NZ241515A - Benzimidazole derivatives, preparation and pharmaceutical compositions thereof - Google Patents

Benzimidazole derivatives, preparation and pharmaceutical compositions thereof

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Publication number
NZ241515A
NZ241515A NZ241515A NZ24151592A NZ241515A NZ 241515 A NZ241515 A NZ 241515A NZ 241515 A NZ241515 A NZ 241515A NZ 24151592 A NZ24151592 A NZ 24151592A NZ 241515 A NZ241515 A NZ 241515A
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NZ
New Zealand
Prior art keywords
group
methyl
benzimidazol
imidazo
biphenyl
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Application number
NZ241515A
Inventor
Norbert Hauel
Berthold Narr
Uwe Ries
Wolfgang Wienen
Michael Entzeroth
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Thomae Gmbh Dr K
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27202166&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NZ241515(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from DE4103492A external-priority patent/DE4103492A1/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of NZ241515A publication Critical patent/NZ241515A/en

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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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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/12—Antihypertensives
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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

New Zealand Paient Spedficaiion for Paient Number £41 515 24 t5 15 r, . XS S-lt , • / . fo'.o.'.v.
Complete Specification Filed: Oess: <9TWR#&i», ^ 14 «>,«. ^ / w. ft7# «J ccrr&tiifaf. .<?7 Publication Date: .-v?.?. r.PJ.
P.O. Journal, No: .../??!?".
V N Class Cont: ijrt rlnAWWre ml i tjf*n *«»n j'' Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION BENZIMIDAZOLE COMPOUNDS WE, DR KARL THOMAE GMBH, a German company of D-7950 Biberach an der Riss, FEDERAL REPUBLIC OF GERMANY hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: N.Z. PATENT OFFir.P -4 FEB 1992 Received (followed by page la) 24151 ia- Benzimidazole Compounds 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 (i) (followed by page 2) 57636001.576 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-, 4- or 5-position by a benzimidazolyl or tetrahydrobenzimidazolyl group, or R2 represents a C1.4-alkylsulphonyloxy group, a benzenesulphonyloxy or phenylalkanesulphonyloxy group, an acylamino group optionally substituted at the nitrogen atom by a 0,^-alkyl group or by a phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenyl group, in which the acyl group is a Cw-alkanoyl group, a (alkoxycarbonyl) group, a C1.6-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenylalkanesulphonyl, naphthalenesulphony1, 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-carboxyphenylcarbonyl-amino 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 totally or partially hydrogenated and may be mono- or di-substituted by alkyl or alkoxy groups whilst the substituents may be identical or different, 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 whislj. a methylene group may be replaced by a carbonyl or.'