IE920373A1 - Benzimidazole compounds - Google Patents
Benzimidazole compoundsInfo
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- IE920373A1 IE920373A1 IE037392A IE920373A IE920373A1 IE 920373 A1 IE920373 A1 IE 920373A1 IE 037392 A IE037392 A IE 037392A IE 920373 A IE920373 A IE 920373A IE 920373 A1 IE920373 A1 IE 920373A1
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- benzimidazol
- imidazo
- alkyl
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
1-Biphenylylmethyl-benzimidazole derivs. of formula (I) and their salts are new. (A) where: R1 = F, Cl, Br, 1-4C alkyl, cycloalkyl, CH2F, CHF2 or CF3 and is in the 4 position; R2 = R2 or may also be R2 when R4 = 1H-tetrazolyl; R'2 = 3-5C alkoxy substd. in the 3, 4 or 5 position by imidazolyl, or 2-5C alkoxy substd. in the 2, 3, 4 or 5 position by benzimidazolyl or tetrahydrobenzimidazolyl; R2 = e.g. (a) 2-(1-imadazolyl)ethoxy, 1-4C alkylsulphonyloxy, OSO2Ph or phenylalkylsulphonyloxy; (b) acylamino opt. N-substd. by 1-6C alkyl, Ph, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenylyl, where acyl is 1-7C alkanoyl, 2-4C alkoxycarbonyl, 1-6C alkylsulphonyl, benzoyl, phenylsulphonyl, phenylalkylsulphonyl, naphthylsulphonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl, where phenyl rings are opt. substd. by 1-2 of F, Cl, Br, Me and OMe, or 3-oxopyridazylinyl or (l) 3-oxodihydropyridazinyl, opt. 2-substd. by alkyl or phenylalkyl and opt. further C-substd. by 1-2 alkyl gps., Het = a C- or imino-bonded 5-membered heteroaromatic ring or a C-bonded 6-membered heteroaromatic ring. (B) where: R1 = H or F, Cl, Br, 1-4C alkyl, CH2F, CHF2 or CF3 in the 5, 6 or 7 position; R2 = Het or a gp. as defined in (l) above; R3 and R4 are as defined in (A); provided that: (a) R2 is not 3-methylimidazo (4,5-b)pyridin-2-yl or 3-n-hexylimidazo(4,5-b) pyridin-2-yl in the 6 position when R1 = H, R3 = n-Pr and R4 = COOH; (b) R2 is not benzoxazol-2-yl in the 5 or 6 position when R1 = H, R3 = n-Pr or n-Bu and R4 = 1H-tetrazolyl; (c) R2 is not 1-methyl-2-benzimidazolyl in the 5 or 6 position or 1-n-butyl-2-benzimidazolyl, 1,5-dimethyl-2-benzimidazolyl or 1-methyl-5-trifluoromethyl -2-benzimidazolyl in the 6 postion when R1 = H, R3 = n-Pr and R4 = COOH; (d) R2 is not 1-methyl-2-benzimidazolyl in the 6 position when R1 = H, R3 = n-Bu and R4 = COOH or 1H-tetrazolyl; (e) R2 is not 2-benzimidazolyl in the 6 position when R1 = H, R3 = n-Bu and R4 = COOH; unless otherwise stated, alkanoyl, alkyl and alkoxy gps. are 1-3C and cycloalkyl gps. are 3-7C.
Description
The present invention is concerned with benzimidazole compounds, the isomers and salts thereof, which are useful pharmaceutically and especially as angiotensin antagonists.
The new benzimidazoles of the present invention are suitable for the treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
EP-A-0 392 317 has already described benzimidazoles which are valuable as angiotensin antagonists.
Viewed from one aspect, the present invention provides compounds of formula I (wherein R, in the 4-position represents a fluorine, chlorine or bromine atom, or a CM-alkyl, a cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group, and - 2 R2 represents a C3.5-alkoxy group substituted in the 3-, 4- or 5-position by an imidazolyl group, or R2 may represent a C2.5-alkoxy group substituted in the 2-, 3-, — or 5-position by a benzimidazolyl or tetrahydrobenzimidazolyl group, or R2 represents a CM-aIkylsulphonyloxy group, a benzenesulphonyloxy or phenylalkanesulphonyloxy group, an acylamino group optionally substituted at the nitrogen atom by a C1_6-alkyl group or by a phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenyl group, in which the acyl group is a C,.7alkanoyl group, a C24(alkoxycarbonyl) group, a Chalky lsulphonyl group, a benzoyl, benzenesulphonyl, phenylalkanesulphonyl, naphthalenesulphonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl group, in which the above-mentioned phenyl nuclei may each be mono- or di-substituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group and the substituents may be identical or different, a phthalimino, homophthalimino, 2-carboxyphenylcarbonylamino or 2-carboxyphenylmethylamino group, in which a carbonyl group in a phthalimino group may be replaced by a methylene, alkyl-methylene or dialkyl-methylene group, and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups, and additionally the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, whilst the substituents may be identical or different and may be totally or partially hydrogenated, a 5-, 6— or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, in which a methylene group may be replaced by a carbonyl or - 3 sulphonyl group, a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene moieties may each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and may have an endomethylene group replaced by an oxygen atom, an amidino group optionally substituted by one or two C,^ alkyl groups, a glutaric acid imino group wherein the n-propylene group may be perfluorinated, or may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, a maleic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the substituents may be identical or different, a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group and containing an imino group, an oxygen or sulphur atom, or an imino group plus an oxygen, sulphur or nitrogen atom, or R2 may represent a 6-membered heteroaromatic ring bound via a carbon atom and containing 1 or 2 nitrogen atoms, whilst the abovementioned heteroaromatic rings may be substituted in the carbon structure by a C,_6 alkyl or by a phenylalkyl group, and an n-propylene or n-butylene group may be linked to the 6-membered heteroaromatic rings via two carbon atoms, or a 1,3-butadienyl group may be linked to both the 5-membered and 6-membered heteroaromatic rings via two adjacent carbon atoms or an n-butylene or 1,3-butadienyl group is linked thereto via an imino group and an adjacent carbon atom and, in an anellated pyridine ring thus formed, a methine group may - 4 be replaced by a nitrogen atom and a vinylene group in the 3-, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or in an anellated phenyl ring thus formed, one or two methine groups may be replaced by N-atoms, whilst additionally the above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted in the carbon structure by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylaminosulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and two methyl substituents in the 1,2-position relative to each other may be linked by a methylene or ethylene bridge and an -NH- group optionally present in an imidazole ring may be substituted by a C,.6-alkyl group, by a phenylalkyl group or by a cycloalkyl group, or a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, in which a phenyl group may be condensed onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, an imidazolidinedione group optionally substituted by an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, a pyridazin-3-one or dihydro-pyridazin-3-one group which may be substituted in the 2-position by an optionally phenyl substituted alkyl group and additionally, in the carbon skeleton, by 1 or 2 alkyl groups, - 5 an Ry-NR^-CO-NR,- group (wherein Rs represents a hydrogen atom or a C,.8-alkyl, C5.7 cycloalkyl or phenylalkyl group, ϊζ, represents a hydrogen atom or a C,_g-alkyl, C3_5-alkenyl, phenyl, phenylalkyl or C5.7-cycloalkyl group, R7 represents a hydrogen atom or a C,.6-alkyl group, or one of the groups Rs, R6 or R7 may also represent a bicyclohexyl or biphenylyl group, or Re and R7 together with the nitrogen atom between them represent an unbranched C^-alkyleneimino group or a morpholino group, or Rs and together represent a C2Jl-alkylene group) , or R2 may represent a 1H,3H-quinazolin-2,4-dion-3-yl or pentamethylene-oxazolin-2-yl group, or, if R4 represents a ΙΗ-tetrazolyl group, R2 may also represent a 2-(imidazol-l-yl)-ethoxy group; or Rj represents a hydrogen atom or in the 5-, 6- or 7position R, represents a fluorine, chlorine or bromine atom or a C,^-alkyl, fluoromethyl, difluoromethyl or trifluoromethyl group; and R2 represents a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group and containing an imino group, an oxygen or sulphur atom or, an imino group plus an oxygen, sulphur or nitrogen atom, or R2 represents a 6-membered heteroaromatic ring bound via a - 6 carbon atom and containing 1 or 2 nitrogen atoms, whilst the above mentioned heteroaromatic rings may be substituted in the carbon skeleton by a C,_6 alkyl or by a phenylalkyl group and an n-propylene or n-butylene group may be linked to the 6-membered heteroaromatic rings via two carbon atoms, or a 1,3-butadienyl group may be linked via two adjacent carbon atoms to both the 5membered and 6-membered heteroaromatic rings or an nbutylene or 1,3-butadienyl group may be linked to said -membered and 6-membered heteroaromatic rings via an imino group and an adjacent carbon atom and, in an anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene group in the 3-, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or in an anellated phenyl ring thus formed, one or two methine groups may be replaced by N-atoms, whilst additionally the above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted on the carbon skeleton by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fluoromethyl, difluoromethyl, trifluoromethy1, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylamino-sulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and two methyl substituents in the 1,2-position relative to each other may be linked by a methylene or ethylene bridge and an NH- group optionally present in an imidazole ring may be substituted by a C145-alkyl group, by a phenylalkyl group or by a cycloalkyl group, with the provisos that where (i) R, represents a hydrogen atom, R3 represents an nbutyl group and R4 represents a carboxy group, then R2 cannot represent a benzimidazol-2-yl group in the - Ί 6-position, and where (ii) R( represents a hydrogen atom, R3 represents an npropyl group and R4 represents a carboxy group, then R2 cannot represent a 3-methylimidazo[4,5-b]pyridin-2-yl or 3-n-hexylimidazo[4,5-b]pyridin-2-yl group in the 6position, and where (iii) R, represents a hydrogen atom, R3 represents an npropyl or n-butyl group and R4 represents a 1Htetrazolyl group, then R2 cannot represent a benzoxazol-2-yl group in the 5- or 6-position, and where (iv) R, represents a hydrogen atom, R3 represents an npropyl group and R4 represents a carboxy group, then R2 cannot represent a l-methylbenzimidazol-2yl group in the 5- or 6-position and cannot represent a l-n-butyl-benzimidazol-2-yl, 1,5dimethylbenzimidazol-2-yl or l-methyl-5trifluoromethyl-benzimidazol-2-yl group in the 6position, and where (v) R, represents a hydrogen atom, R3 represents an nbutyl group and R, represents a carboxy or 1Htetrazolyl group, then R2 cannot represent a 1methylbenzimidazol-2-yl group in the 6-position, or R2 may represent a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, in which a phenyl group may be condensed onto the pyridine ring via 2 adjacent carbon atoms and a methylene group adjacent to the Natom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group; R3 represents a hydrogen atom or a C,.s-alkyl group in - 8 which a methylene group may be replaced by a sulphur atom, or R3 may represent a Cj.jcycloalkyl group, and R4 represents a carboxy, cyano, ΙΗ-tetrazolyl, 1triphenylmethyltetrazolyl, C2_5 (alkoxy carbonyl) , alkanesulphonylaminocarbonyl, arylsulphonylaminocarbonyl or trifluoromethanesulphonylaminocarbonyl group; wherein, unless otherwise specified, each alkanoyl, alkyl or alkoxy moiety contains l to 3 carbon atoms and each cycloalkyl moiety contains 3 to 7 carbon atoms) and the isomers, isomer mixtures and addition salts thereof, in particular the 1,3-isomer mixtures and, for pharmaceutical use, the physiologically acceptable addition salts with inorganic or organic acids or bases.
The groups R,, R2 and R3 may for example represent the following: R, may represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, 1-methyl-n-propyl, 2-methyl-n-propyl, tert.butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, fluoromethyl, difluoromethyl or trifluoromethyl group; R2 may represent a 3-(imidazol-l-yl)propoxy, 4-(imidazol1-yl)butoxy, 5-(imidazol-l-yl)pentoxy, 2-(benzimidazoll-yl)ethoxy, 3-(benzimidazol-l-yl)-propoxy, 4(benzimidazol-l-yl)butoxy, 5-(benzimidazol-l-yl)pentoxy, 2-(tetrahydrobenzimidazol-l-yl)ethoxy, 3(tetrahydrobenzimidazol-l-yl) propoxy, 4-(tetrahydrobenzimidazol-l-yl) butoxy, 5-(tetrahydrobenzimidazol-lyl) pentoxy, methanesulphonyloxy, ethanesulphonyloxy, npropanesulphonyloxy, isopropanesulphonyloxy, nIE 920373 - 9 butanesulphonyloxy, benzenesulphonyloxy, 4fluorobenzenesulphonyloxy, 4-bromobenzenesulphonyloxy, 4-methylbenzenesulphonyloxy, 4-methoxybenzenesulphonyloxy, 3,4-dichlorobenzenesulphonyloxy, phenylmethanesulphonyloxy, 2-phenylethanesulphonyloxy, 3phenylpropanesulphonyloxy, formylamino, acetylamino, propionylamino, butanoylamino, isobutanoylamino, pentanoylamino, 3-methyl-butanoylamino, hexanoylamino, methoxycarbonylamino, ethoxycarbonylamino, npropoxycarbonylamino, isopropoxycarbonylamino, methanesulphonylamino, ethanesulphonylamino, n-propanesulphonylamino, isopropanesulphonylamino, n-butanesulphonylamino, n-pentanesulphonylamino, n-hexanesulphonylamino, benzamido, benzenesulphonylamido, 4fluorobenzenesulphonamido, 4-chlorobenzenesulphonamido, 4-bromobenzenesulphonamido, 4-methylbenzenesulphonamido 4-methoxybenzenesulphonamido, phenylmethanesulphonylamido, 2-phenylethanesulphonylamido, 3-phenylpropanesulphonylamido, naphthalen-l-yl-sulphonamido, naphthalen-2-yl-sulphonylamido, cyclopentylcarbonylamido, cyclohexylcarbonylamido, cycloheptylcarbonylamido, phenylacetylamido, 3-phenylpropionylamido, cyclopentylacetylamido, 3-cyclopentylpropionylamido, cyclohexylacetylamido, 3-cyclohexylpropionylamido, cycloheptylacetylamido, 3-cycloheptylpropionylamido, Nmethyl-formylamino, N-methy1-acetylamino, N-methy1propionylamino, N-methy1-butanoylamino, N-methylisobutanoylamino, N-methy1-pentanoylamino, N-methy1-3methy1-butanoylamino, N-methy1-hexanoylamino, N-methylmethoxycarbonylamino, N-methyl-ethoxycarbonylamino, Nmethyl-n-propoxycarbonylamino, N-methy1-isopropoxycarbonylamino, N-methy1-methanesulphonylamino, N-methy1 ethanesulphonylamino, N-methy1-n-propanesulphonylamino, N-methyl-isopropanesulphonylamino, N-methy1-n-butanesulphonylamino, N-methy1-n-pentanesulphonylamino, Nmethyl-n-hexanesulphonylamino, N-methyl-benzamido, Nmethyl-benzenesulphonylamido, N-methy1-4-fluorobenzeneIE 920373 - 10 sulphonamido, N-methyl-4-chlorobenzenesulphonamido, Nmethy1-4-bromobenzenesulphonamido, N-methy1 - 4 methylbenzenesulphonamido, N-methy1-4-methoxybenzenesulphonamido, N-methy1-phenylmethanesulphonylamido, Nmethyl-2-phenylethanesulphonylamido, N-methy1-3phenylpropanesulphonylamido, N-methy1-naphthalen-l-ylsulphonamido, N-methyl-naphthalen-2-yl-sulphonylamido, N-methyl-cyclopentylcarbonylamido, N-methyl-cyclohexylcarbonylamido, N-methyl-cycloheptylcarbonylamido, Nmethyl-phenylacetylamido, N-methy1-3-phenylpropionylamido, N-methyl-cyclopentylacetylamido, N-methyl-3cyclopentylpropionylamido, N-methy1-cyclohexylacetylamido, N-methyl-3-cyclohexylpropionylamido, N-methy1cycloheptylacetylamido, N-methy1-3-cycloheptylpropionylamido, N-ethyl-formylamino, N-ethyl-acetylamino, Nethyl-propionylamino, N-ethyl-butanoylamino, N-ethy1isobutanoylamino, N-ethyl-pentanoylamino, N-ethy1-3methyl-butanoylamino, N-ethyl-hexanoylamino, N-ethy1methoxycarbonylamino, N-ethyl-ethoxycarbonylamino, Nethyl-n-propoxycarbonylamino, N-ethy1-isopropoxycarbonylamino, N-ethyl-methanesulphonylamino, N-ethylethanesulphonylamino, N-ethy1-n-propanesulphonylamino, N-ethyl-isopropanesulphonylamino, N-ethy1-nbutanesulphonylamino, N-ethy1-n-pentanesulphonylamino, N-ethy1-n-hexanesulphonylamino, N-ethy1-benzamido, Nethyl-benzenesulphonylamido, N-ethyl-4-fluorobenzenesulphonamido, N-ethy1-4-chlorobenzenesulphonamido, Nethyl-4-bromobenzenesulphonamido, N-ethy1-4methylbenzenesulphonamido, N-ethy1-4methoxybenzenesulphonamido, N-ethy1phenylmethanesulphonylamido, N-ethy1-2phenylethanesulphonylamido, N-ethyl-3-phenylpropanesulphonylamido, N-ethyl-naphthalen-l-yl-sulphonamido, Nethyl-naphthalen-2-yl-sulphonylamido, N-ethy1cyclopentylcarbonylamido, N-ethy1-cyclohexylcarbonylamido, N-ethy1-cycloheptylcarbonylamido, N-ethy1phenylacetylamido, N-ethyl-3-phenyl-propionylamido, NIE 920373 - 11 ethyl-cyclopentylacetylamido, N-ethyl-3-cyclopentylpropionylamido, N-ethyl-cyclohexylacetylamido, N-ethyl3-cyclohexylpropionylamido, N-ethyl-cycloheptylacetylamido, N-ethyl-3-cycloheptylpropionylamido, N-n-propylformylamino, N-n-propyl-acetylamino, N-n-propylpropionylamino, N-n-propyl-butanoylamino, N-n-propylisobutanoylamino, N-n-propyl-pentanoylamino, N-n-propyl(3-methyl-butanoyl)amino, N-n-propyl-hexanoylamino, Nisopropyl-formylamino, N-isopropy1-acetylamino, Nisopropyl-propionylamino, N-isopropy1-butanoylamino, Nisopropyl-isobutanoylamino, N-isopropyl-pentanoylamino, N-isopropyl-(3-methyl-butanoyl)amino, N-isopropylhexanoylamino, N-n-butyl-formylamino, N-n-butylacetylamino, N-n-butyl-propionylamino, N-n-butylbutanoylamino, N-n-butyl-isobutanoylamino, N-n-butylpentanoylamino, N-n-butyl-(3-methyl-butanoyl)amino, N-nbutyl-hexanoylamino, N-isobutyl-formylamino, N-isobutylacetylamino, N-isobutyl-propionylamino, N-isobutylbutanoylamino, N-isobutyl-isobutanoylamino, N-isobutylpentanoylamino, N-n-pentyl-formylamino, N-n-pentylacetylamino, N-n-pentyl-propionylamino, N-n-pentylbutanoylamino, N-n-pentyl-isobutanoylamino, N-n-pentylpentanoylamino, N-(1-methyl-butyl)-formylamino, N-(lmethyl-butyl)-acetylamino, N-(1-methyl-butyl)propionylamino, N-(1-methyl-butyl)-butanoylamino, N-(lmethyl-butyl)-isobutanoylamino, N-(1-methyl-butyl)pentanoylamino, N-(2-methyl-butyl)-formylamino, N-(2methyl-butyl)-acetylamino, N-(2-methyl-butyl)propionylamino, N-(2-methyl-butyl)-butanoylamino, N-(2methy1-butyl)-isobutanoylamino, N-(2-methy1-butyl) pentanoylamino, N-(3-methyl-butyl)-formylamino, N-(3methy1-butyl)-acetylamino, N-(3-methyl-butyl)propionylamino, N-(3-methy1-butyl)-butanoylamino, N-(3methy1-butyl)-isobutanoylamino, N-(3-methyl-butyl)pentanoylamino, N-n-hexyl-formylamino, N-n-hexylacetylamino, N-n-hexyl-propionylamino, N-n-hexylbutanoylamino, N-n-hexyl-isobutanoylamino, N-n-hexylIE 