1-2-carboxy lie acid 4'-[[2-n-propyl-6-(l-n-hexyl-imidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid '-[[2-n-butyl-6-(l-n-butyl-imidazol-2-yl)-benzimidazol 1-yl]methyl]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-6-(l-cyclopropyl-imidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 4’-[[2-n-propyl-6-(l-cyclohexyl-imidazol-2-yl) benzimidazol-l-ylJmethyl]biphenyl-2-carboxylie acid - 93 Example 88 4'-[[2-n-Propyl-6-(1,5-dimethyl-benzimidazol-2-yl)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[[2-n-propyl-6-(1,5-dimethyl-benzimidazol-2-yl)benzimidazol-l-ylJmethylJbiphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 48% of theory, Melting point: 256-258°C C33H30N4°2 (514.63) Calculated: C 77.02 H 5.88 N 10.89 Found: 76.91 5.83 10.72 Example 89 4'-[[2-n-Propyl-6-(l-methyl-5-trifluoromethylbenzimidazol-2-yl)-benzimidazol-l-ylJmethylJbiphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4*[[2-n-propyl-6-(l-methyl-5-trifluoromethyl-benzimidazol 2-yl)-benzimidazol-l-ylJ methyl J biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 56% of theory, Melting point: 183-186°C C33H27F3N4°2 ( 5 6 8.61) Calculated: C 69.71 H 4.79 N 9.85 Found: 69.58 4.72 9.80 - 94 Example 90 41-[[2-n-Propyl-6-(5-methyl-imidazolidin-2,4-dion-3-yl) benzimidazol-l-yl]methyl]bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-propyl-6-(5-methyl-imidazolidin-2,4-dion-3-yl)benzimidazol-l-y1]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 29% of theory, Melting point: amorphous C28H26N4°4 (4 82.55) Calculated: C 69.69 H 5.43 N 11.61 Found: 69.67 5.40 11.55 Example 91 *-[(2-n-Propyl-6-(l-methyl-imidazolidin-2,4-dion-3-yl) benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[(2-n-propyl-6-(l-methyl-imidazolidin-2,4-dion-3-yl)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 32% of theory, Melting point: amorphous C28H26N4°4 (4 82.55) Calculated: C 69.69 H 5.43 N 11.61 Found: 69.61 5.38 11.49 Example 92 4·-[(2-n-Propyl-6-(l-butyl-benzimidazol-2-yl)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[(2-n-propyl-6-(l-butyl-benzimidazol-2-yl)-benzimidazol 1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic - 95 acid in methylene chloride.
Yield: 59% of theory, Melting point: sintering from 149°C C35HwN4O2 (542.69) Calculated: C 77.46 H 6.32 N 10.32 Found: 77.37 6.31 10.35 Example 93 1 — [(2-n-Butyl-6-(lH-benzimidazol-2-yl)-benzimidazol-lyl) methyl] biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[ (2-n-butyl-6-(lH-benziraidazol-2-yl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 62% of theory, Melting point: 200-202 °C C32H28N4°2 (500.61) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.54 5.60 11.16 Example 94 4'-[ (2-n-Butyl-6-hexahydrohomophthalimino-benzimidazol1-yl)methyl]biphenyl-2-carboxylic acid 0.4 g (0.64 mMol) of tert.-butyl 4'-[(2-n-butyl-6-(2carboxy-cyclohexylmethylcarbonylamino)-benzimidazol-lyl) -methyl ]biphenyl-2-carboxylate are refluxed for 1¼ hours with stirring in 5 ml of phosphorus oxychloride. After cooling, the mixture is poured onto ice water and the crude product precipitated is removed by suction filtering. This is dissolved in ethanol/water, made alkaline with ammonia and concentrated in vacuo until it crystallises out. It is then suction filtered, washed with water and dried in vacuo at 120°C.
Yield: 0.15 g (42.8% of theory) - 96 Melting point: 241-243 °C C34H35N3°4 (549.66) Calculated: C 74.29 H 6.49 N 7.64 Found: 74.14 6.64 7.81 Example 95 ’-[(2-n-Butyl-6-(7-nitro-benzofurazan-4-yl-amino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared from 4'-[(6-amino-2-n-butyl-benzimidazol-lyl)methyl]biphenyl-2-carboxylic acid and 4-chloro-7nitro-benzofurazan in pyridine at ambient temperature. Yield: 13.1% of theory, Rf value: 0.75 (silica gel, methylene chloride/ethanol = 9:1) C31H26N6°5 (562.58) Calculated: C 66.18 H 4.66 N 14.93 Found: 66.35 4.76 15.13 Example 96 ’ — [[2-Ethyl-6-(pyrrolidinocarbonylamino)-benzimidazoll-yl Jmethyl] biphenyl-2-carboxylic acid-trifluoroacetatesemihydrate Prepared analogously to Example 1 from tert.-butyl 4'[ [2-ethyl-6-(pyrrolidinocarbonylamino)-benzimidazol-lyl J-methyl J biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 80.9% of theory, Melting point: 178-179°C C28H28N4°3 x CF3COOH x 0.5 H2o (591.59) Calculated: C 60.90 H 5.11 N 9.47 Found: 61.10 5.22 9.26 Rf value: 0.48 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5 by volume) - 97 Example 97 ’ - [[2-Methyl-6-(pyrrolidinocarbonylamino)-benzimidazoll-yl Jmethyl ]biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4’[[2-methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-lyl] -methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 82.1% of theory, Melting point: 181-182°C C27H26N4°3 x CF3COOH (568.55) Calculated: C 61.26 H 4.79 N 9.85 Found: 60.99 5.09 9.89 Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5 by volume) Example 98 ’-[[2-n-Propyl-6-(pyrrolidinocarbonylamino)benz imidazol-l-yl ] methyl ] biphenyl-2 -carboxyl ic acidtrif luoroacetate Prepared analogously to Example 1 from tert.