. ' ?/l 1 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 C1.6 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 di-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 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^-alkyl or by a phenylalkyl group which may carry a fused homo- or hetero-cyclic group formed by linkage of an n-propylene or n-butylene group to the 6-membered heteroaromatic rings via two ring carbon atoms, or of a 1,3-butadienyl group to the 5-membered or 6-membered heteroaromatic rings via two adjacent ring carbon atoms or of an n-butylene or 1,3-butadienyl group to the 5-membered or 6-membered heteroaromatic rings via adjacent ring nitrogen and carbon atoms, and in an anellated pyridine ring thup / \ formed, a methine group may j ; f 2415 15 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, an R7-NR6-CO-NR5- group (wherein Rj represents a hydrogen atom or a C^g-alkyl, C5.7 cycloalkyl or phenylalkyl group, R6 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^-alkyl group, or one of the groups R5, R6 or R? may also represent a bicyclohexyl or biphenyl group, or R6 and R7 together with the nitrogen atom between them represent an unbranched C4_6-alkyleneimino group or a morpholino group, or Rj and R6 together represent a C2.4-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 lH-tetrazolyl group, R2 may also represent a 2-(imidazol-l-yl)-ethoxy group; or R, represents a hydrogen atom or in the 5-, 6- or 7-position R1 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 ' ' 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^g 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 5-membered and 6-membered heteroaromatic rings or an n-butylene 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 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^.g-alkyl group, by a phenylalkyl group or by a cycloalkyl group, with the provisos that where (i) Rx represents a hydrogen atom, R3 represents an n-propyl group and R4 represents a carboxy, tert.butoxycarbonyl, cyano or 1H-tetrazolyl group, 24 1 7 then R2 cannot represent a l-methyl-benzimidazol-2-yl group in the 5- or 6-position, and where (ii) Ri represents a hydrogen atom, R3 represents a methyl, ethyl or n-butyl group and R4 represents a cyano or lH-tetrazolyl group, then R2 cannot represent a benzoxazol-2-yl or 1-methyl-benzimidazol-2-yl group in the 6-position, and where (iii) Rx represents a hydrogen atom, R3 represents an n-butyl group and R4 represents a carboxy or tert.butoxycarbonyl group, then R2 cannot represent a benzimidazol-2-yl group in the 6-position, and where (iv) Rx represents a hydrogen atom, R3 represents an n-propyl group and R4 represents a carboxy or tert.butoxycarbonyl group, then R2 cannot represent a 3-methyl-imidazo-[4,5-b]pyridin-2-yl or 3-n-hexyl-imidazo [4,5-b] pyridin-2-yl group in the 6-position, a 1-methyl-benzimidazol-2-yl group in the 6-position substituted in the 5-position by a methyl or trifluoromethyl group, by a fluorine or chlorine atom or in the 6-position by a methyl group, or a 