920373 - 12 pentanoylamino, N-n-propyl-cyclohexylcarbonylamino, N-npropyl-cyclohexylacetylamino, N-n-propyl-3(cyclohexyl)propionylamino, N-isopropylcyclohexylcarbonylamino, N-isopropylcyclohexylacetylamino, N-isopropyl-3-(cyclohexyl)propionylamino, N-n-butyl-cyclohexylcarbonylamino, N-nbutyl-cyclohexylacetylamino, N-n-butyl-3-(cyclohexyl)propionylamino, N-isobutyl-cyclohexylcarbonylamino, Nisobutyl-cyclohexylacetylamino, N-isobutyl-3(cyclohexyl)propionylamino, N-n-pentyl-cyclohexylcarbonylamino, N-n-pentyl-cyclohexylacetylamino, N-npentyl-3-(cyclohexyl)propionylamino, N-n-hexylcyclohexylcarbonylamino, N-n-hexy1-cyclohexylacetylamino, N-n-hexyl-3-(cyclohexyl)propionylamino, phthalimino, 5-methoxy-phthalimino, 5,6-diraethoxyphthalimino, 6-methoxy-phtha1imino, homophthalimino, 4,4-dimethyl-homophthalimino, 7-methoxy-homophthalimino, 6,7-dimethoxy-homophthalimino, 7-methoxy-4,4-dimethylhomophthalimino, 6,7-dimethoxy-4,4-dimethylhomophthalimino , 1,2,3,6-tetrahydrophthalimino, hexahydrophthalimino, cis-hexahydrophthalimino, transhexahydrophthalimino, l-oxo-isoindolin-2-yl, 3,4dimethyl-phthalimino, 4,5-dimethyl-l,2,3,6tetrahydrophthalimino, 4,5-dimethyl-hexahydro phthalimino, 4,5-dimethyl-l-oxo-isoindolin-2-yl, 3,4dimethoxy-phthalimino, 4,5-dimethoxy-l,2,3,6tetrahydrophthalimino, 4,5-diraethoxy-hexahydro phthalimino, 4,5-dimethoxy-l-oxo-isoindolin-2-yl, 2carboxyphenylmethylamino, 2-carboxyphenylmethylenecarbonylamino, pyrrolidino, 2-methylpyrrolidino, 3ethylpyrrolidino, 3-isopropylpyrrolidino, piperidino, 3methylpiperidino, 4-methylpiperidino, 4-ethylpiperidino, 4-isopropylpiperidino, hexamethyleneimino, 3-methylhexamethyleneimino, 4-methylhexamethyleneimino, 3ethylhexamethyleneimino, 4-isopropylhexamethyleneimino, 3,3-dimethyl-pyrrolidino, 3,4-dimethyl-pyrrolidino, 3,3dimethyl-piperidino, 3,4-dimethyl-piperidino, 4,4IE 920373 - 13 dimethyl-piperidino, 3,3-dimethyl-hexamethyleneimino, 3,4-dimethyl-hexamethyleneimino, 4,4-dimethylhexamethyleneimino, 3,5-dimethyl-hexamethyleneimino, 3.3- tetramethylene-pyrrolidino, 3,3-pentamethylenepyrrolidino, 3,3-tetramethylene-piperidino, 3,3pentamethylene-piperidino, 4,4-tetramethylenepiperidino, 4,4-pentamethylene-piperidino, 3,3tetramethylene-hexamethyleneimino, 3,3-pentanethylenehexamethyleneimino, 4,4-tetramethylene-hexamethyleneimino, 4,4-pentamethylene-hexamethyleneimino, 2-oxopyrrolidino, 2-oxo-piperidino, 2-oxo-hexamethyleneimino propanesultam-l-yl, butanesultam-l-yl, pentanesultam-1yl, endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxyiic acid imino, methyl-5-norbornene-2,3-dicarboxylic acid imino, 3,6-endoxo-l,2,3,6-tetrahydrophthalimino, 5-norbornenendo-2,3-dicarboxylic acid imino, glutarimino, 3,3tetramethylene-glutarimino, 3,3-pentamethyleneglutarimino, 2,2-dimethyl-glutarimino, 3-methylglutarimino, 3,3-dimethyl-glutarimino, 3-ethylglutarimino, 3-ethyl-3-methyl-glutarimino, 1,3cyclopentanedicarbonylimino, 2,4-dimethyl-glutarimino, 2.4- di-n-propyl-glutarimino, glutaramino, 3,3tetramethylene-glutaramino, 3,3-pentamethyleneglutaramino, 2,2-dimethyl-glutaramino, 3-methylglutaramino, 3,3-dimethyl-glutaramino, 3-ethylglutaramino, 3-ethyl-3-methyl-glutaramino, 1,3cyclopentanedicarbonylamino, 2,4-dimethyl-glutaramino, 2.4- di-n-propyl-glutaramino, maleic acid amido, maleic acid imido, 2-methyl-maleic acid amido, 3-methyl-maleic acid amido, 2-methyl-maleic acid imido, 2-phenyl-maleic acid amido, 3-phenyl-maleic acid amido, 2-phenyl-maleic acid imido, 2,3-dimethyl-maleic acid amido, 3-methyl-2phenyl-maleic acid amido, 2-methyl-3-phenyl-maleic acid amido, 2-methyl-3-phenyl-maleic acid imido, 2,3diphenyl-maleic acid amido, 2,3-diphenyl-maleic acid amido, pyrrolidin-2-yl, pyrrolidin-2-on-5-yl, piperidin 2-yl, piperidin-2-on-l-yl, piperidin-2-on-6-yl, - 14 quinolin-2-yl, isoquinolin-l-y1, xsoquinolin-3-yl, pyridin-2-yl, 4-methylimidazol-2-y1, l-methylimidazol-4yl, l-methylimidazol-5-yl, l-n-hexylimidazol-4-yl, l-nhexylimidazol-5-yl, l-benzylimidazol-4-yl, 1benzylimidazol-5-yl, 1,2-dimethylimidazol-4-yl, 1,2dimethylimidazol-5-yl, l-n-pentyl-2-methyl-iraidazol-4yl, l-n-pentyl-2-methyl-imidazol-5-yl, l-n-butyl-2methyl-imidazol-4-yl, l-n-butyl-2-methyl-imidazol-5-yl, 1- benzyl-2-methyl-imidazol-4-yl, 1-benzy1-2-methylimidazol-5-yl, benzimidazol-2-yl, 1-methylbenzimidazol2- yl, l-ethylbenzimidazol-2-yl, 1-n-propylbenzimidazol2-yl, l-isopropylbenzimidazol-2-yl, 1-nbutylbenzimidazol-2-yl, l-isobutylbenzimidazol-2-yl, 1n-pentylbenzimidazol-2-yl, l-n-hexylbenzimidazol-2-yl, 1- cyclopropyl-benzimidazol-2-yl, 1cyclobutylbenzimidazol-2-yl, 1-cyclopentylbenzimidazol2- yl, l-cyclohexylbenzimidazol-2-yl, 5-nitrobenzimidazol-2-yl, 5-amino-benzimidazol-2-yl, 5acetamido-benzimidazol-2-yl, 5-methyl-benzimidazol-2-yl, - methoxy-benzimidazol-2-yl, 5-ethoxy-benzimidazol-2-yl, 1- methyl-5-methoxy-benzimidazol-2-yl, 1,5-dimethylbenzimidazol-2-yl, 1,6-dimethyl-benzimidazol-2-yl, 1,4dimethyl-benzimidazol-2-yl, 5,6-dimethyl-benzimidazol-2yl, 1,5,6-trimethyl-benzimidazol-2-yl, 5-chlorobenzimidazol-2-yl, 5-chloro-l-methyl-benzimidazol-2-yl, 6- chloro-l-methyl-benzimidazol-2-yl, 5,6-dichloro-lmethyl-benzimidazol-2-yl, 5-dimethylamino-benzimidazol2- yl, 5-dimethylamino-l-ethyl-benzimidazol-2-yl, 5,6dimethoxy-l-methyl-benzimidazol-2-yl, 5,6-dimethoxy-lethyl-benzimidazol-2-yl, 5-fluoro-l-methyl-benzimidazol2-yl, 6-fluoro-l-methyl-benzimidazol-2-yl, 5trifluoromethyl-benzimidazol-2-yl, 5-trifluoromethyl-1methyl-benzimidazol-2-yl, 4-cyano-l-methyl-benzimidazol2-yl, 5-carboxy-l-methyl-benzimidazol-2-yl, 5aminocarbonyl-benzimidazol-2-yl, 5-aminocarbonyl-lmethyl-benzimidazol-2-yl, 5-dimethylaminosulphonyl-lmethy1-benzimidazο1-2-y1, 5-methoxycarbony1-1-methylIE 920373 - 15 benzimidazol-2-yl, 5-methylaminocarbonyl-l-methylbenzimidazol-2-yl, 5-dimethylaminocarbonyl-l-methylbenzimidazol-2-yl, 4,6-difluoro-l-methyl-benzimidazol-2yl, 5-acetyl-l-methyl-benzimidazol-2-yl, 5,6-dihydroxyl-methyl-benzimidazol-2-yl, imidazo[l,2-a]pyridin-2-yl, -methyl-imidazo[1,2-a]pyridin-2-yl, 6-methylimidazo[1,2-a]-pyridin-2-yl, 7-methyl-imidazo[1,2-a]pyridin-2-yl, 8-methyl-imidazo[l,2-a]pyridin-2-yl, 5,7dimethyl-imidazo[1,2-a]pyridin-2-y1, 6-aminocarbonylimidazo[l,2-a]pyridin-2-yl, 6-chloro-imidazo[1,2-a]pyridin-2-yl, 6-bromo-imidazo[1,2-a]pyridin-2-yl, ,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, 5,7-dimethylimidazo[l,2-a]pyriroidin-2-yl, imidazo[4,5-b]pyridin-2yl, l-methyl-imidazo[4,5-b]pyridin-2-yl, 1-n-hexylimidazo[4,5-b]pyridin-2-yl, 1-cyclopropylimidazo[4,5-b]pyridin-2-yl, 1-cyclohexyl-imidazo[4,5-b]pyridin-2-yl, 4-methyl-imidazo[4,5-b]pyridin-2-yl, 6methyl-imidazo[4,5-b]pyridin-2-yl, 1,4-dimethylimidazo[4,5-b]pyridin-2-yl, 1,6-dimethyl-imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, 1-methylimidazo[4,5-c]pyridin-2-yl, l-n-hexyl-imidazo[4,5-c]pyridin-2-yl, l-cyclopropyl-imidazo[4,5-c]pyridin-2-yl, 1- cyclohexyl-imidazo[4,5-c]pyridin-2-yl, imidazo[2,1-b]thiazol-6-yl, 3-methyl-imidazo[2,l-b]thiazol-6-yl, 2phenyl-imidazo[2,1-b]thiazol-6-yl, 3-phenylimidazo[2,1-b]thiazol-6-yl, 2,3-dimethyl-imidazo[2,1-b]thiazol-6-yl, 2,3-trimethylene-imidazo[2,1-b]thiazol-6yl, 2,3-tetramethylene-imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazof1,2-a]pyrazin-2yl, imidazo[l,2-b]pyridazin-2-yl, imidazo[4,5-c]pyridin2- yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, imidazo[4,5-d]pyridazin-2yl, imidazolidin-2,4-dion-3-yl, 5-methyl-imidazolidin2,4-dion-3-yl, 5-ethyl-imidazolidin-2,4-dion-3-yl, 5-npropyl-imidazolidin-2,4-dion-3-yl, 5-benzylimidazolidin-2,4-dion-3-yl, 5-(2-phenylethyl)IE 920373 - 16 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, l-methyl-imidazolidin-2,4dion-3-yl, l-benzyl-imidazolin-2,4-dion-3-yl, 4,5dihydro-2H-pyridazin-3-on-6-yl, 2-methyl-4,5-dihydro-2Hpyridazin-3-on-6-yl, 2-ethyl-4,5-dihydro-2H-pyridazin-3on-6-yl, 2-n-propyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-isopropyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2benzyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-(2phenylethyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-(3phenylpropyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl, 4methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 5-methyl-4,5dihydro-2H-pyridazin-3-on-6-yl, 4,4-dimethyl-4,5dihydro-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-methy1-pyridazin-3-on-6-y1, 2-ethy1-pyridazin-3-on-6yl, 2-n-propyl-pyridazin-3-on-6-yl, 2-isopropylpyridazin-3-on-6-yl, 2-benzyl-pyridazin-3-on-6-yl, 2-(2phenylethyl)-pyridazin-3-on-6-yl, 2-(3-phenylpropyl)pyridazin-3-on-6-yl, 4-methyl-pyridazin-3-on-6-yl, 5methyl-pyridazin-3-on-6-yl, 4,5-dimethyl-pyridazin-3-on6-yl, 2,4—dimethyl—pyridazin—3—on—6—yl, 2,5-dimethylpyridazin-3-on-6-yl, 2,4,5-trimethyl-pyridazin-3-on-6yl, aminocarbonylamino, methylaminocarbonylamino, dimethylaminocarbonylamino, N-methylaminocarbony1methylamino, N-(dimethylaminocarbonyl)-methylamino, Ndimethylarainocarbonyl-ethylamino, N-dimethylaminocarbonyl-isopropylamino, N-(dimethylaminocarbonyl)-npentylamino, N-methylaminocarbony1-ethylamino, NIE 920373 - 17 methylaminocarbonyl-n-pentylamino, N-methylaminocarbony1-n-hexylamino, N-methylaminocarbony1-noctylamino, N-methylaminocarbonyl-cyclohexylamino, ethylaminocarbonylamino, N-ethylaminocarbony1methylamino, N-ethylaminocarbonyl-ethylamino, Nethylaminocarbony1-n-hexylamino, N-ethylaminocarbony1-nheptylamino, N-ethylaminocarbony1-eyelohexylamino, diethylaminocarbonylamino, N-(diethylaminocarbonyl)methylamino, N-(diethylaminocarbonyl)-ethylamino, N(diethylaminocarbonyl)-n-butylamino, N-(diethylaminocarbonyl) -n-hexylamino, N-(diethylaminocarbonyl)-noctylamino, isopropylaminocarbonylamino, N-isopropylaminocarbonyl-methylamino, n-butylaminocarbonylamino, N(n-butylaminocarbony1)-methylamino, N-(n-butylaminocarbony 1) -ethylamino, N-(n-butylaminocarbonyl)isopropylamino, N-(n-butylaminocarbonyl)-n-butylamino, N-(n-butylaminocarbonyl)-n-hexylamino, N-(n-butylaminocarbonyl) -cyclohexylamino, N-(di-(n-butyl)aminocarbonyl)-amino, N-(di-(n-butyl)-aminocarbonyl)methylamino, N-(di-(n-butyl)-aminocarbonyl)-ethylamino, N-(di-(n-butyl)-aminocarbonyl)-n-butylamino, N-(di-inbutyl) -aminocarbonyl)-n-hexylamino, N-(n-pentylaminocarbonyl) -methylamino, N-(n-pentylaminocarbonyl)ethylamino, N-(n-hexylaminocarbonyl)-ethylamino, nhexylaminocarbonylamino, n-heptylaminocarbonylamino, noctylaminocarbonylamino, N-(n-hexylaminocarbonyl)-nbutylamino, N-(n-hexylaminocarbonyl)-n-pentylamino, N(n-hexylarainocarbonyl)-n-hexylamino, N-(n-hexylaminocarbonyl) -cyclohexylamino, di-(n-hexyl)-aminocarbonylamino, N-(di-(n-hexyl)-aminocarbonyl)-methylamino, N((n-hexyl)-methylaminocarbonyl)-amino, cyclohexylaminocarbonylamino, N-cyclohexylaminocarbonyl-methylaraino, Ncyclohexylaminocarbonyl-ethylamino, N-cyclohexylaminocarbonyl-n-butylamino, N-cyclohexylaminocarbonylisobutylamino, N-cyclohexylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbony1-n-hexylamino, Ncyclohexylaminocarbonyl-cyclohexylamino, N-(ethylIE 920373 - 18 cyclohexylaminocarbonyl)-methylamino, N-(propylcyclohexylaminocarbony1)-methylamino, N-(n-buty1cyclohexylaminocarbony1)-methylamino, allylaminocarbonylamino, benzylaminocarbonylamino, Nbenzylaminocarbonyl-isobutylamino, phenylaminocarbonylamino, pyrrolidinocarbonylamino, pyrrolidinocarbonylmethylamino, piperidinocarbonylamino, hexamethyleneiminocarbonylamino, morpholinocarbonylamino, 3,4,5,6tetrahydro-2-pyrimidon-l-yl, 3-methyl-3,4,5,6tetrahydro-2-pyrimidon-l-yl, 3-ethyl-3,4,5,6-tetrahydro2- pyrimidon-l-yl, 3-n-propyl-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-isopropyl-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-n-butyl-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-isobutyl-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-n-pentyl-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-n-hexyl-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-cyclopentyl-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-cyclohexy1-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-cycloheptyl-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-benzyl-3,4,5,6-tetrahydro-2-pyrimidon1-yl, 3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-methyl3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-ethyl3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-n-propyl3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-isopropyl3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-benzyl3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(2phenylethyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl or 3- (3-phenylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-lyl group; and R3 may represent a hydrogen atom, a methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tert.butyl, npentyl, 1-methy1-butyl, 2-methyl-butyl, 3-methyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto or nbutylmercapto group. - 19 Preferred compounds according to the invention include compounds of formula I wherein R, in the 4-position represents a fluorine, chlorine or bromine atom, a C1.3-alkyl group, or a cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group, and R2 represents a C3_5-alkoxy group substituted in the 3-, 4- or 5-position by an imidazolyl group, or R2 represents a C2.5-alkoxy group substituted in the 2-, 3-, 4- or 5position by a benzimidazolyl or tetrahydrobenzimidazolyl group, an acylamino group optionally substituted at the nitrogen atom by a C,.5-alkyl group, wherein the acyl group is a C2.7-alkanoyl group, a C2^, (alkoxy carbonyl) group, a C,.3-alkylsulphonyl group or a benzenesulphonyl group, a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene in a homophthalimino group may be substituted by one or two alkyl groups, a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group, optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, wherein a methylene group may be replaced by a carbonyl or sulphonyl group, a glutaric acid imino group wherein the n-propylene group may be perfluorinated, or may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, - 20 a maleic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the substituents may be identical or different, an amidino group optionally substituted by one or two CM alkyl groups, a benzimidazol-2-yl group optionally substituted in the 1- position by C^-alkyl or a cycloalkyl group and optionally substituted in the phenyl nucleus by a fluorine atom or by a methyl or trifluoromethyl group, or R2 represents an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[l,2-a]pyrazin2- yl, imidazofl, 2-b]-pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or a carbon attached pyrrolidine, piperidine or pyridine ring in which a phenyl group may be condensed onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, a carbon attached imidazolyl group optionally substituted in the l-position by a C,.3-alkyl group or by a benzyl group, and which may also be substituted in the carbon skeleton by a C,_3-alkyl group, an imidazolidindione group optionally substituted by an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, a pyridazin-3-one or dihydro-pyridazin-3-one group which - 21 may be substituted in the 2-position by a methyl or benzyl group, an R7-NR6-CO-NR5- group (wherein R5 represents a hydrogen atom, a C,.5-alkyl group, a cyclohexyl or benzyl group, Rg represents a hydrogen atom, a C,_6-alkyl group, an allyl, cyclohexyl, benzyl or phenyl group, R7 represents a hydrogen atom or a C,.3-alkyl group or Rg and R7 together with the nitrogen atom between them represent an unbranched C^-alkyleneimino group or a morpholino group or R5 and Rg together represent a C2.3-alkylene group) ; or R[ represents a hydrogen atom or in the 5-, 6- or 7position Rt represents a fluorine, chlorine or bromine atom or a CM-alkyl or a trifluoromethyl group, and R2 represents a benzimidazol-2-yl group optionally substituted in the 1-position by a C,^-alkyl group or by a cycloalkyl group, and optionally substituted in the phenyl nucleus by a fluorine atom or by a methyl or trifluoromethyl group, or R2 represents an imidazo[2,l-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2 yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin 2-yl, imidazo[l,2-b]-pyridazin-2-yl, imidazo[4,5-c]920373 - 22 pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or a carbon attached pyrrolidine, piperidine or pyridine ring in which a phenyl group may be condensed onto the pyridine ring via 2 adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or a carbon attached imidazolyl group optionally substituted in the 1position by a C+j alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a Cb3 alkyl group, with the proviso that where (i) R, represents a hydrogen atom, R3 represents an nbutyl group and R, represents a carboxy group, then R2 cannot represent a benzimidazol-2-yl group in the 6-position; R3 represents a C,.5-alkyl group or a C3.5-cycloalkyl group; and R4 represents a carboxy or ΙΗ-tetrazolyl group; wherein, unless otherwise specified, each alkanoyl, alkyl or alkoxy moiety contains 1 to 3 carbon atoms and each cycloalkyl moiety contains 3 to 7 carbon atoms; and the isomers, isomer mixtures and addition salts thereof.