-butyl 4*[ [2-n-propyl-6-(pyrrolidinocarbonylamino)-benzimidazoll-yl Jmethyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 79.7% of theory, Melting point: 207-208’C C29H30N4°3 x CFjCOOH (596.61) Calculated: C 62.41 H 5.24 N 9.39 Found: 62.38 5.36 9.42 Rf value: 0.55 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5 by volume) - 98 Example 99 4'-[[2-Methylmercapto-6-(pyrrolidinocarbonylamino)benzimidazol-l-yl ] methyl ] biphenyl-2 -carboxylic acidtrifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4'[ [2-methylmercapto-6- (pyrrolidinocarbonylamino) benz imidazol-l-yl] methyl] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 96.1% of theory, Melting point: 177-178 °C x CF3C00H (600.61) Calculated: C 57.99 H 4.53 N 9.33 Found: 57.68 4.75 9.30 Rf value: 0.52 (silica gel; ethyl acetate/ethanol/ammoni = 50:45:5 by volume) Example 100 '-[ [6-(2,3-Dimethylmaleic acid imido)-2-methylmercaptobenzimidazol-l-yl]methyl]bipheny 1-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[6-(2,3-dimethylmaleic acid imido)-2-methylmercaptobenzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 91.7% of theory, Melting point: 276-277 °C C28H23N3°4S (497.57) Calculated: C 67.59 H 4.66 N 8.45 S 6.44 Found: 67.57 4.94 8.40 6.37 Rf value: 0.47 (silica gel; ethyl acetate/ethanol/ammoni = 50:45:5 by volume) - 99 Example 101 4·-[[2-n-Butyl-6-[3-(7-nitrobenzofurazan-4-yl-amino)propionylamino]benzimidazol-l-yljmethyl]-2-(lH-tetrazol - yl)-biphenyl-hydrate Prepared analogously to Example 55 from 4’-[[2-n-butyl6- [3-(7-nitrobenzofurazan-4-yl-amino)-propionylamino]benzimidazol-l-yl]methyl]-2-(1-triphenylmethyl-tetrazol -yl)-biphenyl and 2 N hydrochloric acid in ethanol. Yield: 33.3% of theory, Melting point: 179-181°C x H20 (675.70) Calculated: C 60.43 H 4.92 N 22.80 Found: 60.24 5.09 22.69 Example 102 (2-n-Butyl-6-[3-(7-nitrobenzofurazan-4-yl-amino)propionylamino]benzimidazol-l-yl]methylJbipheny1-2carboxylic acid-trifluoroacetate-hydrate Prepared analogously to Example 1 from tert.-butyl 4’[[2-n-butyl-6-[3-(7-nitrobenzofurazan-4-yl-amino)propionylamino] benz imidazol-l-yl] methyl] biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87.5% of theory, Melting point: 127°C (decomp.) C34H31N?O6 x CF3COOH X H2O (7 65.69) Calculated: C 56.47 H 4.47 N 12.80 Found: 56.68 4.27 12.67 - 100 Example 103 4[6-(2,3-Dimethylmaleic acid imido)-2-methylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[6-(2,3-dimethylmaleic acid imido)-2-methylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 94.4% of theory, Melting point: 327-328’C C28H23N3°4 (4 65.51) Calculated: C 72.25 H 4.98 N 9.03 Found: 72.00 5.08 9.06 Rf value: 0.33 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5 by volume) Example 104 4'-[[6-(2,3-Dimethylmaleic acid imido)-benzimidazol-lyl ]methyl]biphenyl-2-carboxylic acid-semihydrate Prepared analogously to Example 1 from tert.-butyl 4'[[6-(2,3-dimethylmaleic acid imido)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 95.5% of theory, Melting point: 223-224 °C C27H21N3°4 x °·5 H2° (460.49) Calculated: C 70.42 H 4.82 N 9.13 Found: 70.30 4.88 8.81 Rf value: 0.34 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5 by volume) - 101 Example 105 4·-[[6-(2,3-Dimethylmaleic acid imido)-2-n-propylbenzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acidmonohydrate Prepared analogously to Example 1 from tert.-butyl 4'[[6-(2,3-dimethylmaleic acid imido)-2-n-propylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 92.5% of theory, Melting point: 309-310°C C30H27N3O4 X H2O (511.58) Calculated: C 70.44 H 5.71 N 8.21 Found: 70.44 5.64 8.19 Rf value: 0.47 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5 by volume) Example 106 4'—[[6—(2,3—Dimethylmaleic acid imido)-2-ethylbenzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4’[[6-(2,3-dimethylmaleic acid imido)-2-ethylbenzimidazol-l-ylJmethylJ biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87.5% of theory, Melting point: 307-308°C C29H25N3°4 (479.53) Calculated: C 72.64 H 5.25 N 8.76 Found: 72.41 5.37 8.94 Rf value: 0.40 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5 by volume) - 102 Example 107 ' [2-Ethyl-6-(l-methylbenzimidazol-2-yl)-benzimidazoll-yl ]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-ethyl-6-(l-methyl-benzimidazol-2-yl)-benzimidazol-lyl Jmethyl] biphenyl-2 -carboxy late and trifluoroacetic acid in methylene chloride.
Yield: 31% of theory, Melting point: 183-185°C C31H26N4O2 (486.60) Calculated: C 76.52 H 5.39 N 11.52 Found: 76.73 5.49 11.70 Example 108 ' - [ [2-Methyl-6-(butanesultam-l-yl)-benzimidazol-lyl ]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4’-[[2-methyl-6(butanesultam-l-yl)-benzimidazol-l-yl]methyl]-2-cyanobiphenyl and sodium azide in dimethylformamide.
Yield: 27% of theory, Melting point: 173-175’C C26H25N7°2S (499.60) Calculated: C 62.51 H 5.04 N 19.63 S 6.42 Found: 62.39 5.05 19.44 6.33 Mass spectrum: m/e = 499 Example 109 4'-[[2-Methyl-6-(l-methylbenzimidazol-2-yl) benzimidazol-l-ylJmethyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4’-[[2-methyl-6(l-methylbenzimidazol-2-yl)-benzimidazol-l-ylJmethyl]-2cyano-biphenyl and sodium azide in dimethylformamide. - 103 Yield: 26.5% of theory, Melting point: 214-217 °C C30H24N8 (496.80) Calculated: C 72.56 H 4.87 N 22.56 Found: 72.32 5.01 22.23 Example 110 41 2 * *-[[6-(Butanesultam-l-yl)-benzimidazol-1-ylJmethyl]-2(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4'-[[6(butanesultam-l-yl)-benzimidazol-l-ylJmethyl]-2-cyanobiphenyl and sodium azide in dimethylformamide.