1-n-butyl-benzimidazol-2-yl group in the 6-position, and where (v) Rx represents a hydrogen atom, R3 represents an n-butyl group and R4 represents a carboxy group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 6-position substituted in the 5-position by a bromine atom or by a methoxy group, a l-n-butyl-5-trifluoromethyl-benzimidazol-2-yl or l-n-hexyl-5-methyl-benzimidazol-2-yl group in the 6-position, and where i— (followed by page 7a) - 7a - (vi) Rx represents a hydrogen atom, R3 represents an ethyl or n-butyl group and R4 represents a carboxy or tert.butoxycarbonyl group, then R2 cannot represent a l-methylbenzimidazol-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 N-atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group; R3 represents a hydrogen atom or a C^-alkyl group in (followed by page 8) which a methylene group may be replaced by a sulphur atom, or R3 may represent a C3.5cycloalkyl group, and R4 represents a carboxy, cyano, lH-tetrazolyl, 1-triphenylmethyltetrazolyl, C2.5 (alkoxy carbonyl) , alkanesulphonylaminocarbonyl, arylsulphonylamino-carbonyl 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, 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-(imidazol-l-yl)butoxy, 5-(imidazol-l-yl)pentoxy, 2-(benzimidazol-l-yl) ethoxy, 3-(benzimidazol-l-yl)-propoxy, 4-(benzimidazol-l-yl)butoxy, 5-(benzimidazol-l-yl)-pentoxy, 2-(tetrahydrobenzimidazol-l-yl)ethoxy, 3-(tetrahydrobenzimidazol-1-y1)propoxy, 4-(tetrahydrobenzimidazol-l-yl) butoxy, 5-(tetrahydrobenzimidazol-l-yl) pentoxy, methanesulphonyloxy, ethanesulphonyloxy, n-propanesulphonyloxy, isopropanesulphonyloxy, n- butanesulphonyloxy, benzenesulphonyloxy, 4-fluorobenzenesulphonyloxy, 4-bromobenzenesulphonyloxy, 4-methylbenzenesulphonyloxy, 4-methoxybenzene-sulphonyloxy, 3,4-dichlorobenzenesulphonyloxy, phenyl-methanesulphonyloxy, 2-phenylethanesulphonyloxy, 3-phenylpropanesulphonyloxy, formylamino, acetylamino, propionylamino, butanoylamino, isobutanoylamino, pentanoylamino, 3-methyl-butanoylamino, hexanoylamino, methoxycarbonylamino, ethoxycarbonylami.no, n-propoxycarbonylamino, isopropoxycarbonylamino, methane-sulphonylami.no, ethanesulphonylamino, n-propane-sulphonylamino, isopropanesulphonylamino, n-butane-sulphonylamino, n-pentanesulphonylamino, n-hexane-sulphonylamino, benzamido, benzenesulphonylamido, 4-fluorobenzenesulphonamido, 4-chlorobenzenesulphonamido, 4-bromobenzenesulphonamido, 4-methylbenzenesulphonamido, 4-methoxybenzenesulphonamido, phenylmethanesulphony1-amido, 2-phenylethanesulphonylamido, 3-phenylpropane-sulphonylamido, naphthalen-l-yl-sulphonamido, naphthalen-2-yl-sulphonylamido, cyclopentylcarbonyl-amido, cyclohexylcarbonylamido, cycloheptylcarbonyl-amido, phenylacetylamido, 3-phenylpropionylamido, cyclopentylacetylamido, 3-cyclopentylpropionylamido, cyclohexylacetylamido, 3-cyclohexylpropionylamido, cycloheptylacetylamido, 