Particularly preferred compounds according to the invention include those of formula I wherein R, in the 4-position represents a chlorine atom, or a C,.3-alkyl or a tri fluoromethyl group, and - 23 R2 represents a C3_5-alkoxy group substituted in the 3-, — or 5-position by an imidazolyl group, or R2 represents a C2_5-alkoxy group substituted in the 2-, 3-, 4- or 5position by a benzimidazolyl or tetrahydrobenzimidazolyl group, a C2_5 (alkanoyl) amino or N-benzenesulphonyl-methylamino group, a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group, a 5-, 6- or 7-membered alkyleneimino group wherein a methylene group is replaced by a carbonyl or sulphonyl group, a glutaric acid imino group wherein the n-propylene group may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, a maleic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl group optionally substituted in the 1- position by a C145-alkyl group or by a cycloalkyl group, and optionally substituted in the phenyl nucleus by a fluorine atom or by a methyl or trifluoromethyl group, or R2 represents an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl, imidazo[l,2-a]pyrimidin-2yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[l,2-a]pyrazin2- yl, imidazo[1,2-b]-pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, - 24 imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or a carbon attached pyrrolidine, piperidine or pyridine ring in which a phenyl group may be condensed onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or R2 represents an imidazol-4-yl group substituted in the 1-position by a C,_3 alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a C,_3 alkyl group, a pyridazin-3-one or dihydro-pyridazin-3-one group which may be substituted in the 2-position by a methyl or benzyl group, an R7-NRg-CO-NR5- group (wherein Rs represents a hydrogen atom or a C,.5-alkyl, cyclohexyl or benzyl group, Rg represents a hydrogen atom, a C,.6-alkyl group or an allyl, cyclohexyl, benzyl or phenyl group, R7 represents a hydrogen atom or a CM-alkyl group or Rg and R7 together with the nitrogen atom between them represent an unbranched C46-alkyleneimino group or a morpholino group or Rj and Rg together represent a C2.3-alkylene group) ; or Rj represents a hydrogen atom or in the 5-, position R, represents a CM-alkyl group or a 6- or 7IE 920373 - 25 trifluoromethyl group, and R2 represents a benzimidazol-2-yl group optionally substituted in the 1-position by a C,.6-alkyl group or by a cycloalkyl group and optionally substituted in the phenyl nucleus by a fluorine atom or by a methyl or trifluoromethyl group, or R2 represents an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-y1, 5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl, imidazo[l,2-a]pyrimidin-2yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2yl, imidazof1,2-c]pyrimidin-2-yl, imidazof1,2-a]pyrazin2-yl, imidazo[1,2-b]-pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin2-yl group, or a carbon attached pyrrolidine, piperidine or pyridine ring in which a phenyl group may be condensed onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or an imidazol-4-yl group substituted in the l-position by a C,.3 alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a C,.3 alkyl group, with the proviso that where (i) R, represents a hydrogen atom, R3 represents an nbutyl group and R4 represents a carboxy group, then R2 cannot represent a benzimidazol-2-yl group in the 6-position; R3 represents a C^-alkyl group or a C3.5-cycloalkyl group; and R4 represents a carboxy or ΙΗ-tetrazolyl group; wherein, unless otherwise specified, each alkanoyl - 26 alkyl or alkoxy moiety contains 1 to 3 carbon atoms and each cycloalkyl moiety contains 3 to 7 carbon atoms; and the isomers, isomer mixtures and addition salts thereof.
Especially preferred compounds according to the invention include those of formula I wherein Rj in the 4-position represents a chlorine atom or a methyl group, and R2 represents a C3.5-alkoxy group substituted in the 3-, 4- or 5-position by an imidazolyl group, or R2 represents a C2.5-alkoxy group substituted in the 2-, 3-, 4- or 5position by a benzimidazolyl or tetrahydrobenzimidazolyl group, a C2.5 (alkanoy 1) amino group or N-benzenesulphonylmethylamino group, a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group, a 5-, 6- or 7-membered alkyleneimino group, wherein a methylene group is replaced by a carbonyl or sulphonyl group, a maleic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl group optionally substituted in the 1-position by a C13-alkyl group and optionally - 27 substituted in the phenyl nucleus by a fluorine atom, or R2 represents an imidazo[1,2-a]-pyridin-2-yl group, 5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl, imidazof1,2-a]pyrimidin-2-yl or imidazo[2,1-b]thiazol-6yl group, an imidazol-4-yl group substituted in the l-position by a C[_3 alkyl group, a pyridazin-3-one or dihydro-pyridazin-3-one group which may be substituted in the 2-position by a methyl or benzyl group; or R, represents a hydrogen atom or in the 5-, 6- or 7position R, represents a methyl group, and R2 represents a benzimidazol-2-yl group optionally substituted in the l-position by a C,.3-alkyl group, and optionally substituted in the phenyl nucleus by a fluorine atom, or R2 represents an imidazofl,2-a]pyridin-2-yl group, an imidazol-4-yl group substituted in the l-position by a C,_3 alkyl group, with the proviso that where (i) R, represents a hydrogen atom, R3 represents an nbutyl group and R, represents a carboxy group, then R2 cannot represent a benzimidazol-2-yl group in the 6-position; R3 represents a C,.5-alkyl group or a C35-cycloalkyl group; and R^ represents a carboxy or ΙΗ-tetrazolyl group; wherein, unless otherwise specified, each alkanoyl, - 28 alkyl or alkoxy moiety contains 1 to 3 carbon atoms and each cycloalkyl moiety contains 3 to 7 carbon atoms; and the isomers, isomer mixtures and addition salts thereof.
The present invention particularly encompasses the following compounds: 4'-[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-1-yl]-methyl]-bipheny1-2-carboxylie acid; (b) 4'-[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2yl)-benziraidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4' - [[2-n-propyl-4-methyl-6-(l-oxo-isoindolin-2-yl)benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-propyl-4-methyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-[[2-n-butyl-6-(isopropylcarbonylamino)-4-methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4' - [[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-[[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; - 29 4'-[(2-cyclopropyl-4-methyl-6-(l-methylbenzimidazol-2yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid; 4'-[(2-n-propyl-4-methyl-6-(l-methyl-5-fluorobenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl2-carboxylic acid; 4' — [(2-n-propy1-4-methyl-6-(imidazo[1,2-a]pyrimidin-2yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[(2-n-propyl-4-methyl-6-(4,5,6,7-tetrahydroimidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid; 4·-[(2-n-propyl-4-methyl-6-(4,5,6,7-tetrahydroimidazof1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]2-(lH-tetrazol-5-y1)-biphenyl; 4'-[(2-n-propyl-4-chloro-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-propyl-4-methyl-6-{imidazo[2,1-b]thiazol-6-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylie acid; 4'-[[2-ethyl-4-methyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-butyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl)-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)IE 920373 - 30 biphenyl; 4'-[[2-n-propy1-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl) biphenyl; 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; and · -[(2-n-propyl-4-methyl-6-(l-methyl-6-fluorobenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl2-carboxylie acid; and the isomers, isomer mixtures and addition salts thereof.
Viewed from another aspect, the invention provides a process for preparing compounds of formula I and salts thereof which process comprises at least one of the following steps: a) cyclising compound of formula II (wherein R, and R2 are as defined hereinbefore, one of the groups X, or Y, represents a group of formula 11(a) - 31 Γ N \ R8 11(a) and the other group X, or Yj represents a group of the formula 11(b) Z, _Z2 - NH - 'C - R3 (wherein H(b) R2 and R4 are as defined hereinbefore, Rg represents a hydrogen atom or an R3CO- group, R3 is as defined hereinbefore, Z, and Z2, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower (e.g.
C,^) alkyl groups or Z, and Z2 together represent an oxygen or sulphur atom, an optionally C,.3-alkyl substituted imino group, an alkylenedioxy or alkylenedithio group, each having 2 or 3 carbon atoms)) and any corresponding N-oxide thus obtained is reduced; b) reacting a compound of formula III (HD (wherein R, to R3 are as defined hereinbefore) with a biphenyl compound of formula IV (iv) (wherein R, is as defined hereinbefore, and Z3 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or ptoluenesulphonyloxy group); c) (to prepare compounds of formula I wherein R^ represents a carboxy group) converting a compound of formula V (V) (wherein R, to R3 are as defined hereinbefore, and R,' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound; d) (to prepare compounds of formula I wherein R4 represents a ΙΗ-tetrazolyl group) cleaving a protecting group from a compound of formula VI R (VI ) (wherein Ru R2 and R3 are as defined hereinbefore, and R4 represents a ΙΗ-tetrazolyl group protected in the 1- or 3-position by a protecting group); e) (to prepare compounds of formula I wherein R4 represents a ΙΗ-tetrazolyl group) reacting a compound of formula VII (VII) (wherein Rj to R3 are as defined hereinbefore) with hydrazoic acid or a salt thereof; f) (to prepare compounds of formula I wherein R2 represents one of the imidazo[l,2-a]-pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-c]-pyrimidin2-yl, imidazo[l,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl or imidazo(2,1-b]thiazol-6-yl groups) reacting a compound of formula VIII R R D NH (wherein one of the groups A, B, C or D represents a methine group or a nitrogen atom and the remaining groups A, B, C or D represent methine groups, or A and B each represent methine and the -C=D- moiety represents a sulphur atom, R, represents a hydrogen, fluorine, chlorine or bromine atom or an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylaminosulphonyl group, and R10 represents a hydrogen, fluorine or chlorine atom or a methyl, methoxy or hydroxy group; or R, and R10 attached at adjacent ring positions together represent a propylene or n-butylene group) with a compound of formula IX (ix) (wherein R,, R3 and R4 are as defined hereinbefore and Z4 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom); - 35 g) (to prepare compounds of formula I wherein R2 represents one of the benzimidazol-2-yl, imidazof 4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2yl, imidazo[4,5-d]pyridazin-2-yl or purin-8-yl groups) cyclising a compound of formula X (wherein none, one or two of the groups A,, B1; or Dj represents a nitrogen atom and the remaining groups A,, B,, C, or Dt represent methine groups; Rn represents a hydrogen, fluorine, chlorine or bromine atom or an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylarainosulphonyl or dialkylaminosulphonyl group; and R,2 represents a hydrogen, fluorine or chlorine atom or a methyl, methoxy or hydroxy group; one of the groups X2 or Y2 represents an R13-NH- group and the other X2 or Y2 group represents a group of formula X(a) X(a) (wherein Rj, R3 and R4 are as defined hereinbefore; one of the groups R13 or R14 represents a hydrogen atom and the other R13 or R,4 group represents a hydrogen atom, a C,_6-alkyl group or a cycloalkyl group, Z5 and Z6, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower (e.g.
C,_6) alkyl groups or Z5 and Z6 together represent an oxygen or sulphur atom, an optionally C,.3-alkyl substituted imino group, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms)) and reducing any corresponding N-oxide thus obtained, and optionally hydrolysing the resulting product; h) (to prepare compounds of formula I wherein R2 represents a dihydro-pyridazin-3-one or pyridazin-3-one group which may be substituted in the 2-position by a Cj.j-alkyl group optionally substituted by a phenyl group, or in the carbon structure by one or two alkyl groups each having 1 to 3 carbon atoms) reacting a carboxylic acid of formula XII (wherein Rj, R3 and R4 are as defined hereinbefore; and E represents an ethylene or ethenylene group optionally substituted by one or two C,.3alkyl groups) or a reactive acid derivative thereof, such as an ester, amide or halide, with a hydrazine of formula XIII H2N - NHR15 (XIII) (wherein R,5 represents a hydrogen atom or a C,.3-alkyl group optionally substituted by a phenyl group); i) performing the reaction of any one of steps (a) to (h) using a starting material wherein a reactive group is protected by a protecting group and subsequently removinq any protecting group used; j) resolving an isomer mixture into the separate component isomers; k) converting a compound of formula I into an addition salt thereof or converting a salt of a compound of formula I into the compound.
The cyclisation of reaction step (a) is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, - 38 sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, e.g. at temperatures between 0 and 250°C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide.
However, cyclisation may also be carried out without a solvent and/or condensing agent.
However, it is particularly advantageous to carry out the reaction of step (a) by preparing a compound of formula II in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of formula R3COOH, or by acylation of a corresponding o-diamino compound. When the reduction of the nitro group is broken off at the hydroxylamine stage, the N-oxide of a compound of formula I is obtained in the subsequent cyclisation.
The resulting N-oxide is then converted by reduction into a corresponding compound of formula I.
In step (a), the subsequent reduction of the N-oxide of formula I obtained is advantageously 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 - 39 sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50°C, but preferably at ambient temperature.
The reaction of step (b) is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethyl-sulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, preferably at temperatures between 0 and 100°C, e.g. at temperatures between ambient temperature and 50°C.
In the reaction of step (b), a mixture of the 1- and 3isomers is preferably obtained which can if desired subseguently be resolved into the corresponding 1- and 3- isomers, preferably by chromatography using a substrate such as silica gel or aluminium oxide.
In reaction step (c), functional derivatives of the carboxy group such as unsubstituted or substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides, a nitrile group or a tetrazolyl group may be converted into a carboxy group by hydrolysis, esters with tertiary alcohols, e.g. tert.butylester, may be converted into a carboxy group by thermolysis and esters with aralkanols, e.g. benzylester, may be converted into a carboxy group by hydrogenolysis.
The hydrolysis of step (c) is conveniently carried out in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid in the presence of a base such as - 40 sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10°C and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic or trifluoroacetic acid, any alcoholic hydroxy groups present may optionally be simultaneously converted into a corresponding acyloxy group such as a trifluoroacetoxy group.
If R4' in a compound of formula V represents a cyano or aminocarbonyl group, these groups may also be converted into a carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which may also be simultaneously used as solvent, at temperatures between 0 and 50°C.
If 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 p-toluenesulphonic acid, sulphuric, phosphoric or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40°C and 100°C.
If R4' in a compound of 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 - 41 between 0 and 50°C, e.g. at ambient temperature, under a hydrogen pressure of 1 to 5 bar. During hydrogenolysis, other groups may be reduced at the same time, e.g. a nitro group may be reduced to an amino group, a benzyloxy group to a hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen may be replaced by a hydrogen atom.
Suitable protecting groups for step (d) include, for example, triphenyImethy1, tributyl tin or triphenyl tin groups.
In step (d), the cleaving of a protective group used is advantageously carried out in the presence of a hydrohalic acid, preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia, in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol at temperatures between 0 and 100°C, but preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and 150°C, preferably at temperatures between 120 and 14 0°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. Conveniently, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g. sodium azide, in the presence of a weak acid such as ammonium chloride or a tetrazolide salt obtained in the reaction mixture during the reaction with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which is also preferably produced in - 42 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 expediently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, benzene, glycol, glycolmonomethylether, dimethyl-formamide or dioxane, e.g. at temperatures between 0 and 150°C, preferably at temperatures between 20 and 100°C. However, the reaction may also be carried out without solvents.
The cyclisation of step (g) is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, sulpholan, dimethylformamide, tetralin or in an excess of the acylating agent used to prepare the compound of general formula X, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, e.g. at temperatures between 0 and 250°C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid anhydride or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide. However, the cyclisation may also be carried out without a solvent and/or condensing agent.
However, it is particularly advantageous to perform the reaction of step (g) by preparing a compound of formula X in the reaction mixture by reducing a corresponding onitro-amino compound, optionally in the presence of a carboxylic acid of formula XI H00 (XI ) (wherein R,, R3 and R4 are defined as hereinbefore) , or by acylating a corresponding o-diamino compound with a carboxylic acid of formula XI.
When the reduction of the nitro group is broken off at the hydroxylamine stage, subsequent cyclisation produces the N-oxide of a compound of formula I. The N-oxide thus obtained is then converted by reduction into a corresponding compound of formula I.
The subsequent reduction of an N-oxide thus obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50°C, but preferably at ambient temperature.
The subsequent hydrolysis in step (g) is conveniently carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or - 44 trifluoroacetic acid in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10°C and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic or trifluoroacetic acid, any alcoholic hydroxy groups present may simultaneously be converted into a corresponding acyloxy group such as the trifluoroacetoxy group.
The reaction of step (h) is conveniently 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, e.g. at temperatures between 20 and 150°C, but preferably at the boiling temperature of the reaction mixture, and optionally in the presence of an acid such as sulphuric or ptoluenesulphonic acid as condensing agent. The reaction may, however, also be carried out without a solvent.
In step (i), examples of protecting groups for a hydroxy group are trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.-butyl, benzyl and tetrahydropyranyl groups and protecting groups for an amino, alkylamino or imino group include the acetyl, benzoyl, ethoxycarbonyl and benzyl groups.
Step (i) is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between - 45 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is preferably split off by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.
An isomer mixture of a compound of formula I thus obtained may if desired be resolved according to step (j) bY chromatography using a substrate such as silica gel or aluminium oxide.
In step (k), the compounds of formula I obtained may be converted into the acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable salts thereof with inorganic or organic acids. Suitable acids for this purpose include hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric or 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 addition salts thereof. Suitable bases include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of formulae II to XIII which are used as starting materials in the preparation of compounds of - 46 formula I are either known from the literature or may be obtained by known methods.
Thus, for example, a compound of formula II may be obtained by alkylation of a corresponding o-amino-nitro compound and subseguent reduction of the nitro group.
A compound of formula III, V, VI, VII, IX, X or XII used as a starting material may be obtained by acylation of a corresponding o-phenylenediamine or a corresponding oamino-nitro compound, followed by reduction of the nitro group and cyclisation of the subseguently obtained odiamino-phenyl compound, optionally followed by cleaving any protecting group used or by cyclisation of a correspondingly substituted benzimidazole with a corresponding amine or by NH-alkylation of a corresponding ΙΗ-benzimidazole, whilst the isomer mixture thus obtained may then be resolved by conventional methods, e.g. chromatography. Some of the starting compounds mentioned above are described in EP-A-392317.
For example, 2-n-butyl-5-(imidazo[1,2-a]pyridin-2-yl)3H-benzimidazole is obtained by reacting p-aminoacetophenone with butyric acid chloride, followed by nitration, bromination, cyclisation with 2-aminopyridine to form the 6-n-butanoylamido-3-(imidazo[l,2-a]pyridin2-yl)-nitrobenzene, which is subseguently converted into the desired compound by cyclisation, after reduction of the nitro group, or 2-n-butyl-4-methyl-6-(l-methylbenzimidazol-2-yl)-1Hbenzimidazole may be obtained by nitration of methyl 3methyl-4-n-butanoylamido-benzoate, subseguent reduction of the nitro group and cyclisation to yield 2-n-butyl-4methyl-6-raethoxycarbonyl-lH-benzimidazole, which is then converted into the desired compound using 2-methylaminoIE 920373 - 47 aniline with cyclisation.
A benzimidazole in which the alkoxy group is substituted in the 2-, 3-, 4- or 5-position by an imidazole group may be obtained for example by reaction of a corresponding 7-hydroxy-benzimidazole, as described in EP-A-392317, by reaction with a corresponding a, ωdihaloalkane and subsequent reaction with a corresponding imidazole.
The new compounds of formula I and the physiologically acceptable salts thereof have valuable pharmacological properties. They are angiotensin antagonists, particularly angiotensin-II-antagonists.
By way of example, the following compounds were tested for their biological effects as described hereinafter: A = 4'-[[2-n-butyl-7-[3-(imidazol-l-yl)-propyloxy]-4methy1-benz imidazol-l-yl]-methyl]-bipheny1-2carboxylic acid; B = 4'-[[2-n-butyl-7-[3-(benzimidazol-l-yl)-propyloxy]4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid trifluoroacetate; C = 4'-[[2-n-butyl-4-methyl-7-[4-(tetrahydrobenzimidazol-l-yl)-butoxy]-benzimidazol-l-yl]methyl J-biphenyl-2-carboxylic acid; D = 4'-[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid; E = 4'-[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5yl)-biphenyl; - 48 F = 4'—[[2-n—propyl-4-methyl-6-(l-oxo-isoindolin-2—yl) benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; G = 4'-[[2-n-propyl-4-methyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; H = 4'—[[2—n—butyl—6—(2,3—dimethylmaleic acid imino)-4 methyl-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid semihydrate; I = 4'—[[2—n—butyl—6-(isopropylcarbonylamino)—4—methyl benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; J = 4'-[[2-n-butyl-4-methyl-6(morpholinocarbonylamino)-benzimidazol-l-yl]methyl]-biphenyl-2-carboxylic acid; K = 4'-[[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4methyl-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid semitrifluoroacetate; L = 4'-[[2-n-butyl-7-[3-(imidazol-l-yl)-propyloxy]-4methyl-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5 yl)-biphenyl; M = 4'-[(2-cyclopropyl-4-methyl-6-(1methylbenzimidazol-2-yl)-benzimidazol-l-yl)methyl]-biphenyl-2-carboxylie acid; N = 4'-[(2-n-propyl-4-methyl-6-(l-methyl-5-fluorobenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid; 0 = 4'-[(2—n—propyl-4-methyl-6IE 920373 - 49 (imidazo(1,2-a]pyrimidin-2-yl)-benzimidazol-l-yl)methyl]-2-(lH-tetrazol-5-yl)-biphenyl; P = 4'—[(2—n—propyl—4—methyl—6-(5,6,7,8-tetrahydro— imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)methyl]-biphenyl-2-carboxylic acid; Q = 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydroimidazof1,2-a]pyridin-2-yl)-benzimidazol-l-yl)methyl]-2-(lH-tetrazol-5-yl)-biphenyl; R = 4·-[(2-n-propyl-4-chloro-6-(l-methylbenzimidazol-2yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5yl)-biphenyl-hydrochloride; and S = 4'-[[2-n-propyl-4-raethyl-6-(imidazo[2,1-b]thiazol6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid.