Yield: 60.0% of theory, Melting point: 246-249 °C C25H23N7°2S (485.60) Calculated: C 61.84 H 4.77 N 20.19 Found: 61.75 4.92 20.28 Example 111 4'-[ [2-Ethyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol 1- yl]methyl J-2-(ΙΗ-tetrazo1-5-y1)-b ipheny1 Prepared analogously to Example 41 from 4·-[[2-ethyl-6(l-methyl-benzimidazol-2-yl)-benzimidazol-1-ylJmethyl]2- cyano-biphenyl and sodium azide in dimethylformamide. Yield: 41.0% of theory, Melting point: from 178°C (sintering) C31H26N8 (510.60) Calculated: C 72.92 H 5.13 N 21.95 Found: 72.94 5.25 21.71 Mass spectrum: m/e = 510 - 104 Example 112 ' -[[2-Ethyl-6-(N-benzenesulphonyl-methylamino)benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4'-[[2-ethyl-6(N-benzenesulphonyl-methylamino)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 66.0% of theory, Melting point: 226-228 °C C30H27N7O2S (549.70) Calculated: C 65.55 H 4.95 N 17.84 S 5.83 Found: 65.38 4.95 17.59 5.79 Example 113 ' -[[2-n-Propyl-6-(N-benzenesulphonyl-methylamino)benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 41 from 4’-[[2-n-propyl6-(N-benzenesulphonyl-methylamino)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 83.4% of theory, Melting point: 177-179°C C^H^OjS (563.70) Calculated: C 66.05 H 5.18 N 17.40 S 5.69 Found: 65.89 5.14 17.21 5.73 Example 114 ’-[ (2-n-Butyl-6-benzenesulphonyloxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[(2-n-butyl-6-benzenesulphonyloxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride. - 105 Yield: 8.2% of theory, Melting point: 193-195°C C^H^OjS (540.60) Calculated: C 68.92 H 5.22 N 5.18 Found: 68.94 5.08 5.08 Example 115 4'-[[2-n-Butyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H) pyrimidinon-l-yl)-benzimidazol-l-yl]methyl]-2-(1Htetrazol-5-yl)-biphenyl Prepared analogously to Example 55 from 4'-[[2-n-butyl6- (3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)benzimidazol-l-ylJmethyl)-2-(1-triphenylmethyl-tetrazol 5-yl)-biphenyl and methanol in methanolic hydrochloric acid.
Yield: 28.0% of theory, Melting point: from 125’C (decomp.) C^H^NgO (596.80) Calculated: C 72.46 H 6.08 N 18.78 Found: 72.26 5.94 18.85 Example 116 ’ -[[2-n-Butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-benzimidazol-l-yl]-methyl)-2-(1Htetrazol-5-yl)-biphenyl Prepared analogously to Example 55 from 4'-[[2-n-butyl5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)benzimidazol-l-yl]methyl)-2-(1-triphenylmethyl-tetrazol 5-yl)-biphenyl and methanol in methanolic hydrochloric acid.
Yield: 31.0% of theory, Melting point: from 125’C (decomp.) C36H36N8° (596.80) Calculated: C 72.46 H 6.08 N 18.78 Found: - 106 72.27 6.03 18.61 Example 117 4’-[[2-n-Propyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-benzimidazol-l-yl]methyl]-2-(1Htetrazol-5-yl)-biphenyl Prepared analogously to Example 55 from 4'-[[2-n-propyl 6- (3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)benzimidazol-l-ylJmethyl] -2- (1-triphenylmethyl-tetrazol 5-yl)-biphenyl and methanol in methanolic hydrochloric acid.
Yield: 35.0% of theory, Melting point: from 132 °C (decomp.) C35H34N8° (582.71) Calculated: C 72.14 H 5.88 N 19.23 Found: 71.98 6.02 19.11 Example 118 '- [[2-Ethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl) -benzimidazol-l-yl]methyl]-2- (1Htetrazol-5-yl)-biphenyl Prepared analogously to Example 55 from 4'-[[2-ethyl-6(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)benzimidazol-l-yl]methyl]-2-(1-triphenylmethyl-tetrazol 5-yl)-biphenyl and methanol in methanolic hydrochloric acid.
Yield: 22.0% of theory, Melting point: from 106°C (decomp.) <^Η32Ν8Ο (568.68) Calculated: C 71.81 H 5.67 N 19.70 Found: 71.73 5.54 19.92 - 107 Example 119 4' - [ [2-n-Butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)benzimidazol-l-y1]methy1]biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl 4'-[[2-n butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)benzimidazol-l-yl]methyl] biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Yield: 80.0% of theory, Melting point: 276-283 °C C29H28N4O3 (480.60) Calculated: C 72.48 H 5.87 N 11.66 Found: 72.20 6.13 11.53 Mass spectrum: m/e = 480 The following compounds are obtained analogously to Example 119: '-[[2-ethyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol-lyl Jmethyl ]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazol l-ylJmethyl]biphenyl-2-carboxylic acid 4 '-[[2-n-butyl-6-(2H-pyridazin-3-on-6-yl)-benzimidazoll-yl Jmethyl ] biphenyl-2-carboxylic acid 4'-[[2-n-propyl-6-(2-methyl-4,5-dihydro-pyridazin-3-on6-yl)-benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid ’ - [ [ 2-n-propyl-6-(2-benzyl-4,5-dihydro-pyridazin-3-on6-yl)-benzimidazol-l-ylJmethylJbipheny1-2-carboxylie acid - 108 Example 120 4'-[[2-n-Propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl 4'-[[2-n propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl) benzimidazol-l-yl]methyl] biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Yield: 66.0% of theory, Melting point: 236-241’C C28H26N4°3 (4 66.54) Calculated: C 72.09 H 5.62 N 12.01 Found: 71.88 5.61 11.95 Example 121 ’-[[2-Ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl 4·-[[2ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)benzimidazol-l-yl]methyl] biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Yield: 71.0% of theory, Melting point: 255-257°C C27H24N4O3 (452.51) Calculated: C 71.67 H 5.35 N 12.38 Found: 71.41 5.51 12.12 Example 122 4'-[[2-n-Butyl-6-(3-cyclohexyl-propylamino)benzimidazol-1-yl]methy1]bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-(3-cyclohexyl-propylamino)-benzimidazol-1 yl]methyl]biphenyl-2-carboxylate and trifluoroacetic - 109 acid in methylene chloride.
Yield: 85.7% of theory, Melting point: 152-153 °C X 0.75 CFjCOOH (609.24) Calculated: C 69.99 H 6.91 N 6.90 Found: 70.02 6.93 6.84 Rf value: 0.24 (silica gel; ethyl acetate/ethanol/ammonia = 80:40:2 by volume) - 110 In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I, particularly compounds A to L of the pharmacological test report, may be used as the active substance: Example I Ampoules containing 50 mg of active substance per 5 ml Active substance 50 mg kh2po4 2 mg Na2HPO4 x 2H2O 50 mg NaCl 12 mg Water for injections ad 5 ml Preparation: The buffer substances and isotonic substance are dissolved in some of the water. The active substance is added and, once it has been completely dissolved, water is added to make up the required volume.