3-cycloheptylpropionylamido, N-methyl-formylamino, N-methyl-acetylamino, N-methy1-propionylamino, N-methyl-butanoylamino, N-methyl-isobutanoylamino, N-methyl-pentanoylamino, N-methyl-3-ir.ethyl-butanoylamino, N-methyl-hexanoylamino, N-methyl-methoxycarbonylamino, N-methyl-ethoxycarbonylamino, N-methyl-n-propoxycarbonylamino, N-methy1-isopropoxy-carbonylamino, N-methy1-methanesulphonylamino, N-methy1-ethanesulphonylamino, N-methy1-n-propanesulphonylamino, N-methy1-isopropanesulphonylamino, N-methyl-n-butane-sulphonylamino, N-methyl-n-pentanesulphonylamino, N-methyl-n-hexanesulphonylamino, N-methy1-benzamido, N-methyl-benzenesulphonylamido, N-methy1-4-fluorobenzene- 9 1 4 ; \ P- p. sulphonamido, N-methyl-4-chlorobenzenesulphonamido, N-methyl-4-bromobenzenesulphonamido, N-methy1-4-methylbenzenesulphonamido, N-methyl-4-methoxybenzene-sulphonamido, N-methy1-phenylmethanesulphonylamido, N-methyl-2-phenylethanesulphonylamido, N-methy1-3-phenylpropanesulphonylamido, N-methyl-naphthalen-l-yl-sulphonamido, N-methyl-naphthalen-2-yl-sulphonylamido, N-methy1-cyclopentylcarbonylamido, N-methy1-cyclohexyl-carbonylamido, N-methy1-cycloheptylcarbonylamido, N-methyl-phenylacetylamido, N-methy1-3-phenylpropionyl-amido, N-methyl-cyclopentylacetylamido, N-methyl-3-cyclopentylpropionylamido, N-methyl-cyclohexylacetyl-amido, N-methyl-3-cyclohexylpropionylamido, N-methyl-cycloheptylacetylamido, N-methyl-3-cycloheptylpropionyl-amido, N-ethyl-formylamino, N-ethyl-acetylamino, N-ethyl-propionylamino, N-ethyl-butanoylamino, N-ethy1-isobutanoylamino, N-ethyl-pentanoylamino, N-ethyl-3-methyl-butanoylamino, N-ethy1-hexanoylamino, N-ethyl-methoxycarbonylamino, N-ethyl-ethoxycarbonylamino, N-ethy1-n-propoxycarbonylamino, N-ethyl-isopropoxy-carbonylamino, N-ethyl-methanesulphonylamino, N-ethyl-ethanesulphonylamino, N-ethyl-n-propanesulphonylamino, N-ethy1-isopropanesulphonylamino, N-ethy1-n-butanesulphonylamino, N-ethy1-n-pentanesulphonylamino, N-ethy1-n-hexanesulphonylamino, N-ethyl-benzamido, N-ethyl-benzenesulphonylamido, N-ethyl-4-fluorobenzene-sulphonamido, N-ethyl-4-chlorobenzenesulphonamido, N-ethy1-4-bromobenzenesulphonamido, N-ethy1-4-methylbenzenesulphonamido, N-ethyl-4-methoxybenzenesulphonamido, N-ethy1-phenylmethanesulphonylamido, N-ethy1-2-phenylethanesulphonylamido, N-ethy1-3-phenylpropanesulphony lamido, N-ethyl-naphthalen-l-yl-sulphonamido, N-ethyl-naphthalen-2-yl-sulphonylamido, N-ethyl-cyclopentylcarbonylamido, N-ethy1-cyclohexylcarbonyl-amido, N-ethyl-cycloheptylcarbonylamido, N-ethyl-phenylacetylamido, N-ethy1-3-phenyl-propionylamido, N- 24 15 15 - n - ethyl-cyclopentylacetylamido, N-ethy1-3-cyclopentyl-propionylamido, N-ethyl-cyclohexylacetylamido, N-ethyl-3-cyclohexylpropionylamido, N-ethyl-cycloheptylacetyl-amido, N-ethyl-3-cycloheptylpropionylamido, N-n-propyl-formylamino, N-n-propyl-acetylamino, N-n-propyl-propionylamino, N-n-propyl-butanoylamino, N-n-propyl-isobutanoylamino, N-n-propyl-pentanoylamino, N-n-propyl-(3-methyl-butanoyl)amino, N-n-propy1-hexanoylamino, N-isopropyl-formylamino, N-isopropyl-acetylamino, N-isopropyl-propionylamino, N-isopropyl-butanoylamino, N-isopropyl-isobutanoylamino, N-isopropyl-pentanoylamino, N-isopropyl-(3-methyl-butanoyl)amino, N-isopropyl-hexanoylamino, N-n-butyl-formylamino, N-n-butyl-acetylamino, N-n-butyl-propionylamino, N-n-butyl-butanoylamino, N-n-butyl-isobutanoylamino, N-n-butyl-pentanoylamino, N-n-butyl-(3-methyl-butanoyl)amino, N-n-buty1-hexanoylamino, N-isobutyl-formylamino, N-isobutyl-acetylamino, N-isobutyl-propionylamino, N-isobutyl-butanoylamino, N-isobutyl-isobutanoylamino, N-isobutyl-pentanoylamino, N-n-pentyl-formylamino, N-n-pentyl-acetylamino, N-n-pentyl-propionylamino, N-n-pentyl-butanoylamino, N-n-pentyl-isobutanoylamino, N-n-pentyl-pentanoylamino, N-(l-methyl-butyl)-formylamino, N-(l-methy1-buty1)-acetylamino, N-(1-methy1-buty1)-propionylamino, N-(1-methy1-buty1)-butanoylamino, N-(l-methyl-butyl)-isobutanoylamino, N-(1-methyl-butyl)-pentanoylamino, N-(2-methyl-butyl)-formylamino, N-(2-methyl-buty1)-acetylamino, N-(2-methyl-butyl)-propionylamino, N-(2-methyl-butyl)-butanoylamino, N-(2-methyl-butyl)-isobutanoylamino, N-(2-methyl-butyl)-pentanoylamino, N-(3-methyl-butyl)-formylamino, N-(3-methyl-butyl)-acetylamino, N-(3-methyl-butyl)-propionylamino, N-(3-methyl-butyl)-butanoylamino, N-(3-methyl-butyl)-isobutanoylamino, N-(3-methyl-butyl)-pentanoylamino, N-n-hexyl-formylamino, N-n-hexyl-acetylamino, N-n-hexyl-propionylamino, N-n-hexyl-butanoylamino, N-n-hexyl-isobutanoylamino, N-n-hexyl- 2415 15 pentanoylamino, N-n-propyl-cyclohexylcarbonylamino, N-n-propyl-cyclohexylacetylamino, N-n-propyl-3-(cyclohexyl)propionylamino, N-isopropyl-cyclohexylcarbonylamino, N-isopropyl-cyclohexylacetylamino, N-isopropyl-3-(cyclohexyl)-propionylamino, N-n-butyl-cyclohexylcarbonylamino, N-n-butyl-cyclohexylacetylamino, N-n-butyl-3-(cyclohexyl)-propionylamino, N-isobutyl-cyclohexylcarbonylamino, N-isobutyl-cyclohexylacetylamino, N-isobutyl-3-(cyclohexyl)propionylamino, N-n-pentyl-cyclohexyl-carbonylamino, N-n-pentyl-cyclohexylacetylamino, N-n-pentyl-3-(cyclohexyl)propionylamino, N-n-hexyl-cyclohexylcarbonylamino, N-n-hexyl-cyclohexylacetyl-amino, N-n-hexyl-3-(cyclohexyl)propionylamino, phthalimino, 5-methoxy-phthalimino, 5,6-dimethoxy-phthalimino, 6-methoxy-phthalimino, homophthalimino, 4,4-dimethyl-homophthalimino, 7-methoxy-homophthalimino, 6,7-dimethoxy-homophthalimino, 7-methoxy-4,4-dimethyl-homophthalimino, 6,7-dimethoxy-4,4-dimethyl-homophthalimino, 1,2,3,6-tetrahydrophthalimino, hexahydrophthalimino, cis-hexahydrophthalimino, trans-hexahydrophthalimino, l-oxo-isoindolin-2-yl, 3,4-dimethy1-phthalimino, 4,5-dimethyl-l,2,3,6-tetrahydrophthalimino, 4,5-dimethy1-hexahydro phthalimino, 4,5-dimethyl-l-oxo-isoindolin-2-yl, 3,4-dimethoxy-phthalimino, 4,5-dimethoxy-l,2,3,6-tetrahydrophthalimino, 4,5-dimethoxy-hexahydro phthalimino, 4,5-dimethoxy-l-oxo-isoindolin-2-yl, 2-carboxyphenylmethylamino, 2-carboxyphenylmethylene-carbonylamino, pyrrolidino, 2-methylpyrrolidino, 3-ethylpyrrolidino, 3-isopropylpyrrolidino, piperidino, 3-methylpiperidino, 4-methylpiperidino, 4-ethylpiperidino, 4-isopropylpiperidino, hexamethyleneimino, 3-methyl-hexamethyleneimino, 4-methylhexamethyleneimino, 3-ethylhexamethyleneimino, 4-isopropylhexamethyleneimino, 3,3-dimethyl-pyrrolidino, 3,4-dimethyl-pyrrolidino, 3,3-diraethyl-piperidino, 3,4-dimethyl-piperidino, 4,4- dimethyl-piperidino, 3,3-dimethyl-hexamethyleneimino, 3,4-dimethyl-hexamethyleneimino, 4,4-dimethyl-hexamethyleneimino, 3,5-dimethyl-hexamethyleneimino, 