Description of method: Angiotensin II-receptor bonding The tissue (rats lung) is homogenised in Tris-buffer (50 mMol Tris, 150 mMol NaCl, 5 mMol EDTA, pH 7.40) and centrifuged twice for 20 minutes at 20,000 x g. The finished pellets are resuspended in incubating buffer (50 mMol Tris, 5 mMol MgCl2, 0.2% BSA, pH 7.40) 1:75, based on the moist weight of the tissue. Each 0.1 ml of homogenate is incubated for 60 minutes at 37°C with 50 pM [125I]-antiotensin II (NEN, Dreieich, FRG) with increasing concentrations of the test substance in a total volume of 0.25 ml. Incubation is ended by rapid filtration through glass fibre filter mats. The filters are each washed with 4 ml of ice cold buffer (25 mMol Tris, 2.5 mMol MgCl2, 0.1% BSA, pH 7.40). The bound radioactivity is measured using a gamma-counter. The - 50 corresponding IC50 value is obtained from the doseactivity curve.
In the test described, substances A to S show the following IC50 values: Substance IC50 [nM] A 510.0 B 52.0 C 130.0 D 3.7 E 14.0 F 5.0 G 1.2 H 20.0 I 6.6 J 3.5 K 17.0 L 240.0 M 12.0 N 26.0 0 3.4 P 1.2 Q 1.7 R 20.0 S 7.8 In addition, compounds D, E, F, G, Η, M and 0 were tested on conscious renally hypertensive rats for their effect after oral administration using methods known from the literature. At a dosage of 10 mg/kg these compounds exhibited a hypotensive effect.
Moreover, when the above-mentioned compounds were administered in a dose of 30 mg/kg i.v. no toxic side effects, e.g. negative inotropic effects or disorders in heart rhythm, were observed. The compounds are - 51 therefore well tolerated.
In view of their pharmacological properties, the new compounds and the physiologically acceptable addition salts thereof are suitable for the treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
The new compounds and the physiologically acceptable addition salts thereof are also suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetylcholine and dopamine in the brain, the new angiotensin antagonists are also suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's disease, Parkinson syndrome, bulimia and disorders of cognitive function.
Viewed from a further aspect, the present invention provides the use of a compound of formula I or an isomer or physiologically acceptable salt thereof for the manufacture of a therapeutic composition with an angiotensin antagonistic activity.
In particular the present invention provides the use of a compound of formula I or an isomer or physiologically acceptable salt thereof for the manufacture of a therapeutic composition to treat hypertension, pulmonary - 52 diseases, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic nephropathy, glaucoma, gastrointestinal and bladder diseases or to prevent the progression of cardiac insufficiency after myocardial infarction.
Additionally, the present invention provides the use of a compound of formula I or an isomer or physiologically acceptable salt thereof for the manufacture of a therapeutic composition to treat depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function as well as other central nervous system disorders.
Viewed from another aspect, the present invention provides a method of treatment of the human or non-human animal body said method comprising administering to said body a pharmaceutically acceptable form of a compound of formula I or an isomer or salt thereof.
In particular, the present invention provides a method of treatment of the human or non-human animal body said method comprising administering to said body a pharmaceutically acceptable form of a compound of formula I, wherein said body is suffering from hypertension, pulmonary diseases, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic nephropathy, glaucoma, gastrointestinal or bladder diseases or cardiac insufficiency after myocardial infarction.
The present invention also provides a method of treatment of the human or non-human animal body said method comprising administering to said body a pharmaceutically acceptable form of a compound of formula I, wherein said body is suffering from depression, Alzheimer's disease, Parkinson syndrome, - 53 bulimia, disorders of cognitive function or other central nervous system disorders.
The dosage reguired to achieve these effects in adults is generally 20 to 100 mg, preferably 30 to 70 mg, when administered intravenously, or orally 50 to 200 mg, preferably 75 to 150 mg, administered 1 to 3 times a day. For this purpose, the compounds of formula I prepared according to the invention, optionally in conjunction with other active substances, such as hypotensives, diuretics and/or calcium antagonists, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene-glycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
Additional active substances which may be included in the combinations mentioned above might be, for example, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzothiazide, cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosine, atenolol, propranolol, (di)hydralazine-hydrochloride, diltiazem, felodipin, nicardipin, nifedipin, nisoldipin and nitrendipin. The dosage for these active substances is appropriately one fifth of the lowest recommended dose up to 1/1 of the normally recommended dose, i.e., for example, 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorothiazide, 15 to 200 mg of ethacrinic acid, 5 to 80 mg of furosemide, 20 to 480 mg of propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of - 54 nifedipin or 5 to 60 mg of nitrendipin.
The invention is further illustrated by the following, non-limiting Examples. In the Examples (except where otherwise specified) all parts and ratios are given by weight, except for eluant or solvent ratios which are by volume. - 55 Example 1 4' - [[2-n-Butyl-7-[5-(imidazol-l-yl)-pentyloxy]-4-methylbenzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid hydrate 0.7 g (1.15 mMol) of tert.-butyl 4'-[[2-n-butyl-7-[5(imidazol-l-yl)-pentyloxy]-4-methyl-benzimidazol-l-yl]methyl]-biphenyl-2-carboxylate are dissolved in 35 ml of methylene chloride, 5 ml of trifluoroacetic acid are added and the mixture is stirred for 12 hours at ambient temperature. It is diluted with methylene chloride and extracted with water and with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated down in vacuo. The crude product thus obtained is purified over a silica gel column (particle size: 0.063-0.02 mm, ethyl acetate/ethanol/ammonia - 90:10:0.1) and crystallised from acetone.
Yield: 0.19 g (29.9% of theory), Melting point: 185-187°C x H2O (550.70) Calculated: C 71.81 H 7.09 N 9.85 Found: 72.03 7.19 9.71 Mass spectrum: m/e = M+ 550 The following compounds are obtained analogously to Example 1: 4'-[[2-n-butyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3on-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-propy1-4-methy1-6-(4,5-dihydro-2H-pyridaz in-3on-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-ethy1-4-methy1-6-(4,5-dihydro-2H-pyridazin-3-onIE 920373 - 56 6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid ' - [ [2-n-butyl-4-methyl-6-(phenylaminocarbonylamino)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-ethyl-4-methyl-6-(cyclohexylaminocarbonylamino)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4’-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonylamino) -benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-butyl-4-methyl-6-(cyclohexylaminocarbonylamino) -benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4' - [[2-n-propyl-4-methyl-6-(methylaminocarbony1methylamino)-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylic acid 4z - [[2-n-propyl-4-methyl-6-(n-pentylaminocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-propy1-4-methyl-6-(n-pentylaminocarbonylamino) benz imidazol-l-yl]-methyl]-bipheny1-2-carboxy1ic acid 4' - [[2-n-propyl-4-methyl-6-(n-butylaminocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(benzylaminocarbonylamino)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4[2-n-propyl-4-methyl-6-(allylaminocarbonylamino)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid - 57 4' - [[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-bipheny1-2carboxylic acid 4' - [[2-n-propyl-4-methyl-6-(dimethylaminocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-propyl-4-roethyl-6-(dimethylaminocarbonylamino) benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-nbutylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbony1cyclohexylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4' — [[2-n-propyl-4-methyl-6-(methylaminocarbonylbenzylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(n-hexylaminocarbonylcyclohexylamino) -benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(cyclohexylarainocarbonylethylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4' — [[2-n-propyl-4-methyl-6-(dimethylaminocarbony1-npentylamino)-benzimidazol-l-yl]-methyl]-bipheny1-2carboxylic acid 4' - [[2-n-propyl-4-methyl-6-(morpholinocarbonylamino)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid - 58 4'- [[2-n-propyl-4-methyl-6-(pyrrolidinocarbonylamino)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylie acid 4'-[[2-n-propy1-4-methy1-6-(pyrro1id i nocarbony1methylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(piperidinocarbonylamino)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl)-benzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid Example 2 4'-[[2-n-Butyl-7-[3-(imidazol-l-yl)-propyloxy]-4-methy1benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-buty1-7-[3-(imidazol-l-yl)-propyloxy]-4-methy1benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 69.4% of theory, Melting point: 208-210°C C32H34N4°3 (522.64) Calculated: C 73.54 H 6.56 N 10.72 Found: 73.45 6.62 10.60 Rf value: 0.50 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5) Example 3 4'-[[2-n-Butyl-7-[3-(benzimidazol-l-yl)-propyloxy]-4methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid trifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4'IE 920373 - 59 [[2-n-butyl-7-[3-(benzimidazol-l-yl)-propyloxy]-4methy1-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87.8% of theory, Melting point: 221-223°C C36H36N4°3 x CF3COOH (686.72) Calculated: C 66.46 H 5.43 N 8.15 Found: 66.58 5.62 8.31 Rf value: 0.45 (silica gel; ethyl acetate/ethanol/ammonia = 50:45:5) Example 4 4'-[[2-n-Butyl-7-[4-(imidazol-l-yl)-butyloxy]-4-methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid hydrate Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-7-[4-(imidazol-l-yl)-butyloxy]-4-methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 68.5% of theory, Melting point: 126-128°C C33H36N4°3 x H20 (554.68) Calculated: C 71.46 H 6.91 N 10.10 Found: 71.63 7.02 9.98 Mass spectrum: m/e = 536 Example 5 4'-[[2-n-Buty1-7-[2-(benzimidazol-l-yl)-ethoxy]-4methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-7-[2-(benzimidazol-l-yl)-ethoxy]-4-methy1benzimidazol-l-yl]-methy1]-bipheny1-2-carboxy1ate and trifluoroacetic acid in methylene chloride. - 60 Yield: 78.1% of theory, Melting point: 167-169°C (558.68) Calculated: C 75.25 H 6.13 N 10.03 Found: 75.03 6.17 9.95 Example 6 4'-[[2-n-Butyl-7-[5-(benzimidazol-l-yl)-pentyloxy]-4methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-7-[5-(benzimidazol-l-yl)-pentyloxy]-4methy1-benz imidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 7 4'-[[2-n-Butyl-7-[4-(benzimidazol-l-yl)-butyloxy]-4methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-7-[4-(benzimidazol-l-yl)-butyloxy]-4-methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 8 4'-[[2-n-Butyl-4-methyl-7-[4-(tetrahydrobenzimidazol-lyl) -butyloxy]-benzimidazol-l-yl]-methyl]-bipheny1-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[(2-n-butyl-4-methyl-7-[4-(tetrahydrobenzimidazol-l-yl)butyloxy]-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid in methylene - 61 chloride.
Yield: 86% of theory, Melting point: 229-231°C C37H42N4O3 (590.76) Calculated: C 75.23 H 7.17 N 9.48 Found: 75.34 7.06 9.38 Example 9 4'-[[2-n-Propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in dimethylformamide.
Yield: 63.9% of theory, Melting point: 261-263 °C C33H30N4O2 (514.60) Calculated: C 77.02 H 5.87 N 10.89 Found: 76.90 5.85 10.99 The following compounds are obtained analogously to Example 9: 4'-[[2-n-propyl-4-methyl-6-(1-n-propylbenz imidazol-2y1)-benz imidazol-l-yl]-methyl]-biphenyl-2-carboxy1ic acid 4'-[[2-n-propyl-4-methyl-6-(1-n-hexylbenz imidazol-2-yl) benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylie acid 4'-[[2-n-propyl-4-raethyl-6-(l-cyclopropylbenzimidazol-2 yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexylbenzimidazol-2yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid - 62 Example 10 4' - [[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4.3 g (66 mMol) of sodium azide and 3.5 g (66 mMol) of ammonium chloride are added to a solution of 1.60 g (3.3 mMol) of 4'-[[2-n-propyl-4-methyl-6-(1methylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2cyano-biphenyl in 50 ml of dimethylformamide and the mixture is stirred for 24 hours at 14 0°C. Then water is added and the precipitate is removed by suction filtering. The crude product thus obtained is purified by chromatography over silica gel (300 g of silica gel, methylene chloride + 6% ethanol).
Yield: 900 mg (51% of theory), Melting point: 228-230°C C33H3ON8 (538.70) Calculated: C 73.58 H 5.61 N 20.80 Found: 73.48 5.55 20.70 The following compounds are obtained analogously to Example 10: '- [[2-n-propyl-4-methyl-6-(l-n-hexylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(l-cyclobutylbenzimidazol-2yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4'-[[2-n-propyl-4-methyl-6-(l-cyclohexylbenzimidazol-2yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4' -[[2-n-butyl-4-methyl-7-[2-(imidazol-l-yl)-ethoxy]benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl - 63 4'-[[2-n-buty1-7-[3-(imidazol-l-yl)-propyloxy]-4-methylbenzimidazol-1-yl]-methyl]-2-(ΙΗ-tetrazol-5-yl)-biphenyl 4' - [[2-n-buty1-7-[4-(imidazol-l-yl)-butyloxy]-4-methy1benzimidazol-l-yl]-methyl)-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-4-methyl-7-[5-(imidazol-l-yl)-pentyloxy]benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [[2-n-buty1-7-[2-(benzimidazol-l-yl)-ethoxy]-4methy1-benzimidazol-1-y1]-methyl)-2-(lH-tetrazol-5-yl)biphenyl 4'-[[2-n-buty1-4-methy1-7-(3-(benzimidazol-l-yl)propyloxy]-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5yl)-biphenyl 4' - [[2-n-butyl-7-[4-(benzimidazol-l-yl)-butyloxy]-4methyl-benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4' - [[2-n-butyl-4-methyl-7-[5-(benzimidazol-l-yl)pentyloxy]-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5yl)-biphenyl 4' - [[2-n-buty1-7-[2-(4,5,6,7-tetrahydrobenz imidazol-lyl) -ethoxy]-4-methyl-benzimidazol-l-y1]-methyl]-2-(1Htetrazol-5-yl)-biphenyl 4' - [[2-n-buty1-4-methyl-7-[3-(tetrahydrobenzimidazol-1yl)-propyloxy]-benzimidazol-l-yl]-methyl]-2-(1Htetrazol-5-yl)-biphenyl 4' - [[2-n-butyl-7-[4-(tetrahydrobenzimidazol-l-yl) butyloxy]-4-methyl-benzimidazol-l-y1]-methyl]-2-(1Htetrazol-5-yl)-biphenyl - 64 4' - [[2-n-butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-lyl) -pentyloxy]-benzimidazol-l-yl]-methyl]-2-(1Htetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-4-methyl-6-(phenylaminocarbonylamino)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-ethyl-4-methyl-6-(cyclohexylaminocarbonylamino)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl 4'-[[2-propyl-4-methyl-6-(cyclohexylaminocarbonylamino)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-4-methyl-6-(cyclohexylaminocarbonylamino) -benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonylmethylamino)-benziraidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl 4' - [[2-n-propyl-4-methyl-6-(n-pentylaminocarbonylamino)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(n-butylaminocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(benzylaminocarbonylamino)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4·-[[2-n-propyl-4-methyl-6-(allylaminocarbonylamino)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl - 65 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4' - [[2-n-propyl-4-methyl-6-(dimethylaminocarbonylamino)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbony1-nbutylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5yl)-biphenyl 4' - [[2-n-propy1-4-methyl-6-(methylaminocarbonylcyclohexylamino)-benzimidazol-l-yl]-methyl]-2-(1Htetrazol-5-yl)-biphenyl 4·-[(2-n-propyl-4-methyl-6-(methylaminocarbonylbenzylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(n-hexylaminocarbonylcyclohexylamino)-benzimidazol-l-yl]-methyl]-2-(1Htetrazol-5-yl)-biphenyl 4'-[[2-n-propy1-4-methyl-6-(cyclohexylaminocarbony1ethylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonyl-npentylamino)-benzimidazol-l-yl]-methyl)-2-(lH-tetrazol5—yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(morpholinocarbonylamino)benzimidazol-l-yl]-methyl)-2-(lH-tetrazol-5-yl)-biphenyl - 66 4' - [[2-n-propyl-4-methyl-6-(pyrrolidinocarbonylamino)benzimidazol-l-yl]-methyl]-2-(IH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl 4' - [[2-n-propyl-4-methyl-6-(piperidinocarbonylmethylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl 4' -[[2-n-propy1-4-methy1-6-(3-benzyl-3,4,5,6-tetrahydro2(IH)-pyrimidinon-l-yl)-benzimidazol-l-yl]-methyl]-2(lH-tetrazol-5-yl)-biphenyl Example 11 4'-[(2-n-Propyl-4-methyl-6-phthalimino-benzimidazol-lyl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl4-methyl-6-phthalimino-benzimidazol-l-yl)-methyl]-2cyano-biphenyl and sodium azide in dimethylformamide. Yield: 6.8% of theory, Melting point: sintering from 160°C C„H27N7O2 (553.60) Calculated: C 71.59 H 4.92 N 17.71 Found: 71.39 4.88 17.54 Example 12 4'-[(2-n-Butyl-4-methyl-6-phthalimino-benzimidazol-lyl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4z-[(2-n-butyl4-methyl-6-phthalimino-benzimidazol-l-yl)-methyl]-2cyano-biphenyl and sodium azide in dimethylformamide. Yield: 7.1% of theory, - 67 Melting point: sintering from 150°C C34H29N7O2 (567.70) Calculated: C 71.94 H 5.15 N 17.27 Found: 71.75 5.19 17.22 Example 13 4' - [[2-n-Propyl-4-methyl-6-(l-oxo-isoindolin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl4-methyl-6-(l-oxo-isoindolin-2-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 25.0% of theory, Melting point: sintering from 17O°C C33H29N7O (539.60) Calculated: C 73.45 H 5.42 N 18.17 Found: 73.20 5.41 18.33 Example 14 4'-[[2-n-Butyl-4-raethyl-6-(l-oxo-isoindolin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-butyl4-methyl-6-(l-oxo-isoindolin-2-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in d imethy1formamide.
Yield: 21.0% of theory, Melting point: sintering from 165°C C^Hjj^O (553.70) Calculated: C 73.76 H 5.64 N 17.71 Found: 73.58 5.33 17.41 - 68 Example 15 4'-[[2-n-Propyl-4-methyl-6-(butanesultam-l-yl)benz imidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl4-methyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 49.0% of theory, Melting point: Sintering from 186°C C29H3IN7O2S (541.70) Calculated: C 64.30 H 5.77 N 18.10 S 5.92 Found: 64.10 5.39 18.01 5.98 Example 16 z-[[2-Ethyl-4-methyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl)-2-(lH-tetrazol-5-y1)-biphenyl Prepared analogously to Example 10 from 4'-[[2-ethyl-4methyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]-methyl]2-cyano-biphenyl and sodium azide in dimethylformamide. Yield: 60.0% of theory, Melting point: amorphous, sintering from 194°C C28H29N7O2S (527.70) Calculated: C 63.74 H 5.54 N 18.58 S 6.08 Found: 63.83 5.66 18.41 5.82 Example 17 4'-[[2-n-Butyl-4-methyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-butyl4-methyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide . - 69 Yield: 48.0% of theory, Melting point: amorphous, sintering from 183°C C30H33N7O2S (555.70) Calculated: C 64.84 H 5.99 N 17.64 S 5.77 Found: 64.53 5.66 17.63 5.55 Example 18 4'-[[2-n-Propyl-4-ethyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl4-ethyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 27.0% of theory, Melting point: amorphous, sintering from 189°C C30H33N7O2S (555.70) Calculated: C 64.84 H 5.99 N 17.64 S 5.77 Found: 64.81 5.68 17.87 5.31 Example 19 4[2-Ethyl-4-ethyl-6-(butanesultam-l-yl)-benzimidazol1- yl] -methyl] -2- (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 10 from 4'-[[2-ethyl-4ethyl-6-(butanesultara-l-yl)-benzimidazol-l-yl]-methyl]2- cyano-biphenyl and sodium azide in dimethylformamide. Yield: 39.0% of theory, Melting point: amorphous, sintering from 212°C C29H31N7O2S (541.70) Calculated: C 64.30 H 5.77 N 18.10 S 5.92 Found: 64.30 5.51 17.99 5.59 - 70 Example 20 4'-[[2-n-Propyl-4-isopropyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl4-isopropyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide .
Yield: 22.0% of theory, Melting point: amorphous C31H35N7O2S (569.70) Calculated: C 65.35 H 6.19 N 17.21 S 5.63 Found: 65.13 6.10 17.54 5.40 Example 21 4'-[[2-Ethyl-4-isopropyl-6-(butanesultam-l-yl)benz imidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-ethyl-4isopropyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 24.0% of theory, Melting point: amorphous, sintering from 209°C C30H33N7O2S (555.70) calculated: C 64.84 H 5.99 N 17.64 S 5.77 Found: 64.99 5.71 17.43 5.71 Example 22 4' - [[2-n-Propyl-4-trifluoromethyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl4-trifluoromethyl-6-(butanesultam-l-yl)-benzimidazol-lyl] -methyl] -2 -cyano-biphenyl and sodium azide in - 71 dimethy1-formamide.