Example II Ampoules containing 100 mg of active substance per 5 ml Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene- glycol block polymer 250 mg Water for injections ad 5 ml Preparation: Methyl glucamine is dissolved in some of the water and - Ill 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 Magnesium stearate 1.5 mq 200.0 mg Preparation: The active substance, CaHP04, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50°C in a circulating air dryer and screened again.
After the lubricant has been added, the granules are compressed in a tablet making machine.
Example 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 Gelatin 10.0 mg Magnesium stearate 1.0 mg 180.0 mg - 112 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 Polyvinylpyrrolidone 2.8 mg Microcrystalline cellulose 60.0 mg Magnesium stearate 1.2 mq 350.0 mg Preparation: The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm screen and dried at 45°C. After drying, it is screened again and the magnesium stearate is added. This mixture is then compressed into cores.
The cores thus produced are covered with a coating by known methods. Colourings may be added to the coating suspension or solution. - 113 Example VI Capsules containing 250 mg of active substance Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 mq 320.0 mg Preparation: The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The final mixture is packed into size 1 hard gelatine capsules.
Example VII Oral suspension containing 50 mg of active substance per 5 ml Active substance 50.0 mg Hydroxyethylcellulose 50.0 mg Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg Water ad 5.0 ml Preparation: Distilled water is heated to 70°C. Hydroxyethylcellulose is dissolved therein with stirring. By the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient - 114 temperature, sorbic acid, flavouring and active substance are added. The suspension is evacuated with stirring to remove any air. One dose of 50 mg is contained in 5.0 ml.
Example VIII Suppositories containing 100 mg of active substance Active substance Solid fat 100.0 mg 1600.0 mg 1700.0 mg Preparation: The hard fat is melted. At 40°C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38°C and poured into slightly chilled suppository moulds.

Claims (14)

Claims
1. A compound of formula I (wherein R 1 represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, a benzimidazolyl or benzoxazolyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a C^-alkyl group, by a C V3 -alkoxy or by a trifluoromethyl group, and in which the NH-group of the above-mentioned imidazole rings may additionally be substituted by a C V6 -alkyl group or by a C 3 . 7 -cycloalkyl group, an amino group substituted by a bicyclohexylcarbonyl, biphenylcarbonyl, or hydroxy (C 5 . 7 ) -cycloalkyl) aminocarbonyl group, which may additionally be substituted at the N-atom by a C V3 -alkyl group, an aminocarbonylamino group substituted by a bicyclohexyl or biphenyl group and optionally also substituted by one or two C^j-alkyl groups at the N-atom, with the exception of the 2-oxo-3,4-tetramethylene-pyrrolidin-1yl group a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two C 13 -alkyl groups or by a tetramethylene or pentamethylene group, in which a methylene group is replaced by a carbonyl or sulphonyl group, a 3,4,5,6tetrahydro-2(1H)-pyrimidinone group optionally substituted by a C v3 -alkyl or phenyl(C v3 -alkyl) group, a straight-chained or branched hydroxy (C 4 _ 6 -alkyl) aminocarbonyl group, a maleic acid amido or maleic acid imido - 116 group optionally mono- or disubstituted by a C V3 -alkyl group or by a phenyl group, in which the substituents may be identical or different, an imidazoline or imidazole group optionally substituted by a C^^-alkyl group or by a C 3 . 7 -cycloalkyl group, an imidazolidinedione group optionally substituted by a C v3 -alkyl group, by a phenyl(C 13 -alkyl) group or by a tetramethylene, pentamethylene or hexamethylene group, a C 1 . 6 -alkylsulphonyloxy group, a benzenesulphonyloxy group optionally substituted by a C V3 -alkyl group, a C V3 alkylamino or phenyl (Chalky1)amino group substituted by a C 4 . 6 -alkylsulphonyl group or by a phenyl (Chalky 1) sulphonyl group, an amino or C.,_ 3 alkylamino group substituted by a naphthalenesulphonyl group optionally substituted in the naphthalene ring by a di (C V3 alkyl)amino group or by one or two C.,_ 3 -alkoxy groups, a C 3 . 5 alkoxy group substituted in the 3-, 4- or 5-position by an imidazolyl group, a C 25 -alkoxy group substituted in the 2—, 3-, 4- or 5-position by a benzimidazolyl or tetrahydro-benzimidazolyl group, a pyridazin-3-one or dihydro-pyridazin-3-one group optionally substituted in the 2-position by an optionally phenyl-substituted C v 3 alkyl group and optionally additionally substituted at a carbon atom by 1 or 2 C V3 alkyl groups, a pyrrolidino, piperidino or hexamethyleneimino group substituted by two C^j-alkyl groups, a 7-nitrobenzofurazan-4-ylamino(C 2 . 3 alkanoyl)amino group, a heptamethyleneimino, 1H, 3H-quinazolin-2,4-dion-3-yl, pentamethylene-oxazolin2-yl, benzofuran-carbonylamino or 7-nitro-benzofurazan4-yl-amino group, and where R 3 represents a carboxy group and R 2 represents an n-butyl group, R 1 in the 6-position may also represent an amino group substituted by a phenylsulphonyl, cyclohexylmethylaminocarbonyl, 2-carboxycyclohexylmethylcarbonyl, 2-tert.butoxycarbonyl-cyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6-tetrahydrobenzoyl, N-methylIE 912563 - 117 phenylaminocarbonyl or 3-cyclohexylpropyl group, a methylamino group substituted by a propylsulphonyl, phenylsulphonyl, methylphenylsulphonyl or chlorophenylsulphonyl group, an n-pentylamino group substituted by a phenylsulphonyl or methoxyphenylsulphonyl group, an npropylamino group substituted by a methylphenylsulphonyl or methoxyphenylsulphonyl group, an isopropylamino group substituted by a benzoyl or chlorophenylsulphonyl group, an N-acety 1-cyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido, hexahydrohomophthalimido, Nmethanesulphonyl-2-phenylethylamino, N-chlorophenylsulphonyl-benzylamino, piperidino, 4-methyl-piperidino or hexamethyleneimino group, and where represents a carboxy group and R 2 represents an nbutyl group, Rf in the 5- or 6-position may also represent a 2-oxo-l,2-dihydro-3,4-tetramethylenepyrrolidin-l-yl, 3-carboxy-propionyl or 3-carboxy-2methyl-propionyl group, and where R 3 represents a carboxy group and R 2 represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, Rf in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R 3 represents a tetrazolyl group and R 2 represents an n-butyl group, Rf in the 5- or 6-position may also represent an n-pentylamino group substituted by a methyl-aminocarbonyl or cyclohexylaminocarbonyl group and Rf in the 6-position may represent a 3,3-dimethylglutaric acid imido or 4,4-tetramethylene-glutaric acid imido group, and where R 3 represents a tetrazolyl group and R-, represents an ethyl or n-propyl group, R, in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and - 118 where R 3 represents a tert. butoxycarbonyl group and R 2 represents an n-butyl group, R 1 in the 6-position may also represent a 2-carboxycyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group; R 2 represents a hydrogen atom or a straight-chained or branched C V5 -alkyl group in which a methylene group may optionally be replaced by a sulphur atom; R 3 represents a carboxy, cyano, ΙΗ-tetrazolyl or 1triphenylmethyl-tetrazolyl group or a (C.,_ 4 alkoxy) carbonyl group; and R 4 represents a hydrogen, fluorine, chlorine or bromine atom); and isomers and salts thereof.