Yield: 17.0% of theory, Melting point: 199-203°C C29H28F3N7O2S (595.70) Calculated: C 58.48 H 4.74 N 16.46 Found: 58.28 4.43 16.22 Example 23 4'-[[2-n-Propyl-4-methyl-6-(N-benzenesulphonylmethylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl 4- methyl-6-(N-benzenesulphonyl-methylamino)benzimidazol-l-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 42.0% of theory, Melting point: 161-163°C C32H31N7O2S (577.70) Calculated: C 66.53 H 5.41 N 16.97 S 5.55 Found: 66.32 5.36 16.70 5.31 Example 24 4'-[[2-n-Butyl-4-methyl-6-(N-benzenesulphonylmethylamino) -benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5- yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-butyl4-methyl-6-(N-benzenesulphonyl-methylamino)benzimidazol-l-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 37.0% of theory, Melting point: 150-153°C C33H33N7°2S (591.70) Calculated: C 66.98 H 5.62 N 16.57 Found: 66.71 5.38 16.39 - 72 The following compounds are obtained analogously to Example 24: 4'-[[2-ethyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4' - [[2-n-propy1-4-methyl-6-(4,5-dihydro-2H-pyridazin-3on-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5yl)-biphenyl 4' - [[2-n-butyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3on-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro 2(IH)-pyrimidinon-l-yl)-benzimidazol-l-yl]-methyl]-2(lH-tetrazol-5-yl)-biphenyl 4'-[[2-ethyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro2(IH)-pyrimidinon-l-yl)-benzimidazol-l-yl]-methyl]-2(lH-tetrazol-5-yl)-biphenyl Example 25 4'-[[2-n-Buty1-4-methyl-6-(1-methylbenz imidazol-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 48.0% of theory, Melting point: 233-235°C C34H32N4°2 (528.70) Calculated: C 77.25 H 6.10 N 10.60 Found: 77.10 5.98 10.46 - 73 Example 26 4'-[[2-n-Butyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-butyl4-methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-lyl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 41.0% of theory, Melting point: 235-237°C C34H32N8 (552.70) Calculated: C 73.89 H 5.84 N 20.28 Found: 73.67 5.81 19.93 The following compounds are obtained analogously to Example 26: 4z - [[2-n-butyl-4-methyl-6-(1-ethylbenz imidazol-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4z-[[2-n-buty1-4-methyl-6-(1-cyclopropylbenz imidazol-2yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4z-[[2-n-butyl-4-methyl-6-(l-n-pentylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4·-[[2-n-butyl-4-methyl-6-(1-cyclopentylbenzimidazol-2yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl Example 27 4z-[[2-n-Propyl-4-methyl-6-(2-oxo-piperidin-l-yl) benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4z-[[2-n-propylIE 920373 - 74 4-methyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 51.0% of theory, Melting point: amorphous, from 140°C (sintering) C30H31N7O (505.60) Calculated: C 71.26 H 6.18 N 19.39 Found: 71.08 6.22 19.47 Example 28 4' - [[2-n-Buty1-4-methy1-6-(2-oxo-piperidin-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-butyl4-methyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide .
Yield: 39.0% of theory, Melting point: amorphous, from 128°C (sintering) C31H33N7O (519.70) Calculated: C 71.65 H 6.40 N 18.87 Found: 71.44 6.23 18.59 Example 29 4·-[[2-n-Propy1-4-methy1-6-(2-oxo-piperidin-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared from 4'-[[2-n-propyl-4-methyl-6-(2-oxopiperidin-l-yl) -benzimidazol-l-yl]-methyl]-2-(2triphenylmethyl-tetrazol-5-yl)biphenyl by cleaving the triphenylmethyl group with methanolic hydrochloric acid. Yield: 51.0% of theory, Melting point: amorphous, sintering from 115°C C30H31N7O (505.60) Calculated: C 71.26 H 6.18 N 19.39 Found: 71.51 6.39 19.09 - 75 Example 30 4'-[[2-n-Propyl-6-(imidazo[l,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-propyl-6-(imidazo[l,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 54.0% of theory, Melting point: 202-204°C Cj,H26N4O2 (486.60) Calculated: C 76.52 H 5.39 N 11.52 Found: 76.33 5.32 11.30 The following compounds may be prepared analogously to Example 30: 4'-[[2-n-propy1-6-(8-methyl-imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-butyl-6-(6-methyl-imidazo[l,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propy1-6-(5,7-dimethyl-imidazof1,2-a]pyridin-2yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-6-(6-aminocarbonyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2carboxylic acid 4'-[[2-n-butyl-6-(6-chloro-imidazo[l,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4'-[[2-n-propyl-6-(imidazo[l,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid - 76 4' — [[2-n-propy1-6-(imidazo[2,l-b]thiazol-6-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-butyl-6-(2,3-dimethyl-imidazo[2,1-b]thiazol-6yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Example 31 4' —[[2-n-Buty1-6-(imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazoll-yl] -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 41.0% of theory, Melting point: 193-195°C C32H2gN4O2 (500.60) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.73 5.48 11.00 Example 32 4'-[[2-n-Propyl-6-(imidazo[l,2-a]pyridin-2-yl)benz imidazol-l-yl)-methyl]-2-(lH-tetrazol-5-y1)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl6-(imidazo[l,2-a]pyridin-2-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 28.0% of theory, Melting point: 187-189°C C31H26N8 (510.60) Calculated: C 72.92 H 5.13 N 21.95 Found: 72.80 4.97 21.74 - 77 The following compounds may be prepared analogously to Example 32: 4'-[[2-n-propy1-6-(7-methyl-imidazo[1,2-a]pyridin-2-yl)benz imidazol-l-yl]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl 4'-[[2-n-propy1-6-(5-methyl-imidazo[1,2-a]pyridin-2-yl) benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [[2-n-butyl-6-(6-bromo-imidazo[1,2-a]pyridin-2-yl)benziraidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [[2-n-propyl-6-(5,7-dimethyl-imidazo[1,2-a]pyrimidin2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4' — [[2-n-butyl-6-(3-methyl-imidazo[2,1-b]thiazol-6-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl '-([2-n-propy1-6-(2-phenyl-imidazo[2,1-b]thiazol-6-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 33 4'-[[2-n-Butyl-6-(imidazo[l,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-butyl6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 23.0% of theory, Melting point: 170-173°C C32H28Ng (524.60) Calculated: C 73.26 H 5.38 N 21.36 Found: 73.09 5.32 21.20 - 78 Example 34 4'-[[2-n-Propy1-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.-butyl 4Z[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-y1)benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 38.0% of theory, Melting point: 195-197°C (after evaporation and without recrystallisation) Melting point: 299-303°C (methylene chloride/ethanol = 20:1) C32H28N4°2 (500.60) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.55 5.61 10.87 The following compounds may be prepared analogously to Example 34: 4' - [[2-n-propy1-4-methy1-6-(8-methy1-imidazo[1,2-a] pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-butyl-4-methy1-6-(7-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-buty1-4-methyl-6-(6-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4·-[[2-n-propy1-4-methyl-6-(5-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4'-[[2-n-propy1-4-methyl-6-(5,7-dimethyl-imidazole 1, 2 -a] pyr idin-2-yl) -benzimidazol-l-yl]-methyl]IE 920373 - 79 biphenyl-2-carboxylic acid 4'-[[2-ethyl-4-methyl-6-(6-aminocarbony1-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid 4·-[[2-ethyl-4-methyl-6-(6-chloro-imidazo[1,2-a]pyridin2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Example 35 4·-[[2-n-Propy1-4-methy1-6-(imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl4- methyl-6-(imidazo[l,2-a)pyridin-2-yl)-benzimidazol-lyl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 21.0% of theory, Melting point: sintering from 181 °C C32H28N8 (524.60) Calculated: C 73.26 H 5.38 N 21.36 Found: 73.10 5.24 21.13 The following compounds may be prepared analogously to Example 35: 4·-[[2-n-propy1-4-methy1-6-(5-methyl-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5- yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl - 80 Example 36 4'-[[2-n-Butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-4-methyl-6-(imidazo[l,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 51.0% of theory, Melting point: 194-197°C C33H30N4O2 (514.60) Calculated: C 77.02 H 5.88 N 10.89 Found: 76.81 5.78 10.64 The following compounds are obtained analogously to Example 36: 4'-[[2-n-propyl-6-(pyrrolidin-2-on-5-yl)-benzimidazol-1 yl]-methyl]-biphenyl-2-carboxylie acid 4’-[[2-n-propyl-6-(pyrrolidin-2-y1)-benzimidazol-l-yl]methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-6-(quinolin-2-yl)-benzimidazol-l-yl]methyl]-biphenyl-2-carboxylic acid 4' - [[2-n-butyl-6-(quinolin-2-yl)-benzimidazol-l-yl]methyl]-bipheny1-2-carboxylie acid 4' - [[2-n-propyl-6-(isoquinolin-3-yl)-benzimidazol-l-yl] methyl]-biphenyl-2-carboxylic acid 4'-[[2-ethyl-6-(isoquinolin-3-yl)-benzimidazol-l-yl]methyl]-bipheny1-2-carboxy1ic acid - 81 Example 37 4'-[[2-n-Buty1-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-butyl4-methyl-6-(imidazof1,2-a]pyridin-2-yl)-benzimidazol-lyl ] -methyl ] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 26.0% of theory, C33H3ON8 (538.60) Calculated: C 73.58 H 5.61 N 20.80 Found: 73.39 5.40 20.92 The following compounds are obtained analogously to Example 37: 4'-[[2-n-propy1-6-(pyrrolidin-2-on-5-yl)-benzimidazol-lyl ]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4·-[[2-n-propy1-6-(pyrrolidin-2-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-y1)-biphenyl 4' - [[2-n-propy1-6-(piperidin-2-on-6-yl)-benzimidazol-lyl] -methyl ]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-6-(piperidin-2-on-6-yl)-benzimidazol-lyl ]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-6-(piperidin-2-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-6-(piperidin-2-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-ethyl-6-(pyridin-2-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl - 82 4'-[[2-n-propy1-6-(pyridin-2-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-6-(pyridin-2-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [[2-n-propyl-6-(quinolin-2-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-6-(quinolin-2-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-6-(isoquinolin-3-yl)-benzimidazol-l-yl] methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4[[2-ethyl-6-(isoquinolin-3-yl)-benzimidazol-l-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 38 ' - [[2-n-Butyl-4-methyl-6-(2,2-dimethylpropionylamino)benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-4-methyl-6-(2,2-dimethylpropionylamino)benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 39 4'-[[2-n-Butyl-7-[2-(tetrahydrobenzimidazol-l-yl)ethoxy]-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-7-[2-(tetrahydrobenzimidazol-l-yl)-ethoxy]4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid in methylene - 83 chloride.
Yield: 81% of theory, Melting point: 236-237°C C35H38N4O3 (562.71) Calculated: C 74.71 H 6.81 N 9.96 Found: 74.51 6.79 9.98 Example 40 4' — [[2-n-Buty1-4-methyl-7-[5-(tetrahydrobenz imidazol-lyl) -pentyloxy]-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-buty1-4-methy1-7-(5-(tetrahydrobenzimidazol-l-yl)pentyloxy]-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Example 41 4' — [[2-n-Butyl-7-[3-(tetrahydrobenzimidazol-l-yl)propyloxy]-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-butyl-7-[3-(tetrahydrobenzimidazol-l-yl)propyloxy]-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 42 4·-[[2-n-Propy1-4-methy1-6-(imidazo[1,2-a]pyrimidin-2yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4·IE 920373 - 84 [[2-n-propy1-4-methy1-6-(imidazo[1,2-a]pyrimidin-2-yl)benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 47% of theory, Melting point: 224-226°C (after evaporation and without recrystallisation) Melting point: 294-297°C (methylene chloride/ethanol = 20:1) C31H27N5O2 (501.60) Calculated: C 74.23 H 5.43 N 13.96 Found: 74.10 5.31 13.66 Example 43 4' - [[2-n-Propyl-4-methy1-6-(imidazo[2,1-b]thiazol-6-yl) benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-propy1-4-methy1-6-(imidazo[2,1-b]thiazol-6-yl)benz imidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 43% of theory, Melting point: 192-195°C (after evaporation and without recrystallisation) Melting point: >300°C (methylene chloride/ethanol - 20:1) C30H26N4O2S (506.64) Calculated: C 71.12 H 5.17 N 11.06 S 6.33 Found: 70.97 5.19 10.88 6.09 The following compounds may be prepared analogously to Example 43: 4' - [[2-n-propyl-4-methyl-6-(3-methyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 4' - [[2-n-propy1-4-methy1-6-(2,3-dimethyl-imidazo[2,1-b] thiazol-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid - 85 4'-[[2-n-butyl-4-methyl-6-(2,3-trimethylene-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-raethyl-6-(2,3-tetramethyleneimidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid 4'-[[2-ethy1-4-methy1-6-(2-phenyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2carboxylic acid Example 44 4'-([2-n-Propy1-4-methy1-6-(imidazo[2,1-b]thiazol-6-yl)benz imidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-lyl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 21% of theory, Melting point: amorphous, sintering from 196°C ^-30^26^8^ (530.67) Calculated: C 67.90 H 4.94 N 21.12 S 6.04 Found: 67.77 4.84 21.00 5.87 The following compounds may be prepared analogously to Example 44: 4'-[[2-n-propyl-4-methyl-6-(3-methyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl 4' - [[2-n-butyl-4-methyl-6-(2,3-dimethy1-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl - 86 4 z - [[2-n-butyl-4-methyl-6-(2,3-trimethylene-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(1Htetrazol-5-yl)-biphenyl 4z-[[2-ethy1-4-methy1-6-(2,3-tetramethylene-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(1Htetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(2-phenyl-imidazo[2,1-b] thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol5-yl)-biphenyl Example 45 4Z —[[2-n-Propyl-4-methyl-6-(benzimidazol-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4·-[[2-n-propyl4-methyl-6-(benzimidazol-2-yl)-benzimidazol-l-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide .
Yield: 28% of theory, Melting point: 202-205°C C32H28N8 (524.64) Calculated: C 73.26 H 5.38 N 21.36 Found: 73.01 5.22 21.56 The following compounds are obtained analogously to Example 45: 4z-[[2-ethyl-4-methyl-6-(benzimidazol-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4z-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4z-[[2-n-propyl-4-methyl-6-(1-n-hexy1-benz imidazol-2yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)IE 920373 - 87 biphenyl 4' - [[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol 2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4'-[[2-n-propyl-4-methyl-6-(1-cyclohexy1-benzimidazolyl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl Example 46 4'-[[2-n-Propyl-4-methyl-6-(benzimidazol-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 43% of theory, Melting point: 239-242°C C32H28N4O2 (500.61) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.55 5.60 11.41 The following compounds are obtained analogously to Example 46: 4'-[[2-ethyl-4-methyl-6-(benzimidazol-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(1-n-hexy1-benz imidazol-2yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid - 88 4'-[[2-n-propy1-4-methy1-6-(1-cyclopropyl-benzimidazo12-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-{1-cyclohexy1-benz imidazol-2yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Example 47 4'-[[2-n-Buty1-7-[3-(imidazol-l-yl)-propyloxy]-4-methylbenzimidazol-l-yl ] -methyl ] -2- ( lH-tetrazol-5-yl)-biphenyl Prepared from 4'-[[2-n-butyl-7-[3-(imidazol-l-yl)propyloxy]-4-methyl-benzimidazol-l-yl]-methyl]-2-(1triphenylmethyl-tetrazol-5-yl)-biphenyl by cleaving the 1-triphenylmethyl group by means of ethanol/hydrochloric acid.
Yield: 89.8% of theory, Melting point: 83-87°C C32H34N8O X 1.5 H2O (573.69) Calculated: C 66.99 H 6.50 N 19.53 Found: 66.83 6.52 19.43 Example 48 4'-[[6-(N-Benzenesulphonyl-methylamino)-2-n-butyl-4methyl-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4#[[6-(N-benzenesulphonylmethylamino)-2-n-butyl-4-methylbenzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 95.6% of theory, Melting point: 211-212°C C33H33N3O4S (567.70) Calculated: C 69.80 H 5.86 N 7.40 S 5.65 Found: 69.52 5.92 7.33 5.84 - 89 Example 49 4'-[[6-(N-Benzenesulphonyl-n-pentylamino)-2-n-butyl-4methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4Z[[6-(N-benzenesulphonyl-n-pentylamino)-2-n-butyl-4methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 81.8% of theory, Melting point: 232-233°C C37H41N3O4S (623.81) Calculated: C 71.24 H 6.62 N 6.74 S 5.14 Found: 71.30 6.77 6.68 5.33 Example 50 4'-[[2-n-Butyl-6-(isopropylcarbonylamino)-4-methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4Z[[2-n-butyl-6-(isopropylcarbonylamino)-4-methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 86.3% of theory, Melting point: 313-315°C C30H33N3O3 (483.61) Calculated: C 74.51 H 6.88 N 8.69 Found: 74.37 7.10 8.74 Example 51 4'-[[2-n-Butyl-6-(2,3-dimethylmaleic acid imino)-4methy1-benz imidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid-semihydrate Prepared analogously to Example l from tert.butyl 4ZIE 920373 -90[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methylbenzimidazol-l-yl ] -methyl ] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 88.9% of theory, Melting point: 321-322°C C32H31N3°4 x °·5 H2° (530.62) Calculated: C 72.43 H 6.08 N 7.92 Found: 72.89 6.16 7.89 Example 52 4'-[[6-(2,3-Dimethylmaleic acid imino)-2-n-propyl-4methyl-benziraidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid semihydrate Prepared analogously to Example 1 from tert.butyl 4'[[6-(2,3-dimethylmaleic acid imino)-2-n-propy1-4-methyl benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 75.4% of theory, Melting point: 329-331°C C31H29N3°4 x 0.5 H2o (516.60) Calculated: C 72.08 H 5.85 N 8.13 Found: 72.04 5.84 7.96 Example 53 4'-[(6-Acetamino-2-n-butyl-4-methyl-benzimidazol-l-yl)methyl]-biphenyl-2-carboxylic acid trifluoroacetate semihydrate Prepared analogously to Example 1 from tert.butyl 4'[(6-acetamino-2-n-butyl-4-methyl-benzimidazol-l-yl)methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 95.7% of theory, Melting point: 112-114°C (amorphous) C2gH29N3O3 x CF3COOH X 0.5 H20 (578.59) - 91 Calculated: C 62.28 H 5.40 N 7.26 Found: 62.57 5.46 7.21 Example 54 4'-[[2-n-Butyl-4-methyl-6-(morpholinocarbonylamino)benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.butyl 4'[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)benz imidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 80.9% of theory, Melting point: 279-281°C ¢3^34^04 (52 6.64) Calculated: C 70.70 H 6.51 N 10.64 Found: 70.48 6.50 10.51 Example 55 4'-[[2-n-Butyl-6-(cyclohexylaminocarbonylamino)-4methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid semitrifluoroacetate Prepared analogously to Example 1 from tert.butyl 4'[[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4-methylbenzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 76.9% of theory, Melting point: 288-289°C C33H3gN4O3 X 0.5 CFjCOOH (595.70) Calculated: C 68.55 Found: 69.08 H 6.51 N 9.41 7.02 9.65 - 92 Example 56 4' - [[2-n-Propy1-4-isopropy1-6-(l-oxo-isoindolin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propy14-isopropyl-6-(l-oxo-isoindolin-2-yl)-benzimidazol-lyl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 14% of theory, Melting point: amorphous C35H33N7° (567.71) Calculated: C 74.05 H 5.86 N 17.27 Found: 73.97 5.82 17.26 Mass spectrum: M+ = 567 Example 57 4'-[[2-n-Propyl-5-(imidazo[l,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[[2-n-propy1-5-(imidazo[1,2-aJpyridin-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 32% of theory, Melting point: 250-253°C C31H26N4°2 (486.60) Calculated: C 76.52 H 5.39 N 11.52 Found: 76.28 5.47 11.27 Example 58 4'-[(2-n-Propy1-4-ethy1-6-(1-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl)-bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propy1-4-ethy1-6-(l-methylbenzimidazol-2-yl)IE 920373 - 93 benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 64% of theory, Melting point: 217-219°C C34H32N4O2 (528.70) Calculated: C 77.24 H 6.10 N 10.60 Found: 77.12 6.09 10.75 Example 59 4'-[(2-n-Propyl-4-ethyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl4-ethyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-lyl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 15% of theory, Melting point: 215-217°C C^Ng (552.70) Calculated: C 73.89 H 5.84 N 20.28 Found: 73.66 6.02 20.56 Example 60 4'-[(2-Cyclopropyl-4-methyl-6-(l-methylbenzimidazol-2yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-cyclopropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 52% of theory, Melting point: 244-246°C C33H28N4O2 (512.60) Calculated: C 77.32 H 5.51 N 10.93 Found: 77.75 5.71 10.94 - 94 Example 61 4'-[(2-Cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 10 from 4'-[(2cyclopropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 59% of theory, Melting point: 245-247°C C33H28N8 (53 6.65) Calculated: C 73.86 H 5.26 N 20.88 Found: 73.95 5.42 20.90 Example 62 4'-((2-Cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-cyclobutyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 63% of theory, Melting point: 189-191°C ^Η30Ν4Ο2 (52 6.60) Calculated: C 77.55 H 5.74 N 10.64 Found: 77.35 5.92 10.40 - 95 Example 63 4'-[(2-Cyclobutyl-4-methyl-6-(l-methylbenzimidazol-2yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 10 from 4'-[(2cyclobutyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 61% of theory, Melting point: 197-199°C W, (550.70) Calculated: C 74.16 H 5.49 N 20.35 Found: 74.12 5.74 20.67 Example 64 4'-[(2-n-Propy1-4-methyl-6-(1-methy1-5-fluorobenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propyl-4-methyl-6-(1-methy1-5-fluoro-benzimidazol 2-yl)-benzimidazol-l-y)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 34% of theory, Melting point: 250-252°C C33H29FN4O2 (53 2.60) Calculated: C 74.42 H 5.49 N 10.52 Found: 74.14 5.64 10.54 The following compounds are obtained analogously to Example 64: 4z-[(2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazoll-yl) -methyl]-biphenyl-2-carboxylie acid - 96 4'-[(2-n-propyl-4-methyl-6-(quinolin-2-yl)-benzimidazoll-yl) -methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propyl-4-methyl-6-(isoquinolin-3-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4Z —[(2-n-propyl-4-methyl-6-(isoquinolin-l-yl)benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylie acid Example 65 4'-[(2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazoll-yl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 16.5% of theory, Melting point: from 275°C (decomp.) CjjHjjNg X H2O (543.65) Calculated: C 68.49 H 5.38 N 23.19 Found: 68.25 5.50 23.37 The following compounds are obtained analogously to Example 65: z-[(2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazoll-yl) -methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[(2-n-propy1-4-methy1-6-(quinolin-2-yl)-benzimidazoll-yl) -methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4z-[(2-n-propyl-4-methyl-6-(isoquinolin-3-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4z-[(2-n-propyl-4-methyl-6-(isoquinolin-l-yl)IE 920373 - 97 benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 66 4'-[(2-n-Propy1-4-methyl-6-(5,6,7,8-tetrahydroimidazo [1 ,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 67% of theory, Melting point: from 240°C (sinters) c32H32N4°2 (504.64) Calculated: C 76.16 H 6.39 N 11.10 Found: 75.94 6.46 11.20 The following compounds are obtained analogously to Example 66: 4'-[(2-n-buty1-4-methy1-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Example 67 4·-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(1Htetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2IE 920373 - 98 yl)-benzimidazol-l-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 73.5% of theory, Melting point: from 275°C (decomp.) C32H32N8 (528.67) Calculated: C 72.70 H 6.10 N 21.20 Found: 72.40 6.07 21.48 The following compounds are obtained analogously to Example 67: 4·-[(2-n-butyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(1Htetrazol-5-yl)-biphenyl 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(1Htetrazol-5-yl)-biphenyl Example 68 4'-[(2-n-Propyl-4-methyl-6-(l-methyl-6-fluorobenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-bipheny12-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propyl-4-methyl-6-(l-methyl-6-fluoro-benzimidazol 2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 76% of theory, Melting point: 243-245°C C33H29FN4O2 (532.60) Calculated: 74.42 H 5.49 N 10.52 Found: 74.74 5.52 10.77 Mass spectrum: m/e = 532 - 99 Example 69 4' - [(2-n-Propyl-4-chloro-6-(l-oxo-isoindolin-2-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propyl-4-chloro-6-(l-oxo-isoindolin-2-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 7.5% of theory, Melting point: 209-210°C C32H26C1N3O3 (53 6.04) Mass spectrum: m/e = 535/537 Rf value: 0.25 (silica gel; methylene chloride/ethanol 9:1) Example 70 4'-[(2-n-Propyl-4-chloro-6-(1-methylbenzimidazol-2-yl) benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propyl-4-chloro-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 52.7% of theory, Melting point: 292-295°C C32H27CN4O2 (535.06) Rf value: 0.30 (silica gel; methylene chloride/ethanol 19:1) Calculated: C 71.90 H 5.08 N 10.45 Cl 6.63 Found: 71.29 5.21 10.40 6.76 - 100 Example 71 4' - [(2-n-Propy1-4-chloro-6-(1-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl hydrochloride Prepared analogously to Example 10 from 4'-[(2-n-propyl4-chloro-6-(l-methylbenzimidazol-2-yl)-benzimidazol-lyl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 54.8% of theory, Melting point: sintering from 204°C C32H27C1N8 X HCl (595.55) Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate = 1:1 and 1% glacial acetic acid) Calculated: C 62.55 H 4.71 N 18.85 Cl 11.85 Found: 62.34 4.97 18.84 11.57 Example 72 4'-[(2-n-Propyl-4-chloro-6-(l-oxo-isoindolin-2-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4(2-n-propy14-chloro-6-(l-oxo-isoindolin-2-yl)-benzimidazol-l-yl)methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 24.6% of theory, Melting point: 246-248°C C32H26C1N7O (5 6 0.0 8) Rf value: 0.15 (silica gel; methylene chloride/ethanol = 9:1) Calculated: C 69.00 H 4.67 N 17.55 Cl 6.40 Found: 68.26 4.75 17.73 6.97 The following compound is obtained analogously to Example 72: - 101 4'-[(2-n-propy1-4-methyl-6-(4-methyl-imidazol-2-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 73 4'-[(2-n-Propyl-4-chloro-6-(cyclohexylaminocarbony1amino)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propyl-4-chloro-6-(cyclohexylaminocarbonylamino)benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 75% of theory, Melting point: 222-224°C C31H33C1N4O3 (545.09) Rf value: 0.15 (silica gel; methylene chloride/ethanol = 19:1) Calculated: C 68.50 H 6.10 N 10.30 Cl 6.48 Found: 68.89 5.98 10.02 7.04 Example 74 4'-[(2-n-Propy1-4-methyl-6-amidino-benzimidazol-l-yl)methyl]-biphenyl-2-carboxylic acid hydrate a) Methyl 4'-[(2-n-propyl-4-roethyl-6-amidinobenzimidazol-l-vl)-methvll-biphenyl-2-carboxylate 2.1 g (5 mMol) of methyl 4'(2-n-propyl-4-methyl-6cyano-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate are dissolved in 250 ml of methanol at ambient temperature with stirring. Hydrogen chloride is introduced at 10-20°C for 3 hours whilst cooling with ice. The mixture is then stirred for a further 3 hours at ambient temperature. The solvent is distilled off in vacuo. the residue is twice mixed with ether and concentrated by evaporation. The imino ether formed is - 102 taken up in 250 ml of methanol and mixed with 10.0 g of ammonium carbonate. The reaction mixture is stirred for 12 hours at ambient temperature. After the solvent has been removed in vacuo the residue is purified over a silica gel column (particle size 0.063-0.032 mm), using as eluant mixtures of methylene chloride and methanol of increasing polarity (9:1 and 8:2). The uniform fractions are evaporated down in vacuo.
Yield: 1.5 g (58% of theory) Rf value: 0.15 (silica gel; eluant: methylene chloride/methanol = 9:1) b) 4'—[(2-n-Propyl-4-methyl-6-amidino-benzimidazol-lyl)-methyl1-biphenvl-2-carboxvlic acid 0.51 g (1.0 mMol) of methyl 4'-[(2-n-propyl-4-methyl-6amidino-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylate are dissolved in 6 ml of tetrahydrofuran. 2.8 ml of 1.4 M aqueous lithium hydroxide solution and 3 ml of water are added and the mixture is stirred for 2 days at ambient temperature. Then a solution of 300 mg of ammonium chloride in 4 ml of water is added. After the mixture is stirred for 5 minutes, the precipitate formed is suction filtered, washed with acetone and dried over potassium hydroxide.
Yield: 0.25 g (59% of theory), Melting point: 270-271°C (decomp.) C26H26N4O2 x H2O (42 6.53) Calculated: C 70.25 H 6.35 N 12.60 Found: 70.04 6.23 12.50 Rf value: 0.55 (silica gel; eluant: methylene chloride/methanol/ammonia = 2:1:0.25) The following compound is obtained analogously to Example 74: 4'-[(2-n-propy1-4-methy1-6-(3-methyl-imidazol-2-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid - 103 Example 75 4'-[(2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid a) 3-Methyl-4-butvrylamino-5-nitro-acetophenone 32.6 g (148 mmol) of 3-methyl-4-butyrylaminoacetophenone are added in batches at -15°C to 300 ml of fuming nitric acid with stirring, and stirred for a further 30 minutes at -15°C. The reaction mixture is then poured onto 3 litres of ice, with stirring, the crude product precipitated is suction filtered, washed with 400 ml of water, dried and purified by recrystallisation from ethanol/diethylether (1:1).
Yield: 23.8 g (61.0% of theory), Rf value: 0.32 (silica gel; methylene chloride), Rf value: 0.48 (silica gel; methylene chloride/methanol = 50:1). b) 3-Methvl-4-butvrylamino-5-nitro-l-bromoacetophenone A solution of 16.0 g (200 mmol) of bromine in 140 ml of dioxane is added dropwise to a solution of 23.8 g (90 mmol) of 3-methyl-4-butyrylamino-5-nitro-acetophenone in 900 ml of dichloromethane at ambient temperature, with stirring, so slowly that total decolorisation of the reaction mixture occurs constantly. The mixture is then stirred for a further two hours, then the reaction mixture is evaporated to dryness in vacuo, the residue obtained is triturated with about 20 ml of dichloromethane/diethylether (1:1), suction filtered and then dried. 23g (74% of theory) of 3-methyl-4butyrylamino-5-nitro-fo-bromoacetophenone are thus obtained, still containing about 10% starting material. The product is further reacted without any more purification.
Rf value: 0.69 (silica gel; methylene chloride/methanol = 50:1) - 104 Rf value: 0.84 (silica gel; methylene chloride/methanol = 9:1). c) 2-Butyrvlamino-3-nitro-5-(imidazo-4-yl)-toluene A solution of 6.8 g (20 mmol) of 3-methyl-4butyrylaroino-5-nitro-S)-bromoacetophenone in 20 ml of formamide is heated to 140°C for two hours. The cooled solution is then poured into about 50 ml of IN ammonia and stirred for about 15 minutes. The crude product precipitated is suction filtered, washed with about 50 ml of water and dried. In this way, 4.4 g (75% of theory) of the product are obtained, which is further reacted without any more purification.
Rf value: 0.29 (silica gel; methylene chloride/methanol = 9:1) d) 2-Butyrvlamino-3-nitro-5-(l-methyl-imidazol-4-yl)toluene 1.3 g (9.5 mmol) of methyliodide are added dropwise at ambient temperature to a solution of 2.5 g (8.7 mmol) of 2-butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene and 5.2g (30 mmol) of potassium carbonate dihydrate in 30 ml of dimethylsulfoxide and the mixture is then stirred for two hours. The reaction mixture is then stirred into about 150 ml of water and extracted four times with 25ml of ethylacetate. The organic extracts are washed with about 30 ml of water, dried and evaporated down. The crude product thus obtained is purified by column chromatography (300 g of silica gel, eluant: methylene chloride/methanol = 30:1).
Yield: 640 mg (24% of theory), Rf value: 0.54 (silica gel; methylene chloride/methanol = 9:1) e) 2-Butyrvlamino-3-amino-5-(l-methyl-imidazol-4-yl)toluene 640 mg (2.1 mmol) of 2-butyrylamino-3-nitro-5-(1-methylIE 920373 - 105 imidazol-4-yl)-toluene are hydrogenated in 30 ml of methanol after the addition of about 200 mg of palladium/charcoal (20%) at ambient temperature under a hydrogen pressure of 5 bar. After all the hydrogen has been absorbed the catalyst is removed by filtering and the filtrate is evaporated down. The crude product obtained is further reacted without any more purification.
Yield: 600 mg (100% of theory), Rf value: 0.23 (silica gel; methylene chloride/methanol = 9:1) f) 2-n-Propyl-4-methvl-6-(l-methvl-imidazol-4-yl)benzimidazole 600 mg (2.1 mmol) of 2-butyrylamino-3-amino-5-(1-methylimidazol-4-yl)-toluene are refluxed for one hour in 10ml of glacial acetic acid. Then the mixture is evaporated to dryness in vacuo, the residue is mixed with about 15 ml of water, made alkaline with ammonia and extracted four times with about 10 ml of ethylacetate. The organic extracts are washed with about 15 ml of water, dried and finally evaporated down. The crude product thus obtained is further reacted without any more purification.
Yield: 420 mg (79% of theory), Rf value: 0.37 (silica gel; methylene chloride/methanol = 9:1) g) Tert.butyl-4'-Γ f2-n-propyl-4-roethyl-6-(1-methvlimidazol-4-vl)-benzimidazol-l-yl) methyl1-biphenyl-2carboxylate 280 mg (0.8 mmol) of tert.butyl-4'-bromomethy1-biphenyl2-carboxylate are added to a solution of 200 mg (0.79 mmol) of 2-n-propyl-4-methyl-6-(l-methyl-imidazol-4-yl)benzimidazole and 90 mg (0.8 mmol) of potassium tert.butoxide in 5 ml of dimethylsulfoxide and the mixture is stirred for 90 minutes at ambient - 106 temperature. The mixture is then stirred into about 40 ml of water and extracted four times with about 10 ml of ethylacetate. The organic extracts are washed with 10 ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel, eluant: dichloromethane/methanol = 30:1).
Yield: 230 mg (56% of theory), Rf value: 0.61 (silica gel; methylene chloride/methanol = 9:1) h) 4z-Γ2-n-Propyl-4-methvl-6-(l-methyl-imidazol-4-vl) benzimidazol-l-vl)-methyl1-biphenvl-2-carboxvlic acid A solution of 230 mg (0.44 mmol) of tert.butyl-4(2-npropy1-4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazoll-yl) -methyl]-biphenyl-2-carboxylate and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane was stirred overnight at ambient temperature and then evaporated to dryness. The residue was dissolved in about 5 ml of dilute sodium hydroxide solution, the solution was neutralised with acetic acid, the precipitate was suction filtered, washed with water and dried.
Yield: 120 mg (59% of theory); Melting point: 293-295°C Rf value: 0.39 (silica gel; methylene chloride/methanol = 9:1) The following compounds are obtained analogously to Example 75: 4'-[(2-n-propyl-4-methyl-6-(l-ethyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propy1-4-methyl-6-(l-n-hexyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid - 107 4’-[(2-n-propy1-4-methy1-6-(l-benzyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propyl-4-methyl-6-(l-isopropyl-imidazol-4-y1)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propyl-4-methyl-6-(l-cyclohexyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Example 76 4'-[(2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazol-l-yl)methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 24% of theory, Melting point: 255-257’C Rf-value: 0.24 (silica gel; methylene chloride/methanol = 9:1) c29h28N8 x H2° (506.62) Calculated: C 68.75 H 5.97 N 22.12 Found: 68.90 5.97 22.03 The following compounds are obtained analogously to Example 76: 4(2-n-propy1-4-methyl-6-(l-ethyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[(2-n-propyl-4-methyl-6-(l-n-hexyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4·-[(2-n-propy1-4-methyl-6-(1-benzyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid - 108 4'-[(2-n-propy1-4-methy1-6-(1-isopropyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[(2-n-propyl-4-methyl-6-(l-cyclohexyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 77 4'-[2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(1Htetrazol-5-vl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-ethyl-4methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2yl)-benzimidazol-l-yl)methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 21% of theory Melting point: amorphous Rf-value: 0.27 (silica gel; methylene chloride/ethanol = 9:1) C3,H3ONg (514.64) Calculated: C 72.35 H 5.88 N 21.78 Found: 72.01 5.82 21.44 Example 78 4' - [(2-n-Propy1-4-methy1-6-(8-methyl-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propyl-4-methyl-6-(8-methyl-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride. - 109 Yield: 87% of theory Melting point: 295-297 °C Rf-value: 0.34 (silica gel; methylene chloride/ethanol = 9:1) C33H30N4O2 X H20 (532.65) Calculated: C 74.41 H 6.05 N 10.52 Found: 74.81 6.05 10.43 Example 79 4'-[(2-n-Propy1-4-methy1-6-(2-pyridyl)-benzimidazol-lyl) -methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyΓ 4-methyl-6-(2-pyridyl)-benzimidazol-l-yl)-methyl]-2cyano-biphenyl and sodium azide in dimethylformamide. Yield: 56% of theory, Melting point: from 136°C (decomp.) C30H27N7 X 0.5 H2O (494.60) Calculated: C 72.85 H 5.71 N 19.83 Found: 72.45 6.01 19.83 Example 80 4'-[(2-n-Propy1-4-methyl-6-(8-methyl-imidazo[1,2a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(1Htetrazol-5-vl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl 4-methy1-6-(8-methyl-imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 19% of theory, Melting point: amorphous Rf-value: 0.36 (silica gel; methylene chloride/ethanol = 9:1) C33H3ON8 (53 8.61) mass spectrum: m/e = 538 - 110 Example 81 4'-((2-Ethy1-4-methy1-6-(5,6,7,8-tetrahydro-imidazo[1,2a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2carboxvlic acid Prepared analogously to Example 1 from tert.butyl 4z-(2ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 50% of theory, Melting point: > 300°C Rf-value: 0.16 (silica gel; methylene chloride/ethanol = 9:1) Example 82 4'-[(2-n-Propyl-4-methyl-6-(l-isopropyl-iraidazol-4-yl)benzimidazol-l-vl)-methyl]-biphenvl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propyl-4-methyl-6-(l-isopropyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 84% of theory, Melting point: 285-286*C Rf-value: 0.55 (silica gel; methylene chloride/methanol = 9:1) - Ill Example 83 4'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)benzimidazol-l-yl)-methyl1-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl4-methyl-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-lyl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 18% of theory Melting point: amorphous Rf-value: 0.29 (silica gel; methylene chloride/methanol = 9:1) C31H32N8 (516.66) Mass spectrum: m/e = 516 Example 84 4'-[(2-n-Propyl-4-methyl-6-(l-n-hexyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propy1-4-methyl-6-(l-n-hexyl-imidazol-4-y1) benzimidazol-l-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride.
Example 85 4'-[(2-n-Propy1-4-methy1-6-(1-benzyl-imidazo1-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'[(2-n-propy1-4-methyl-6-(l-benzyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride. - 112 Example 86 4'-[(2-n-Propyl-4-methyl-6-(l-n-hexyl-imidazol-4-yl)benzimidazol-l-yl)-methyl1-2-(lH-tetrazol-5-vl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl4-methyl-6-(l-n-hexyl-imidazol-4-yl)-benzimidazol-l-yl)methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Example 87 4'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-y1)benzimidazol-l-yl)-methvl1-2-(lH-tetrazol-5-vl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl4-methyl-6-(l-benzyl-imidazol-4-yl)-benzimidazol-l-yl)methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide. - 113 In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I, particularly those compounds wherein R4 represents a carboxy- or 1Htetrazolyl group, may be used as the active substance: Example 1 Ampoules containing 50 mg of active substance per 5 ml Composition: Active substance 50 mg KH2PO4 2 mg Na2HPO4 x 2H2O 5 0 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 Composition: Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene- glycol block polymer 250 mg Water for injections ad 5 ml - 114 Preparation: Methyl glucamine is dissolved in some of the water and the active substance is dissolved with stirring and heating. After the addition of solvents (glycolfurol and polyethyleneglycol - polypropyleneglycol block copolymer), water is added to make up the desired volume.
Example III Tablets containing 50 mg of active substance Composition: Active substance 50.0 mg Calcium phosphate 70.0 mg Lactose 40.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 1.5 mq 200.0 mg Preparation: The active substance, CaHPO4, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50°C in a circulating air dryer and screened again.
After the lubricant (magnesium stearate) has been added, the granules are compressed in a tablet making machine. - 115 Example IV Coated tablets containing 50 mg of active substance Composition: Active substance 50.0 mg Lysine 25.0 mg Lactose 60.0 mg Corn starch 34.0 g Gelatin 10.0 mg Magnesium stearate 1.0 mq 180.0 mg Preparation: The active substance is mixed with the excipients and moistened with an agueous 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 Composition: 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 - 116 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 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.
Example VI Capsules containing 250 mg of active substance Composition: 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. - 117 Example VII Oral suspension containing 50 mg of active substance per 5 ml Composition: 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. With the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and active substance are added. The suspension is evacuated with stirring to remove any air. One dose of 50 mg is contained in 5.0 ml.