2. A compound of formula I as claimed in claim 1 wherein R 1 represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, a benzimidazolyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, or by a methyl, methoxy or trifluoromethyl group, and in which the NHgroup of the above-mentioned imidazole rings may additionally be substituted by a C.,_ 6 -alkyl group or by a C 3 . 6 -cycloalkyl group, a benzoxazol-2-yl group optionally substituted by a methyl group, an amino group substituted by a bicyclohexylcarbonyl, biphenylcarbonyl or benzofuryl-2-carbonyl group, an aminocarbonylamino group substituted in the 3-position by a bicyclohexyl or biphenyl group, a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two methyl groups or by a tetramethylene or pentamethylene group wherein a methylene group is - 119 replaced by a carbonyl or sulphonyl group, a 3,4,5,6tetrahydro-2(1H)-pyrimidinone group optionally substituted by a methyl or benzyl group, a hydroxy (C 4 alkyl)aminocarbonyl group, a maleic acid amido or maleic acid imido group optionally substituted by one or two substituents which may be the same or different selected from methyl and phenyl groups, an imidazolin-2-yl or imidazol-2-yl group substituted in the 1-position by a C V6 -alkyl group or by a C 3 . 7 -cycloalkyl group, an imidazolidinedione group optionally substituted by a methyl, benzyl, tetramethylene or pentamethylene group, a methylamino or benzylamino group substituted by a butanesulphonyl group or by a phenylmethanesulphonyl group, an amino or methylamino group substituted by a naphthalenesulphonyl group in which the naphthalene ring may be substituted by a dimethylamino group or by 2 methoxy groups, a pyridazin-3-one or dihydro-pyridazin3-one group optionally substituted by a methyl or benzyl group, a pyrrolidino, piperidino or hexamethyleneimino group substituted by two methyl groups, a heptamethyleneimino, 1H,3H-quinazolin-2,4-dion-3-yl, hydroxycyclohexylamino-carbonyl, 4,5-pentamethyleneoxazolin-2-yl, 7-nitro-benzofurazan-4-yl-amino or 7nitro-benzofurazan-4-yl-aminopropionylamino group, and where R 3 represents a carboxy group and R 2 represents an n-butyl group, R 1 in the 6-position may also represent an amino group substituted by a phenylsulphonyl, cyclohexylmethylaminocarbonyl, 2-carboxycyclohexylmethylcarbonyl, 2-tert.-butoxycarbonyl-cyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6-tetrahydrobenzoyl, Nmethyl-phenylaminocarbonyl or 3-cyclohexylpropyl group, a methylamino group substituted by a propylsulphonyl, phenylsulphonyl, 4-methylphenylsulphonyl or 4chlorophenylsulphonyl group, an n-pentylamino group substituted by a phenylsulphonyl or 4-methoxyphenylsulphonyl group, an n-propylamino group substituted by a - 120 4-methy Ipheny lsulphonyl or 4-methoxyphenyl sulphonyl group, an isopropylamino group substituted by a benzoyl or 4-chlorophenylsulphonyl group, an N-acetylcyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido, hexahydrohomophthalimido, N-methanesulphonyl-2phenylethylamino, N-(4-chlorophenylsulphonyl)benzylamino, piperidino, 4-methyl-piperidino or hexamethyleneimino group, and where R 3 represents a carboxy group and R 2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent a 2-oxo-1,2-dihydro-3,4-tetramethylenepyrrolidin-l-yl, 3-carboxy-propionyl or 3-carboxy-2methyl-propionyl group, and where R 3 represents a carboxy group and R 2 represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R 1 in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R 3 represents a tetrazolyl group and R 2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent an n-pentylamino group substituted by a methylaminocarbonyl or cyclohexylaminocarbonyl group and R 1 in the 6-position may also represent a 3,3-dimethylglutaric acid imido or 4,4-tetramethylene-glutaric acid imido group, and where R 3 represents a tetrazolyl group and R 2 represents an ethyl or n-propyl group, R 1 in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and where R 3 represents a tert.butoxycarbonyl group and R 2 represents an n-butyl group, R 1 in the 6-position may also represent a 2-carboxy-cyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group; - 121 R 2 represents a hydrogen atom or a straight-chained or branched C v4 -alkyl group in which a methylene group may be replaced by a sulphur atom; Rj represents a carboxy, cyano, ΙΗ-tetrazolyl or 1triphenylmethyl-tetrazolyl group or a (C 14 alkoxy)carbonyl group; and R 4 represents a hydrogen, fluorine, chlorine or bromine atom; and the 1-, 3-isomer mixtures and salts thereof with organic or inorganic acids or bases.
3. A compound of formula I as claimed in claim 1 or claim 2 wherein R 1 in the 6-position represents a l-methylbenzimidazol-2yl, 3,4,5,6-tetrahydro-phthalimino, 2,3-diphenyl-maleic acid imido, 2,3-dimethyl-maleic acid imido, N-phenylmethanesulphonyl-methylamino, 2-oxo-pyrrolidin-l-yl, 2oxo-piperidin-l-yl, 2-oxo-hexamethyleneimino, 2-oxo-3,4tetramethylene-pyrrolidin-2-yl, 3,3-dimethylglutarimido, N-methylaminocarbonyl-n-pentylamino, propanesultam-l-yl or butanesultam-l-yl group; R 2 represents a methyl, ethyl, n-propyl or n-butyl group R 3 represents a carboxy or ΙΗ-tetrazolyl group; and R 4 represents a hydrogen atom; and the salts thereof with organic or inorganic acids or bases.