Example VIII Suppositories containing 100 mg of active substance Composition: Active substance Solid fat (e.g. lard) 100.0 mg 1600.0 mq 1700.0 mg - 118 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 (15)
1. Compounds of formula (wherein R, in the 4-position represents a fluorine, chlorine or bromine atom or a C M -alkyl, cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group, and R 2 represents a C 3 .j-alkoxy group substituted in the 3-, 4— or 5-position by an imidazolyl group, or R 2 may represent a C 2 . 5 -alkoxy group substituted in the 2-, 3-, 4— or 5-position by a benzimidazolyl or tetrahydrobenzimidazolyl group, or R 2 represents a C M -alkylsulphonyloxy group, a benzenesulphonyloxy or phenylalkanesulphonyloxy group, an acylamino group optionally substituted at the nitrogen atom by a C^-alkyl group or by a phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenyl group, in which the acyl group is a C,_ 7 alkanoyl group, a C 2j , (alkoxy carbonyl) group, a C M alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenylalkanesulphonyl, naphthalenesulphony1, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl group, in which the above-mentioned phenyl nuclei may - 120 each be mono- or di-substituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group and the substituents may be identical or different, a phthalimino, homophthalimino, 2-carboxyphenylcarbonylamino or 2-carboxyphenylmethylamino group, in which a carbonyl group in a phthalimino group may be replaced by a methylene, alkyl-methylene or dialkyl-methylene group, and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups, and additionally the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, whilst the substituents may be identical or different and may be totally or partially hydrogenated, a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, in which a methylene group may be replaced by a carbonyl or sulphonyl group, a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene moieties may each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and may have an endomethylene group replaced by an oxygen atom, an amidino group optionally substituted by one or two C,^ alkyl groups, a glutaric acid imino group wherein the n-propylene group may be perfluorinated, or may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, a maleic acid imido group optionally mono- or diIE 920373 - 121 substituted by an alkyl or phenyl group, whilst the substituents may be identical or different, a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group and containing an imino group, an oxygen or sulphur atom, or an imino group plus an oxygen, sulphur or nitrogen atom, or R 2 may represent a 6-membered heteroaromatic ring bound via a carbon atom and containing 1 or 2 nitrogen atoms, whilst the abovementioned heteroaromatic rings may be substituted in the carbon structure by a C,^ alkyl or by a phenylalkyl group, and an n-propylene or n-butylene group may be linked to the 6-membered heteroaromatic rings via two carbon atoms, or a 1,3-butadienyl group may be linked to both the 5-membered and 6-membered heteroaromatic rings via two adjacent carbon atoms or an n-butylene or 1,3-butadienyl group is linked thereto via an imino group and an adjacent carbon atom and, in an anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene group in the 3—, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or in an anellated phenyl ring thus formed, one or two methine groups may be replaced by N-atoms, whilst additionally the above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted in the carbon structure by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylaraino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylaminosulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and two methyl substituents in the 1,2-position relative to each other may be linked by a methylene or ethylene bridge and an - 122 -NH- group optionally present in an imidazole ring may be substituted by a C^-alkyl group, by a phenylalkyl group or by a cycloalkyl group, or a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, in which a phenyl group may be condensed onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, an imidazolidinedione group optionally substituted by an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, a pyridazin-3-one or dihydro-pyridazin-3-one group which may be substituted in the 2-position by an optionally phenyl substituted alkyl group and additionally, in the carbon skeleton, by 1 or 2 alkyl groups, an R 7 —NR^—CO—NRj— group (wherein R 5 represents a hydrogen atom or a C,_ g -alkyl, C 5 . 7 cycloalkyl or phenylalkyl group, R^ represents a hydrogen atom or a C,. 8 -alkyl, C 3 . 5 -alkenyl, phenyl, phenylalkyl or C 5 . 7 -cycloalkyl group, R 7 represents a hydrogen atom or a C 1 . 6 -alkyl group, or one of the groups R s , Rj or R 7 may also represent a bicyclohexyl or biphenylyl group, or R6 and R 7 together with the nitrogen atom between them represent an unbranched C 4 . 6 -a Iky lene imino group or a - 123 morpholino group, or Rj and Rj; together represent a C-^-alkylene group), or R 2 may represent a 1H,3H-quinazolin-2,4-dion-3-yl or pentamethylene-oxazolin-2-yl group, or, if R4 represents a ΙΗ-tetrazolyl group, R 2 may also represent a 2-(imidazol-l-yl)-ethoxy group; or Rj represents a hydrogen atom or in the 5-, 6- or 7position Rj represents a fluorine, chlorine or bromine atom or a C,^-alkyl, fluoromethyl, difluoromethyl or trifluoromethyl group, and R 2 represents a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group and containing an imino group, an oxygen or sulphur atom or, an imino group plus an oxygen, sulphur or nitrogen atom, or R 2 represents a 6-membered heteroaromatic ring bound via a carbon atom and containing 1 or 2 nitrogen atoms, whilst the above mentioned heteroaromatic rings may be substituted in the carbon skeleton by a Cj. 6 alkyl or by a phenylalkyl group and an n-propylene or n-butylene group may be linked to the 6-membered heteroaromatic rings via two carbon atoms, or a 1,3-butadienyl group may be linked via two adjacent carbon atoms to both the 5membered and 6-membered heteroaromatic rings or an nbutylene or 1,3-butadienyl group may be linked to said 5-membered and 6-membered heteroaromatic rings via an imino group and an adjacent carbon atom and, in an anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene group in the 3—, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or in an anellated phenyl ring thus formed, one or two methine groups may be replaced by N-atoms, whilst - 124 additionally the above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted on the carbon skeleton by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylamino-sulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and two methyl substituents in the 1,2-position relative to each other may be linked by a methylene or ethylene bridge and an NH- group optionally present in an imidazole ring may be substituted by a C^-alkyl group, by a phenylalkyl group or by a cycloalkyl group, with the provisos that where (i) R, represents a hydrogen atom, R 3 represents an nbutyl group and R 4 represents a carboxy group, then R 2 cannot represent a benzimidazol-2-yl group in the 6-position, and where (ii) Rj represents a hydrogen atom, R 3 represents an npropyl group and R4 represents a carboxy group, then R 2 cannot represent a 3-methylimidazo[4,5-b]pyridin-2-yl or 3-n-hexylimidazo[4,5-b]pyridin-2-yl group in the 6position, and where (iii) R, represents a hydrogen atom, R 3 represents an npropyl or n-butyl group and R 4 represents a 1Htetrazolyl group, then R 2 cannot represent a benzoxazol-2-yl group in the 5- or 6-position, and where (iv) Rj represents a hydrogen atom, R 3 represents an npropyl group and R,, represents a carboxy group, - 125 then R 2 cannot represent a 1-methylbenzimidazol-2yl group in the 5- or 6-position and cannot represent a l-n-butyl-benzimidazol-2-yl, 1,5dimethylbenzimidazol-2-yl or l-methyl-5trifluoromethyl-benzimidazol-2-yl group in the 6position, and where (v) Rj represents a hydrogen atom, R 3 represents an nbutyl group and Rj represents a carboxy or 1Htetrazolyl group, then R 2 cannot represent a 1methylbenzimidazol-2-yl group in the 6-position, or R 2 may represent a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, in which a phenyl group may be condensed onto the pyridine ring via 2 adjacent carbon atoms and a methylene group adjacent to the Natom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group; R 3 represents a hydrogen atom or a C^-alkyl group in which a methylene group may be replaced by a sulphur atom, or R 3 may represent a C 3 . 5 cycloalkyl group; and R4 represents a carboxy, cyano, ΙΗ-tetrazoly1, 1triphenylmethyltetrazolyl, C 2 . 5 (alkoxycarbonyl) , alkanesulphonylaminocarbonyl, arylsulphonylaminocarbonyl or trifluoromethanesulphonylaminocarbonyl group; wherein, unless otherwise specified, each alkanoyl, alkyl or alkoxy moiety contains 1 to 3 carbon atoms and each cycloalkyl moiety contains 3 to 7 carbon atoms) and the isomers, isomer mixtures and addition salts thereof.
2. Compounds of general formula I as claimed in claim - 126 (wherein Rj in the 4-position represents a fluorine, chlorine or bromine atom, a C,. 3 -alkyl group or a cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl group, and R 2 represents a C 3 . 5 -alkoxy group substituted in the 3-, 4- or 5-position by an imidazolyl group, or R 2 represents a C 2 . 5 -alkoxy group substituted in the 2-, 3-, 4- or 5position by a benzimidazolyl or tetrahydrobenzimidazolyl group, an acylamino group optionally substituted at the nitrogen atom by a C 1 . J -alkyl group, wherein the acyl group is a C 2 . 7 -alkanoyl group, a C 2 ^(alkoxycarbonyl) group, a C 13 -alkylsulphonyl group or a benzenesulphonyl group, a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene in a homophthalimino group may be substituted by one or two alkyl groups, a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group, optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, wherein a methylene group may be replaced by a carbonyl or sulphonyl group, a glutaric acid imino group wherein the n-propylene group may be perfluorinated, or may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, a maleic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the - 127 substituents may be identical or different, an amidino group optionally substituted by one or two C 14 alkyl groups, a benzimidazol-2-yl group optionally substituted in the 1- position by Cj. 6 -alkyl or a cycloalkyl group and optionally substituted in the phenyl nucleus by a fluorine atom or by a methyl or trifluoromethyl group, or R 2 represents an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin2- yl, imidazo[l,2-b]-pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or a carbon attached pyrrolidine, piperidine or pyridine ring in which a phenyl group may be condensed onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, a carbon attached imidazolyl group optionally substituted in the 1-position by a C,. 3 -alkyl group or by a benzyl group, and which may also be substituted in the carbon skeleton by a C,. 3 -alkyl group, an imidazolidindione group optionally substituted by an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, a pyridazin-3-one or dihydro-pyridazin-3-one group which may be substituted in the 2-position by a methyl or benzyl group, - 128 an Rj-NRt-CO-NRj- group (wherein R 5 represents a hydrogen atom, a C,. 5 -alkyl group, a cyclohexyl or benzyl group, R 6 represents a hydrogen atom, a C 16 -alkyl group, an allyl, cyclohexyl, benzyl or phenyl group, R 7 represents a hydrogen atom or a C,. 3 -alkyl group or Rg and R 7 together with the nitrogen atom between them represent an unbranched C 4 . 6 -alkyleneimino group or a morpholino group or R 5 and Rg together represent a C 2 . 3 -alkylene group) ; or R, represents a hydrogen atom or in the 5-, 6- or 7position R, represents a fluorine, chlorine or bromine atom or a C M -alkyl or a trifluoromethyl group, and R 2 represents a benzimidazol-2-yl group optionally substituted in the l-position by a C,. 6 -alkyl group or by a cycloalkyl group, and optionally substituted in the phenyl nucleus by a fluorine atom or by a methyl or trifluoromethyl group, or R 2 represents an imidazo[2,1-b]thiazol-6-yl, imidazofl,2-a]pyridin-2-yl, 5,6,7,8-tetrahydroimidazo [1,2-a]pyridin-2-y1, imidazo[1,2-a]pyrimidin-2yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2 yl, imidazo[1,2-c]pyrimidin-2-yl, imidazof1,2-a]pyrazin· 2-yl, imidazofl,2-b]-pyridazin-2-yl, imidazof4,5-c]pyridin-2-yl, purin-8-yl, imidazof4,5-b]pyrazin-2-yl, imidazof4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or a carbon attached pyrrolidine, - 129 piperidine or pyridine ring in which a phenyl group may be condensed onto the pyridine ring via 2 adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or a carbon attached imidazolyl group optionally substituted in the 1position by a Cj_ 3 alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a Cj_ 3 alkyl group, with the proviso that where (i) R, represents a hydrogen atom, R 3 represents an nbutyl group and R, represents a carboxy group, then R 2 cannot represent a benzimidazol-2-yl group in the 6-position; R 3 represents a Cj. 5 -alkyl group or a C 3 _ 5 -cycloalkyl group; and R4 represents a carboxy or ΙΗ-tetrazolyl group; wherein, unless otherwise specified, each alkanoyl, alkyl or alkoxy moiety contains 1 to 3 carbon atoms and each cycloalkyl moiety contains 3 to 7 carbon atoms) and the isomers, isomer mixtures and addition salts thereof.
3. Compounds of formula I as claimed in claim 1, (wherein R, in the 4-position represents a chlorine atom, or a C,. 3 -alkyl or a trifluoromethyl group, and R 2 represents a C 3 . 5 -alkoxy group substituted in the 3-, 4. - or 5-position by an imidazolyl group, or R 2 represents a C 2 . 5 -alkoxy group substituted in the 2-, 3-, 4- or 5position by a benzimidazolyl or tetrahydrobenzimidazolyl - 130 group, a C 25 (alkanoyl) amino or N-benzenesulphonyl-methylamino group, a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group, a 5-, 6- or 7-membered alkyleneimino group wherein a methylene group is replaced by a carbonyl or sulphonyl group, a glutaric acid imino group wherein the n-propylene group may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, a maleic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl group optionally substituted in the 1- position by a C b6 -alkyl group or by a cycloalkyl group, and optionally substituted in the phenyl nucleus by a fluorine atom or by a methyl or trifluoromethyl group, or R 2 represents an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin2- yl, imidazo[1,2-b]-pyridazin-2-y1, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or a carbon attached pyrrolidine, piperidine or pyridine ring in which a phenyl group may be condensed onto the pyridine - 131 ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or R 2 represents an imidazol-4-yl group substituted in the 1-position by a C,. 3 alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a C,_ 3 alkyl group, a pyridazin-3-one or dihydro-pyridazin-3-one group which may be substituted in the 2-position by a methyl or benzyl group, an R 7 —NRg—CO—NR 5 — group (wherein R 5 represents a hydrogen atom or a C^-alkyl, cyclohexyl or benzyl group, Rg represents a hydrogen atom, a C,_g-alkyl group or an allyl, cyclohexyl, benzyl or phenyl group, R 7 represents a hydrogen atom or a C 13 -alkyl group or Rg and R 7 together with the nitrogen atom between them represent an unbranched C 4 _g-alkyleneimino group or a morpholino group or Rj and Rg together represent a C 2 . 3 -alkylene group) ; or Rj represents a hydrogen atom or in the 5-, 6- or 7position R, represents a C lJt -alkyl group or a trifluoromethyl group, and R 2 represents a benzimidazol-2-yl group optionally substituted in the 1-position by a C,. 6 -alkyl group or by - 132 a cycloalkyl group and optionally substituted in the phenyl nucleus by a fluorine atom or by a methyl or trifluoromethyl group, or R 2 represents an imidazo[2,l-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydroimidazofl,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin2-yl, imidazo[1,2-b]-pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin2-yl group, or a carbon attached pyrrolidine, piperidine or pyridine ring in which a phenyl group may be condensed onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or an imidazol-4-yl group substituted in the 1-position by a C,. 3 alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a Cj_ 3 alkyl group, with the proviso that where (i) Rj represents a hydrogen atom, R 3 represents an nbutyl group and R4 represents a carboxy group, then R 2 cannot represent a benzimidazol-2-yl group in the 6-position; R 3 represents a Cj.j-alkyl group or a C 3 _ 5 -cycloalkyl group; and R4 represents a carboxy or ΙΗ-tetrazolyl group; wherein, unless otherwise specified, each alkanoyl, alkyl or alkoxy moiety contains l to 3 carbon atoms and each cycloalkyl moiety contains 3 to 7 carbon atoms) and the isomers, isomer mixtures and addition salts - 133 thereof.
4. Compounds of formula I as claimed in claim 1, (wherein R, in the 4-position represents a chlorine atom or a methyl group, and R 2 represents a C 3 . 5 -alkoxy group substituted in the 3-, 4- or 5-position by an imidazolyl group, or R 2 represents a C 2 . 5 -alkoxy group substituted in the 2-, 3-, 4- or 5position by a benzimidazolyl or tetrahydrobenzimidazolyl group, a C 2 . 5 (alkanoyl)amino group or N-benzenesulphonylmethylamino group, a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group, a 5-, 6- or 7-membered alkyleneimino group, wherein a methylene group is replaced by a carbonyl or sulphonyl group, a maleic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the substituents may be identical or different, a benzimidazol-2-yl group optionally substituted in the 1-position by a C^-alkyl group and optionally substituted in the phenyl nucleus by a fluorine atom, or R 2 represents an imidazo[1,2-a]-pyridin-2-yl group,
5. ,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl, imidazof1,2-a]pyrimidin-2-yl or imidazo[2,1-b]thiazol-6IE 920373 - 134 yl group, an imidazol-4-yl group substituted in the l-position by a C,_ 3 alkyl group, a pyridazin-3-one or dihydro-pyridazin-3-one group which may be substituted in the 2-position by a methyl or benzyl group; or R, represents a hydrogen atom or in the 5-, 6- or 7position R, represents a methyl group, and R 2 represents a benzimidazol-2-yl group optionally substituted in the 1-position by a C,. 3 -alkyl group, and optionally substituted in the phenyl nucleus by a fluorine atom, or R 2 represents an imidazo[1,2-a]pyridin-2-yl group, an imidazol-4-yl group substituted in the 1-position by a C,_ 3 alkyl group, with the proviso that where (i) Rf represents a hydrogen atom, R 3 represents an nbutyl group and R, represents a carboxy group, then R 2 cannot represent a benzimidazol-2-yl group in the 6. -position; R 3 represents a C,_ 5 -alkyl group or a C 3 . 5 -cycloalkyl group; and R, represents a carboxy or ΙΗ-tetrazolyl group; wherein, unless otherwise specified, each alkanoyl, alkyl or alkoxy moiety contains 1 to 3 carbon atoms and each cycloalkyl moiety contains 3 to 7 carbon atoms) and the isomers, isomer mixtures and addition salts thereof. - 135 5. A compound as claimed in claim 1 being: 4'-[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; (b) 4'-[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-propy1-4-methy1-6-(l-oxo-isoindolin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-propyl-4-methyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4 z -[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-[[2-n-butyl-6-(isopropylcarbonylamino)-4-methylbenzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid; 4'-[[2-n-buty1-4-methyl-6-(morpholinocarbonylamino)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4 z - [[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4methy1-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid; 4 z -[(2-cyclopropy1-4-methy1-6-(1-methylbenzimidazol-2yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; 4 z -[(2-n-propy1-4-methyl-6-(1-methy1-5-fluorobenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenylIE 920373 - 136 2-carboxylic acid; 4'-[(2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2yl)-benzimidazol-l-yl)-methyl J-2-(lH-tetrazol-5-yl)biphenyl; 4'-[(2-n-propyl-4-methyl-6-(4,5,6,7-tetrahydroimidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid; 4'-[(2-n-propyl-4-methyl-6-(4 ,5,6,7-tetrahydroimidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]2 —(lH-tetrazol-5-yl)-biphenyl; 4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4 f — [[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-[[2-ethyl-4-methyl-6-(butanesultam-l-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-butyl-4-methy1-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-propyl-6-(imidazo[l,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid; 4'-[[2-n-propy1-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)IE 920373 - 137 benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; 4'-[[2-n-propy1-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)benzimidazol-1-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl; and 4·-[(2-n-propy1-4-methy1-6-(1-methy1-6-fluorobenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl2-carboxylic acid; or an isomer, isomer mixture or addition salt thereof.
6. A pharmaceutical composition containing a compound of formula I according to any one of claims 1 to 5 or a physiologically acceptable addition salt thereof together with one or more inert carriers or diluents.