4. A compound as claimed in any one of claims 1 to 3 being - 122 4·-[[2-n-propyl-6-(l-methylbenzimidazol-2-yl) benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid; 4 1 -[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid; 4'-[[2-n-b u tyl-6-(2,3-diphenyl-maleic acid imido)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid; 4'—[[2—n-butyl—6—(2,3—dimethyl—maleic acid imido)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid; 4 ·-[[2-n-butyl-6-(N-phenylmethanesulphonyl-methylamino)benzimidazol-l-ylJmethyl]biphenyl-2-carboxylic acid; 4 '-[[2-n-butyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-lyl ]methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 4 [2-n-butyl-6-(2-oxo-pyrrolidin-l-yl)-benzimidazol-lyl ]methyl] -2- (lH-tetrazol-5-yl) -biphenyl; 4 · — [[2-n-butyl-6-(2-oxo-hexamethyleneimino)benzimidazol-l-ylJmethyl]-2-(lH-tetrazol-5-yl)-biphenyl; 4·-[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazoll-yl Jmethyl ]—2—(lH-tetrazol-5-yl)-biphenyl; 4 ’-[[2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)benzimidazol-l-ylJmethyl]-2-(lH-tetrazol-5-yl)-biphenyl ; 4’-[[2-n-butyl-6-(cyclohexylaminocarbonyl-npentylamino)-benzimidazol-l-ylJmethyl]-2-(lH-tetrazol-5yl)-biphenyl; 4'-[[2-n-butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-lyl)-benzimidazol-l-ylJmethyl]bipheny1-2-carboxylic acid; - 123 4 ' - [[2-n-butyl-6-(propanesultam-l-yl)-benzimidazol-1yljmethyl]-2-(lH-tetrazol-5-yl)-biphenyl; 4'-[[2-n-propyl-6-(butanesultam-l-yl)-benzimidazol-lyl Jmethyl]-2-(lH-tetrazol-5-yl)-biphenyl; 4 ·-[ [2-n-butyl-6-(butanesultam-l-yl)-benzimidazol-lyl Jmethyl ]-2-(lH-tetrazol-5-yl)-biphenyl; 4'-[[2-n-propyl-6-(l-methyl-benzimidazol-2-yl)benzimidazol-l-ylJmethyl]-2-(lH-tetrazol-5-yl)-biphenyl; or 4 ' [2-n-propyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-lyl Jmethyl J-2-(lH-tetrazol-5-yl)-biphenyl; or a salt thereof with an organic or inorganic acid or base.
5. A compound as claimed in any one of claims 1 to 4 being a physiologically acceptable salt of a compound of formula I.
6. A process for the prepartion of compounds as claimed in claim 1, said process comprising at least one of the following steps: a) cyclising a compound of formula II (wherein Rf is as defined in any one of claims 1 to 4; - 124 one of the groups X 1 or Y, represents a group of formula and the other group X 1 or Y 1 represents a group of formula Z 1 Z 2 - NH - X C - R 2 ; R 2 , R 3 and R 4 are as defined in any one of claims 1 to 4, Rg represents a hydrogen atom or an R 2 CO group; Z 1 and Z 2 , which may be the same or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups, or Z 1 and Z 2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C^j-alkyl group, or a C 2 . 3 -alkylenedioxy or C 2 . 3 alkylenedithio group, with the proviso that one of the groups X 1 or Y 1 must represent a group of formula \ cor 2 - 125 or Z \ / Zz - NH - C - R 2 ) or an N-oxide thereof and optionally subsequently reducing a cyclized N-oxide thus obtained; b) reacting a benzimidazole of formula III \ (wherein R 1 and R 2 are as defined in any one of claims 1 to 4), with a biphenyl compound of formula IV λ // *4 (iv) (wherein R 3 and R 4 are as defined in any one of claims 1 to 4; and Z 3 represents a nucleophilic leaving group); c) (to prepare a compound of formula I wherein R 3 represents a carboxy group) converting a compound of formula V (V) 126 (wherein R 2 and R 4 are as defined in any one of claims 1 to 4; R 1 ’ is a group R 1 as defined in any one of claims 1 to 4 or a 3-( (C V3 alkoxy)carbonyl)propionyl or 3-( (C V3 alkoxy)carbonyl)-2-methylpropionyl group? and R 3 ' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound; or d) (to prepare a compound of formula I wherein R 3 represents a ΙΗ-tetrazolyl group) cleaving a protecting group from a compound of formula VI R (VI ) (wherein R v R 2 and R 4 are as defined in any one of claims 1 to 4; and R 3 represents a ΙΗ-tetrazolyl group protected in the 1or 3-position by a protecting group); e) (to prepare a compound of formula I wherein R 3 represents a ΙΗ-tetrazolyl group) reacting a compound of formula VII - 127 (wherein Rf, R2 and R 4 are as defined in any one of claims 1 to 4) with hydrazoic acid or a salt thereof; f) (to prepare compounds of formula I wherein Rf represents a pentamethylene-oxazolin-2-yl group) reacting a compound of formula VIII (wherein R2, R 3 and R 4 are as defined in any one of claims 1 to 4) with 1-aminomethyl-cyclohexanol in the presence of an acid-activating agent; g) (to prepare a compound of formula I wherein Rf represents a 2-oxo-3,4-tetramethylene-pyrrolidin-l-yl group) hydrogenating a compound of formula IX (wherein R 2 , R 3 and R 4 are as defined in any one of claims 1 to 4) ; h) (to prepare compounds of formula I wherein Rf represents an amino group substituted by a - 128 bicyclohexylcarbonyl or biphenylcarbonyl group, which may additionally be substituted at the N-atom by a C V3 ~ alkyl group, an aminocarbonylamino group substituted by a bicyclohexyl or biphenyl group and optionally additionally substituted by one or two C 13 ~alkyl groups at the N-atom, a maleic acid amido or maleic acid imido group optionally mono- or disubstituted by substituents selected from C^j-alkyl and phenyl groups, a C V3 alkylamino or phenyl(C V3 alkyl)amino substituted by a C 4 _ 6 alkylsulphonyl group or by a phenyl (C 1 . 3 -alkyl) sulphonyl group, an amino or C V3 alkylamino group substituted by a naphthalenesulphonyl group and optionally substituted in the naphthalene ring by a di (C 1 . 3 alkyl) amino group or by one or two C V3 -alkoxy groups, a 7-nitro-benzofurazan-4yl-amino(C 2 . 3 alkanoyl)amino group, a benzofurancarbonylamino or 7-nitro-benzofurazan-4-yl-amino group, and where R 3 represents a carboxy group and R 2 represents an n-butyl group, R 1 in the 6-position may also represent an amino group substituted by a phenylsulphonyl, cyclohexylmethylaminocarbonyl, 2-carboxycyclohexylmethylcarbonyl, 2-tert.-butoxycarbonylcyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6tetrahydrobenzoyl, N-methyl-phenylaminocarbonyl or 3cyclohexylpropyl group, a methylamino group substituted by a propylsulphonyl, phenylsulphonyl, methyIphenylsulphonyl or chlorophenylsulphonyl group, an n-pentylamino group substituted by a phenylsulphonyl or methoxyphenylsulphonyl group, an n-propylamino group substituted by a methylphenylsulphonyl or methoxyphenylsulphonyl group, an isopropylamino group substituted by a benzoyl or chlorophenylsulphonyl group, an N-acetylcyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido, hexahydrohomophthalimido, N-methanesulphonyl-2phenylethylamino or N-chlorophenylsulphonyl-benzylamino group, and - 129 where R 3 represents a carboxy group and R2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent a 2-oxo-l,2-dihydro-3,4-tetramethylenepyrrol idin-l-yl group, and where R 3 represents a carboxy group and R2 represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R 1 in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R 3 represents a tetrazolyl group and Rz represents an n-butyl group, R 1 in the 5- or 6-position may also represent an n-pentylamino group substituted by a methylamino-carbonyl or cyclohexylaminocarbonyl group and R 1 in the 6-position may also represent a 3,3dimethyl-glutaric acid imido or 4,4-tetramethyleneglutaric acid imido group, and where R 3 represents a tetrazolyl group and R 2 represents an ethyl or n-propyl group, R 1 in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and where R 3 represents a tert.-butoxycarbonyl group and R 2 represents an n-butyl group, R 1 in the 6-position may also represent a 2-carboxy-cyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group) reacting a compound of formula X (wherein - 130 R 2 , R 3 and R 4 are as defined in any one of claims 1 to 4; and R 6 represents a hydrogen atom, an n-pentyl, cyclohexylmethyl, C V3 -alkyl or phenyl(C 13 alkyl) group) with a compound of formula XI Z 4 - W - R 7 (XI) (wherein Z 4 represents a nucleophilic leaving group; W represents a -CO- or -SO 2 ~ group; and R ? represents a 2-hydroxycarbonyl-ethenyl group wherein the ethenyl moiety is mono- or disubstituted by substituents selected from C 1 . 3 -alkyl and phenyl groups, a C 3 . 6 -alkyl group, a phenyl (Chalky 1) group, a naphthalene group optionally substituted by a di(C V3 alkyl)amino group or by one or two C V3 alkoxy groups, a methyl, phenyl, methylphenyl, methoxyphenyl, chlorophenyl, biphenyl, bicyclohexyl, 2-carboxycyclohexylmethyl, 2-carboxy-3,4,5,6-tetrahydrophenyl, 3carboxy-1,1-dimethyl-propyl, 3-carboxy-2,2tetramethylene-propyl, 7-nitro-benzofurazan-4-ylaminomethyl or 7-nitro-benzofurazan-4-yl-aminoethyl group, and where W represents a -CO- group, R ? may also represent an RgNR^, group wherein Rg represents a hydrogen atom or a C 13 -alkyl group, R? represents a methyl, cyclohexyl, cyclohexylmethyl, phenyl, biphenyl or bicyclohexyl group, or R 8 and R? together with the nitrogen atom between them represent a pyrrolidino group, or - 131 Z 4 together with R? represents another carbonnitrogen bond, and R 7 together with W may also represent a 7-nitrobenzofurazan-4-yl-amino group) or with a reactive derivative of a carboxylic acid of formula XI; i) (to prepare compounds of formula I wherein Rf represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, a benzimidazolyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a Cf. 3 -alkyl group, by a Cf 3 -alkoxy group or by a trifluoromethyl group, and in which the NH-group of the above-mentioned imidazole rings may additionally be substituted by a Cf. 6 -alkyl group or by a C 3 . 7 -cycloalkyl group, a hydroxy(C 5 . 7 -cycloalkyl)aminocarbonyl group, which may additionally be substituted at the N-atom by a C 13 -alkyl group, or a straight-chained or branched hydroxy (C 4 . 6 alkyl)aminocarbonyl group) reacting a compound of formula XII (wherein R 2 , R 3 and R 4 are as defined in any one of claims 1 to 4) or a reactive derivative thereof with an amine of formula XIII N - H (XIII) - 132 (wherein R 10 represents a hydrogen atom, a cycloalkyl group or a C V6 -alkyl group; and R n represents a C 4 . 6 -hydroxyalkyl group, a C 5 . ? -hydroxycycloalkyl group or a 2-aminophenyl group which may be substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a C 1 . 3 ~alkyl group, by a C V3 alkoxy group or by a trifluoromethyl group, a 2aminocyclohexyl or 2-aminopyridyl group) optionally with simultaneous decarboxylation; j) (to prepare compounds of formula I wherein R 1 represents a dihydro-pyridazin-3-one or pyridazin-3-one group which may be substituted in the 2-position by an optionally phenyl-substituted C 1 . 3 -alkyl group or at a carbon atom by one or two C 1 . 3 -alkyl groups) reacting a carboxylic acid of formula XIV (wherein R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1 to 4; and A represents an ethylene or ethenylene group optionally substituted by one or two C V3 -alkyl groups) or a reactive acid derivative thereof with a hydrazine of formula XV h 2 n - nhr 12 (XV) (wherein R 12 represents a hydrogen atom or an optionally phenylsubstituted C 1 _ 3 -alkyl group) ; - 133 k) resolving a 1-, 3-isomer mixture of a compound of formula I thus obtained by isomer separation into the 1and 3-isomers thereof; l) converting a compound of formula I thus obtained into a salt thereof or a salt of a compound of formula I into the free compound; and m) carrying out a reaction according to any one of said steps (a) to (1) in which one or more groups are protected by a protecting group and subsequently removing any protecting group used.
7. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 4 or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.
8. Use of a compound of formula I as claimed in any one of claims 1 to 4 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of cardiac insufficiency progression after myocardial infarct, or for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
9. A method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), cardiac insufficiency progression following myocardial infarction, diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases said method comprising administering to said body a compound 134 of formula I as claimed in any one of claims 1 to 4 or a physiologically acceptable salt thereof
10. A compound of formula I as claimed in claim 1 or a pharmaceutical composition thereof substantially as herein disclosed in any one of the Examples.
11. Each and every novel compound, composition, process, use and method as herein disclosed.
12. A process for the preparation of compounds of formula I as defined in claim 1 substantially as described herein by way of Example.
13. A compound of formula I as defined in claim 1 whenever prepared by a process as claimed in claim 6 or claim 12.
14. A pharmaceutical composition substantially as described herein by way of Example.
IE256391A 1990-07-23 1991-07-22 Benzimidazoles IE912563A1 (en)

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DE4105324A DE4105324A1 (en) 1990-07-23 1991-02-20 New 1-bi:phenylyl:methyl benzimidazole derivs.

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Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8904174D0 (en) * 1989-02-23 1989-04-05 British Bio Technology Compounds
NZ232785A (en) * 1989-03-15 1991-03-26 Janssen Pharmaceutica Nv 5-(1,2 benzisoxazol-, benzimidazol and benzisothiazol-3- yl)-1h-benzimadazol-2-yl carbamic acid ester derivatives preparatory processes, intermediates and anthelmintic compositions
IE70593B1 (en) * 1989-09-29 1996-12-11 Eisai Co Ltd Biphenylmethane derivative the use of it and pharmacological compositions containing same
SI9210098B (en) * 1991-02-06 2000-06-30 Dr. Karl Thomae Benzimidazoles, drugs with this compounds, and process for their preparation
US5602127A (en) * 1991-02-06 1997-02-11 Karl Thomae Gmbh (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists
DE4225756A1 (en) * 1992-01-22 1994-03-10 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
US5594003A (en) * 1991-02-06 1997-01-14 Dr. Karl Thomae Gmbh Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists
DE4224752A1 (en) * 1992-04-11 1994-02-03 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
DE4224133A1 (en) * 1992-07-22 1994-01-27 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
US5614519A (en) * 1991-02-06 1997-03-25 Karl Thomae Gmbh (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists
US5798364A (en) * 1992-03-26 1998-08-25 Merck Patent Gesellschaft Mit Beschrankter Haftung Imidazopyridines
SG42942A1 (en) * 1991-09-10 1997-10-17 Tanabe Seiyaku Co Imidazopyridine derivatives and process for preparation thereof
EP0543263A3 (en) * 1991-11-16 1993-08-25 Dr. Karl Thomae Gmbh Benziimidazoles, pharmaceuticals containing them and process for their preparation
DE4219534A1 (en) * 1992-02-19 1993-12-16 Thomae Gmbh Dr K Substituted biphenylyl derivatives, pharmaceutical compositions containing them and methods for their preparation
DE4207904A1 (en) * 1992-03-12 1993-09-16 Thomae Gmbh Dr K SUBSTITUTED BENZIMIDAZOLYL DERIVATIVES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
US5612360A (en) * 1992-06-03 1997-03-18 Eli Lilly And Company Angiotensin II antagonists
DE4237656A1 (en) * 1992-06-13 1993-12-16 Merck Patent Gmbh benzimidazole derivatives
GB9218449D0 (en) 1992-08-29 1992-10-14 Boots Co Plc Therapeutic agents
DE4304455A1 (en) * 1993-02-15 1994-08-18 Bayer Ag Heterocyclic substituted phenyl-cyclohexane-carboxylic acid derivatives
DE4408497A1 (en) * 1994-03-14 1995-09-21 Thomae Gmbh Dr K New bi:phenyl-methyl-benzimidazole derivs.
US5753672A (en) * 1994-04-19 1998-05-19 Tanabe Seiyaku Co., Ltd. Imidazopyridine derivatives and process for preparing the same
WO1996000730A1 (en) * 1994-06-29 1996-01-11 Smithkline Beecham Corporation Vitronectin receptor antagonists
DK0882718T3 (en) * 1995-12-28 2005-12-12 Astellas Pharma Inc benzimidazole
TW453999B (en) 1997-06-27 2001-09-11 Fujisawa Pharmaceutical Co Benzimidazole derivatives
SE9903028D0 (en) 1999-08-27 1999-08-27 Astra Ab New use
DE10314702A1 (en) * 2003-03-31 2004-10-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for the preparation of telmisartan
CA2542499A1 (en) * 2003-10-16 2005-04-28 Teva Pharmaceutical Industries Ltd. Preparation of candesartan cilexetil
JP2008503595A (en) * 2004-10-15 2008-02-07 テバ ファーマシューティカル インダストリーズ リミティド Preparation of telmisartan
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
MX354786B (en) 2007-06-04 2018-03-21 Synergy Pharmaceuticals Inc AGONISTS OF GUANYLATE CYCLASE USEFUL FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS, INFLAMMATION, CANCER and OTHER DISORDERS.
CA2726917C (en) 2008-06-04 2018-06-26 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2010009319A2 (en) 2008-07-16 2010-01-21 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
US8829035B2 (en) 2009-05-29 2014-09-09 Sumitomo Chemical Company, Limited Agent for treatment or prevention of diseases associated with activity of neurotrophic factors
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
EP2970384A1 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
JP6606491B2 (en) 2013-06-05 2019-11-13 シナジー ファーマシューティカルズ インコーポレイテッド Ultra high purity agonist of guanylate cyclase C, method for producing and using the same
JP6461118B2 (en) 2013-06-21 2019-01-30 ゼニス・エピジェネティクス・リミテッドＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｌｔｄ． Novel substituted bicyclic compounds as bromodomain inhibitors
NZ714669A (en) 2013-06-21 2021-07-30 Zenith Epigenetics Ltd Novel bicyclic bromodomain inhibitors
EA201690087A1 (en) 2013-07-31 2016-08-31 Зенит Эпидженетикс Корп. NEW QUINAZOLINONS AS BROMOMODENIAL INHIBITORS
JP2017523214A (en) * 2014-08-05 2017-08-17 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Heterocyclic kinase inhibitor
WO2016087936A1 (en) 2014-12-01 2016-06-09 Zenith Epigenetics Corp. Substituted pyridinones as bromodomain inhibitors
CA2966449A1 (en) 2014-12-11 2016-06-16 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
CN107406438B (en) 2014-12-17 2021-05-14 恒翼生物医药科技(上海)有限公司 Inhibitors of bromodomains

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820843A (en) * 1987-05-22 1989-04-11 E. I. Du Pont De Nemours And Company Tetrazole intermediates to antihypertensive compounds
US4880804A (en) * 1988-01-07 1989-11-14 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking benzimidazoles
EP0400835A1 (en) * 1989-05-15 1990-12-05 Merck & Co. Inc. Substituted benzimidazoles as angiotensin II antagonists
AU645022B2 (en) * 1989-06-30 1994-01-06 E.I. Du Pont De Nemours And Company Fused-ring aryl substituted imidazoles
IE70593B1 (en) * 1989-09-29 1996-12-11 Eisai Co Ltd Biphenylmethane derivative the use of it and pharmacological compositions containing same
IL95975A (en) * 1989-10-24 1997-06-10 Takeda Chemical Industries Ltd N-benzyl- 2-alkylbenzimidazole derivatives, their production and pharmaceutical compositions containing them
IL96019A0 (en) * 1989-10-31 1991-07-18 Fujisawa Pharmaceutical Co Imidazole derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same

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