7. A process for preparing the compounds as claimed in any one of claims 1 to 5, said process comprising at least one of the following steps: a) cyclising compound of formula II (wherein R, and R 2 are as defined in any one of claims 1 to 5, one of the groups X, or Y, represents a group of formula H(a) - 138 - 11(a) and the other group Xj or Y, represents a group of the formula 11(b) Z, Z 2 H(b) x z - NH - C - R 3 (wherein R 2 and R4 are as defined in claims 1 to 5, R g represents a hydrogen atom or an R 3 CO- group, R 3 is as defined in any one of claims 1 to 5, Z t and Z 2 , which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups or Ζγ and Z 2 together represent an oxygen or sulphur atom, an optionally C]. 3 -alkyl substituted imino group, an alkylenedioxy or alkylenedithio group, each having 2 or 3 carbon atoms)) and any corresponding N-oxide thus obtained is reduced; b) reacting a compound of formula III - 139 (wherein Rj to R 3 are as defined in any one of claims 1 to 5) , with a biphenyl compound of formula IV (wherein R, is as defined in any one of claims 1 to 5, and Z 3 represents a nucleophilic leaving group); c) (to prepare compounds of formula I wherein R, represents a carboxy group) converting a compound of formula V (wherein R, to R 3 are as defined in any one of claims 1 to 5, and R,' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound; d) (to prepare compounds of formula I wherein R 4 represents a ΙΗ-tetrazolyl group) cleaving a protecting group from a compound of formula VI 140 (VI) (wherein R t , R 2 and R 3 are as defined in any one of claims 1 to 5; and R4 represents a ΙΗ-tetrazolyl group protected in the 1- or 3-position by a protecting group); e) (to prepare compounds of formula I wherein R 4 represents a ΙΗ-tetrazolyl group) reacting a compound of formula VII (wherein R, to R 3 are as defined in any one of claims 1 to 5) with hydrazoic acid or a salt thereof; f) (to prepare compounds of formula I wherein R 2 represents one of the imidazof1,2-a]-pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-c]-pyrimidin2-yl, imidazo(l,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl or imidazo[2,1-b]thiazol-6-yl groups mentioned in any one of claims 1 to 5) reacting a compound of formula VIII (wherein one of the groups A, B, C or D represents a methine group or a nitrogen atom and the remaining groups A, B, C or D represent methine groups, or A and B each represent methine and the -C=D- moiety represents a sulphur atom, Rj represents a hydrogen, fluorine, chlorine or bromine atom or an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylaminosulphonyl group, and R I0 represents a hydrogen, fluorine or chlorine atom or a methyl, methoxy or hydroxy group; or R, and R 10 attached at adjacent ring positions together represent a propylene or n-butylene group) with a compound of formula IX (wherein R,, R 3 and R, are as defined in any one of claims 1 to 5 and Z 4 represents a nucleophilic leaving group); - 142 g) (to prepare compounds of formula I wherein R 2 represents one of the benzimidazol-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[4, 5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2yl, imidazo[4,5-d]pyridazin-2-yl or purin-8-yl groups mentioned in any one of claims 1 to 5) cyclising a compound of formula X (X) (wherein none, one or two of the groups A lz B,, C, or D, represents a nitrogen atom and the remaining groups A,, B,, C, or D, represent methine groups; R n represents a hydrogen, fluorine, chlorine or bromine atom or an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylarainosulphonyl or dialkylaminosulphonyl group; and R I2 represents a hydrogen, fluorine or chlorine atom or a methyl, methoxy or hydroxy group; one of the groups X 2 or Y 2 represents an R 13 -NH- group and the other X 2 or Y 2 group represents a group of formula X(a) (wherein R 1; R 3 and R, are as defined in any one of claims 1 to 5; one of the groups R l3 or R 14 represents a hydrogen atom and the other R, 3 or R 14 group represents a hydrogen atom, a Cj-g-alkyl group or a cycloalkyl group; Z 5 and Z 6 , which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups or Z 5 and Z 6 together represent an oxygen or sulphur atom, an optionally C^-alkyl substituted imino group, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms)), and reducing any corresponding N-oxide thus obtained, and optionally hydrolysing the resulting product; h) (to prepare compounds of formula I wherein R 2 represents a dihydro-pyridazin-3-one or pyridazin-3-one group which may be substituted in the 2-position by a Cj^-alkyl group optionally substituted by a phenyl group, or in the carbon structure by one or two alkyl groups each having 1 to 3 carbon atoms) reacting a carboxylic acid of formula XII 144 H00C-E-C0 (χιι) (wherein Ri, R 3 and R 4 are as defined in any one of claims 1 to 5; and E represents an ethylene or ethenylene group optionally substituted by one or two C,. 3 alkyl groups) , or a reactive acid derivative thereof, with a hydrazine of formula XIII H 2 N - NHR,5 (XIII) (wherein R 15 represents a hydrogen atom or a C^-alkyl group optionally substituted by a phenyl group); i) performing the reaction of any one of steps (a) to (h) using a starting material wherein a reactive group is portected by a protecting group and subseguently removing any protecting group used; j) resolving an isomer mixture into the separate component isomers; k) converting a compound of formula I into an addition salt thereof or converting a salt of a compound of formula I into the compound.
8. Use of a compound of formula I as defined in any one of claims 1 to 5 or an isomer or physiologically acceptable salt thereof for the manufacture of a therapeutic composition with an angiotensin antagonistic activity. - 145
9. Use of a compound of formula I as defined in any one of claims 1 to 5 or an isomer or physiologically acceptable salt thereof for the manufacture of a therapeutic composition to treat hypertension, pulmonary diseases, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic nephropathy, glaucoma, gastrointestinal and bladder diseases or to prevent the progression of cardiac insufficiency after myocardial infarction.
10. Use of a compound of formula I as defined in any one of claims 1 to 5 or an isomer or physiologically acceptable salt thereof for the manufacture of a therapeutic composition to treat depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function as well as other central nervous system disorders.
11. A method of treatment of the human or non-human animal body said method comprising administering to said body a pharmaceutically acceptable form of a compound of formula I as defined in any one of claims l to 5 or an isomer or salt thereof.
12. A method of treatment as claimed in claim 11 wherein said body is suffering from hypertension, pulmonary diseases, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic nephropathy, glaucoma, gastrointestinal or bladder diseases or cardiac insufficiency after myocardial infarction.
13. A method of treatment as claimed in claim 11, wherein said body is suffering from depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function or other central nervous system disorders. - 146
14. A compound as claimed in any one of claims 1 to 5 substantially as disclosed in any one of the Examples.
15. Each and every novel compound, composition, process, method and use as herein disclosed.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4103492A DE4103492A1 (en) | 1991-02-06 | 1991-02-06 | New 1-(1,4-bi:phenyl-methyl) benzimidazole(s) as angiotensin II antagonists |
| DE4117121A DE4117121A1 (en) | 1991-02-06 | 1991-05-25 | BENZIMIDAZOLE, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| DE4137812A DE4137812A1 (en) | 1991-02-06 | 1991-11-16 | New 1-(1,4-bi:phenyl-methyl) benzimidazole(s) as angiotensin II antagonists |
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| IE920373A1 true IE920373A1 (en) | 1992-08-12 |
| IE81111B1 IE81111B1 (en) | 2000-03-08 |
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| JP (1) | JP2709225B2 (en) |
| AT (1) | ATE166346T1 (en) |
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| CA (1) | CA2060624C (en) |
| CH (1) | CH0502314H1 (en) |
| CZ (1) | CZ287607B6 (en) |
| DE (2) | DE59209330C5 (en) |
| DK (1) | DK0502314T3 (en) |
| ES (1) | ES2118095T4 (en) |
| FI (1) | FI105547B (en) |
| HK (1) | HK1011145A1 (en) |
| HR (1) | HRP940752B1 (en) |
| HU (2) | HU217084B (en) |
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| LU (3) | LU90372I2 (en) |
| MX (1) | MX9200509A (en) |
| NL (2) | NL990007I2 (en) |
| NO (3) | NO301585B1 (en) |
| NZ (1) | NZ241515A (en) |
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| US8691999B2 (en) | 2004-05-11 | 2014-04-08 | Cipla Limited | Process for the preparation of telmisartan |
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| 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 |
| DE4225756A1 (en) | 1992-01-22 | 1994-03-10 | Thomae Gmbh Dr K | Benzimidazoles, medicaments containing these compounds and process for their preparation |
| TW274551B (en) * | 1991-04-16 | 1996-04-21 | Takeda Pharm Industry Co Ltd | |
| DE4207904A1 (en) * | 1992-03-12 | 1993-09-16 | Thomae Gmbh Dr K | SUBSTITUTED BENZIMIDAZOLYL DERIVATIVES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| US5972990A (en) † | 1992-04-10 | 1999-10-26 | Brigham And Women's Hospital, Inc. | Methods for reducing risk of repeat myocardial infarction and increasing survival in heart attack victims |
| GB9218449D0 (en) | 1992-08-29 | 1992-10-14 | Boots Co Plc | Therapeutic agents |
| DE4315349A1 (en) * | 1992-10-06 | 1994-11-10 | Thomae Gmbh Dr K | Benzimidazoles, medicaments containing these compounds and process for their preparation |
| JP3057471B2 (en) | 1993-06-07 | 2000-06-26 | 武田薬品工業株式会社 | Agent for preventing or treating angiotensin II-mediated diseases |
| DE4408497A1 (en) * | 1994-03-14 | 1995-09-21 | Thomae Gmbh Dr K | Benzimidazoles, medicaments containing these compounds and process for their preparation |
| MY119312A (en) * | 1995-10-06 | 2005-05-31 | Novartis Ag | At 1-receptor antagonists for preventing and treating postischemic renal failure and for protecting ischemic kidneys |
| TW453999B (en) * | 1997-06-27 | 2001-09-11 | Fujisawa Pharmaceutical Co | Benzimidazole derivatives |
| AU742506B2 (en) * | 1997-10-17 | 2002-01-03 | Eurogene Limited | The use of inhibitors of the renin-angiotensin system |
| AU1042199A (en) * | 1998-11-06 | 2000-05-29 | Boehringer Ingelheim International Gmbh | Antihypertensive medicaments containing lacidipine and telmisartan |
| CN1636561A (en) * | 1998-12-23 | 2005-07-13 | 诺瓦提斯公司 | Use of at-1 receptor antagonist for treating diseases associated with an increase of at-1 receptors |
| EP1013273A1 (en) * | 1998-12-23 | 2000-06-28 | Novartis AG | Use of AT-1 receptor antagonist or AT-2 receptor modulator for treating diseases associated with an increase of AT-1 or AT-2 receptors |
| US6358986B1 (en) | 1999-01-19 | 2002-03-19 | Boehringer Ingelheim Pharma Kg | Polymorphs of telmisartan |
| DE19901921C2 (en) * | 1999-01-19 | 2001-01-04 | Boehringer Ingelheim Pharma | Polymorphs of telmisartan, process for their preparation and their use in the manufacture of a medicament |
| SE9903028D0 (en) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| PE20020617A1 (en) | 2000-08-22 | 2002-08-05 | Novartis Ag | COMPOSITION INCLUDING AN AT1 RECEPTOR ANTAGONIST AND AN INSULIN SECRETION POTENTIAL OR AN INSULIN SENSITIZER |
| DE10153737A1 (en) * | 2001-10-31 | 2003-05-28 | Boehringer Ingelheim Pharma | Crystalline sodium salt of telmisartan, process for its preparation and its use for the manufacture of a medicament |
| US6737432B2 (en) | 2001-10-31 | 2004-05-18 | Boehringer Ingelheim Pharma Kg | Crystalline form of telmisartan sodium |
| KR100876302B1 (en) † | 2002-01-16 | 2008-12-31 | 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 | Method for preparing telmisartan, which is in fact amorphous form |
| EG24716A (en) | 2002-05-17 | 2010-06-07 | Novartis Ag | Combination of organic compounds |
| DE10335027A1 (en) | 2003-07-31 | 2005-02-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of telmisartan and simvastatin for treatment or prophylaxis of cardiovascular, cardiopulmonary and renal diseases e.g. hypertension combined with hyperlipidemia or atherosclerosis |
| DE10306179A1 (en) | 2003-02-13 | 2004-08-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Composition useful for preventing stroke comprises dipyridamole or its salt, acetyl salicylic acid and an angiotensin II antagonist |
| DE10314702A1 (en) * | 2003-03-31 | 2004-10-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for the preparation of telmisartan |
| US9029363B2 (en) | 2003-04-30 | 2015-05-12 | Boehringer Ingelheim International Gmbh | Telmisartan sodium salt pharmaceutical formulation |
| DE10319450A1 (en) * | 2003-04-30 | 2004-11-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical formulation of telmisartan sodium salt |
| DE10319592A1 (en) * | 2003-05-02 | 2004-11-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Treatment of diabetic retinopathy with angiotensin II receptor blockers |
| US7732162B2 (en) | 2003-05-05 | 2010-06-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases |
| GB0316546D0 (en) | 2003-07-15 | 2003-08-20 | Novartis Ag | Process for the manufacture of organic compounds |
| US7829552B2 (en) | 2003-11-19 | 2010-11-09 | Metabasis Therapeutics, Inc. | Phosphorus-containing thyromimetics |
| MX2007004426A (en) * | 2004-10-15 | 2007-06-14 | Teva Pharma | Process for preparing telmisartan. |
| WO2006046593A1 (en) | 2004-10-27 | 2006-05-04 | Daiichi Sankyo Company, Limited | Benzene compound having 2 or more substituents |
| ITMI20050801A1 (en) | 2005-05-03 | 2006-11-04 | Dipharma Spa | PROCEDURE FOR THE PREPARATION OF TELMISARTAN |
| WO2006136916A2 (en) * | 2005-06-20 | 2006-12-28 | Glenmark Pharmaceuticals Limited | Substantially pure micronized particles of telmisartan and pharmaceutical compositions containing same |
| US7884214B2 (en) * | 2005-07-19 | 2011-02-08 | Matrix Laboratories Limited | Process for the preparation of Telmisartan |
| ES2246742B1 (en) * | 2005-09-06 | 2007-02-01 | Prous Institute For Biomedical Research S.A. | USE OF A DERIVATIVE OF IMIDAZOLE. |
| EP1908469A1 (en) | 2006-10-06 | 2008-04-09 | Boehringer Ingelheim Vetmedica Gmbh | Angiotensin II receptor antagonist for the treatment of systemic diseases in cats |
| US8242151B2 (en) | 2007-02-07 | 2012-08-14 | Kyowa Hakko Kirin Co., Ltd. | Tricyclic compounds |
| FR2916757B1 (en) * | 2007-05-30 | 2009-07-17 | Servier Lab | NOVEL DIAZENIUMDIOLATE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| US20100120694A1 (en) | 2008-06-04 | 2010-05-13 | Synergy Pharmaceuticals, Inc. | Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| US7879802B2 (en) | 2007-06-04 | 2011-02-01 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| TWI406850B (en) * | 2007-06-05 | 2013-09-01 | Theravance Inc | Dual-acting benzoimidazole antihypertensive agents |
| CN101743228B (en) * | 2007-07-03 | 2014-01-29 | 新梅斯托克尔卡托瓦纳兹德拉韦尔公司 | Process for preparing telmisartan |
| CA2705921A1 (en) * | 2007-12-11 | 2009-06-18 | Theravance, Inc. | Dual-acting benzoimidazole derivatives and their use as antihypertensive agents |
| US8445693B2 (en) | 2008-03-20 | 2013-05-21 | Lek Pharmaceuticals D.D. | Catalyzed carbonylation in the synthesis of angiotensin II antagonists |
| EP2103588A1 (en) | 2008-03-20 | 2009-09-23 | Lek Pharmaceuticals D.D. | 2'-Halobiphenyl-4-yl intermediates in the synthesis of angiotensin II antagonists |
| EP2103609A1 (en) | 2008-03-20 | 2009-09-23 | Lek Pharmaceuticals D.D. | Catalyzed carbonylation in the synthesis of angiotensin ii antagonists |
| WO2009123483A1 (en) | 2008-03-31 | 2009-10-08 | Zaklady Farmaceutyczne Polpharma Sa | Process for preparation of telmisartan |
| WO2009135646A2 (en) | 2008-05-05 | 2009-11-12 | Farmaprojects, Sa | Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale |
| EP2123648A1 (en) | 2008-05-20 | 2009-11-25 | Chemo Ibérica, S.A. | A process for the preparation of Telmisartan. |
| WO2010004385A1 (en) * | 2008-06-17 | 2010-01-14 | Aurobindo Pharma Limited | Process for the preparation of pure 4'-[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid |
| EP2149566A1 (en) | 2008-07-15 | 2010-02-03 | Chemo Ibérica, S.A. | A process for the preparation of telmisartan |
| ES2624828T3 (en) | 2008-07-16 | 2017-07-17 | Synergy Pharmaceuticals Inc. | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and others |
| WO2010016549A1 (en) | 2008-08-06 | 2010-02-11 | 協和発酵キリン株式会社 | Tricyclic compound |
| US20120046364A1 (en) | 2009-02-10 | 2012-02-23 | Metabasis Therapeutics, Inc. | Novel Sulfonic Acid-Containing Thyromimetics, and Methods for Their Use |
| SI2443094T1 (en) | 2009-06-19 | 2013-08-30 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of telmisartan |
| EP2277866A1 (en) | 2009-06-22 | 2011-01-26 | Inke, S.A. | Process for preparing telmisartan |
| WO2011002425A2 (en) | 2009-07-02 | 2011-01-06 | Bilgig Mahmut | Pharmaceutical composition increasing solubility and stability |
| WO2011002423A2 (en) | 2009-07-02 | 2011-01-06 | Mahmut Bilgic | Solubility enhancing pharmaceutical composition |
| TR200906506A2 (en) | 2009-08-24 | 2011-03-21 | Bi̇lgi̇ç Mahmut | Solid dosage forms containing telmisartan. |
| EP2305650A1 (en) | 2009-09-21 | 2011-04-06 | Chemo Ibérica, S.A. | Novel process for the preparation of telmisartan |
| CN101798300B (en) * | 2010-02-23 | 2013-09-25 | 陈志龙 | N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like |
| WO2011149438A1 (en) | 2010-05-28 | 2011-12-01 | Mahmut Bilgic | Combination of antihypertensive agents |
| WO2011161123A2 (en) | 2010-06-21 | 2011-12-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Multilayer pharmaceutical tablet comprising telmisartan and a diuretic |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| EA025946B1 (en) | 2010-10-27 | 2017-02-28 | Крка, Товарна Здравил, Д. Д., Ново Место | Multilayer pharmaceutical composition comprising telmisartan and amlodipine |
| AU2012303683B2 (en) | 2011-08-26 | 2016-09-08 | Wockhardt Limited | Methods for treating cardiovascular disorders |
| EP2612658A1 (en) | 2012-01-05 | 2013-07-10 | Laboratorios Lesvi, S.L. | Pharmaceutical compositions of 4'-[(1,4'dimethyl-2'-propyl[2,6'-bi-1h-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid and is 6-chloro-3,4-dihydro-2h-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide |
| AU2014235209B2 (en) | 2013-03-15 | 2018-06-14 | Bausch Health Ireland Limited | Guanylate cyclase receptor agonists combined with other drugs |
| CA2905438A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| EP3004138B1 (en) | 2013-06-05 | 2024-03-13 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| ES2806135T3 (en) | 2013-06-21 | 2021-02-16 | Zenith Epigenetics Ltd | New bicyclic bromodomain inhibitors |
| ES2661437T3 (en) | 2013-06-21 | 2018-04-02 | Zenith Epigenetics Corp. | New substituted bicyclic compounds as bromodomain inhibitors |
| EP3027604B1 (en) | 2013-07-31 | 2019-02-20 | Zenith Epigenetics Ltd. | Novel quinazolinones as bromodomain inhibitors |
| EP2979691A1 (en) | 2014-07-30 | 2016-02-03 | Boehringer Ingelheim International GmbH | Oral disintegrating tablet |
| EP3227281A4 (en) | 2014-12-01 | 2018-05-30 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
| CA2966449A1 (en) | 2014-12-11 | 2016-06-16 | Zenith Epigenetics Ltd. | Substituted heterocycles as bromodomain inhibitors |
| 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 |
| JP5871294B1 (en) | 2015-02-27 | 2016-03-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Immediate release oral tablets |
| KR20170001921A (en) | 2015-06-26 | 2017-01-05 | 대원제약주식회사 | A pharmaceutical composition comprising telmisartan with increased stability and a preparation method thereof |
| KR20170012703A (en) | 2015-07-22 | 2017-02-03 | 대원제약주식회사 | A pharmaceutical composition comprising telmisartan and a preparation method thereof |
| JP6411662B2 (en) | 2016-05-30 | 2018-10-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Fixed volume formulation |
| KR101872726B1 (en) | 2016-07-28 | 2018-06-29 | 주식회사 씨트리 | Telmisartan methanesulfonate and pharmaceutical composition comprising the same |
| KR20250007040A (en) | 2017-07-07 | 2025-01-13 | 베링거잉겔하임베트메디카게엠베하 | Angiotensin ii receptor antagonist for the prevention or treatment of systemic diseases in cats |
| CN111918866B (en) * | 2018-03-30 | 2023-07-04 | 千纸鹤治疗公司 | Heterocyclic compounds |
| EP4373474A1 (en) | 2021-07-22 | 2024-05-29 | KRKA, D.D., Novo Mesto | Bilayer tablet comprising telmisartan and indapamide |
| JP2024536342A (en) * | 2021-10-04 | 2024-10-04 | ボルト バイオセラピューティクス、インコーポレーテッド | Asymmetric bis-benzimidazole sting agonist immunoconjugates and uses thereof |
| US20240390317A1 (en) | 2023-05-24 | 2024-11-28 | Boehringer Ingelheim Vetmedica Gmbh | Combination treatment and/or prevention of cardiac diseases in non-human mammals comprising one or more sglt-2 inhibitors and pimobendan and/or telmisartan |
| US20240390332A1 (en) | 2023-05-24 | 2024-11-28 | Boehringer Ingelheim Vetmedica Gmbh | Combination treatment and/or prevention of renal diseases and/or hypertension in non-human mammals comprising one or more SGLT-2 inhibitors and telmisartan |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
| DE3928177A1 (en) * | 1989-04-08 | 1991-02-28 | Thomae Gmbh Dr K | BENZIMIDAZOLE, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| CA2016710A1 (en) * | 1989-05-15 | 1990-11-15 | Prasun K. Chakravarty | Substituted benzimidazoles as angiotensin ii antagonists |
| IE64514B1 (en) * | 1989-05-23 | 1995-08-09 | Zeneca Ltd | Azaindenes |
| GB8911854D0 (en) * | 1989-05-23 | 1989-07-12 | Ici Plc | Heterocyclic compounds |
| IL94390A (en) * | 1989-05-30 | 1996-03-31 | Merck & Co Inc | Di-substituted imidazo fused 6-membered nitrogen-containing heterocycles and pharmaceutical compositions containing them |
| IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
| US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| RU1836357C (en) * | 1990-07-23 | 1993-08-23 | Др.Карл Томэ ГмбХ | Benzimidazole derivatives, their isomers, mixtures of isomers, hydrates or their physiologically bearable salts possessing properties antagonistic to angiotenzine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8691999B2 (en) | 2004-05-11 | 2014-04-08 | Cipla Limited | Process for the preparation of telmisartan |
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