3.3-tetramethylene-pyrrolidino, 3,3-pentamethylene-pyrrolidino, 3,3-tetramethylene-piperidino, 3,3-pentamethylene-piperidino, 4,4-tetramethylene-piperidino, 4,4-pentamethylene-piperidino, 3,3-tetramethylene-hexamethylene imino, 3,3-pentamethylene-hexamethyleneimino, 4,4-tetramethylene-hexamethylene-imino, 4,4-pentamethylene-hexamethyleneimino, 2-oxo-pyrrolidino, 2-oxo-piperidino, 2-oxo-hexamethyleneimino propanesultam-l-yl, butanesultam-l-yl, pentanesultam-1-yl, endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic acid imino, methyl-5-norbornene-2,3-dicarboxylic acid imino, 3,6-endooxo-l,2,3,6-tetrahydrophthalimino, 5-norbornen-endo-2,3-dicarboxylic acid imino, glutarimino, 3,3-tetramethylene-glutarimino, 3,3-pentamethylene-glutarimino, 2,2-dimethyl-glutarimino, 3-methyl-glutarimino, 3,3-dimethyl-glutarimino, 3-ethyl-glutarimino, 3-ethyl-3-methyl-glutarimino, 1,3-cyclopentanedicarbonylimino, 2,4-dimethyl-glutarimino, 2.4-di—n-propyl-glutarimino, glutaramino, 3,3-tetramethylene-glutaramino, 3,3-pentamethylene-glutaramino, 2,2-dimethyl-glutaramino, 3-methyl-glutaramino, 3,3-dimethyl-glutaramino, 3-ethyl-glutaramino, 3-ethyl-3-methyl-glutaramino, 1,3-cyclopentanedicarbonylamino, 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-2-phenyl-maleic acid amido, 2-methyl-3-phenyl-maleic acid amido, 2-methyl-3-phenyl-maleic acid imido, 2,3-diphenyl-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, quinolin-2-yl, isoquinolin-l-yl, isoquinolin-3-yl, pyridin-2-yl, 4-methylimidazol-2-yl, l-methylimidazol-4-ylf l-methylimidazol-5-yl, l-n-hexylimidazol-4-yl, l-n-hexylimidazol-5-yl, l-benzylimidazol-4-yl, 1-benzylimidazol-5-yl, 1,2-dimethylimidazol-4-yl, 1,2-dimethylimidazol-5-yl, l-n-pentyl-2-methyl-imidazol-4-yl, l-n-pentyl-2-methyl-imidazol-5-yl, l-n-butyl-2-methyl-imidazol-4-yl, 1-n-buty1-2-methyl-imidazol-5-yl, 1-benzyl-2-methyl-imidazol-4-yl, l-benzyl-2-methyl-imidazol-5-yl, benzimidazol-2-yl, 1-methylbenzimidazol- 2-yl, l-ethylbenzimidazol-2-yl, 1-n-propylbenzimidazol-2-yl, l-isopropylbenzimidazol-2-yl, 1-n-butylbenzimidazol-2-yl, l-isobutylbenzimidazol-2-yl, 1-n-pentylbenzimidazol-2-yl, l-n-hexylbenzimidazol-2-yl, 1-cyclopropyl-benzimidazol-2-y1, 1- cyclobutylbenzimidazol-2-yl, 1-cyclopentylbenzimidazol- 2-yl, l-cyclohexylbenzimidazol-2-yl, 5-nitro-benzimidazol-2-yl, 5-amino-benzimidazol-2-yl, 5-acetamido-benziinidazol-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-dimethyl-benzimidazol-2-yl, 1,6-dimethyl-benzimidazol-2-yl, 1,4-dimethyl-benzimidazol-2-yl, 5,6-dimethyl-benzimidazol-2~ yl, 1,5,6-trimethyl-benzimidazol-2-yl, 5-chloro-benzimidazol-2-yl, 5-chloro-l-methyl-benzimidazol-2-yl, 6-chloro-l-methyl-benzimidazol-2-yl, 5,6-dichloro-l-methyl-benzimidazol-2-yl, 5-dimethylamino-benzimidazol- 2-yl, 5-dimethylamino-l-ethyl-benzimidazol-2-yl, 5,6-dimethoxy-l-methyl-benzimidazol-2-yl, 5,6-dimethoxy-l-ethyl-benzimidazol-2-yl, 5-fluoro-1-methy1-benzimidazol-2-yl, 6-fluoro-1-methyl-benzimidazol-2-y1, 5- trifluoromethyl-benzimidazol-2-yl, 5-trifluoromethyl-1-methyl-benzimidazol-2-yl, 4-cyano-1-methy1-benzimidazol-2-yl, 5-carboxy-l-methyl-benzimidazol-2-yl, 5-aminocarbonyl-benzimidazol-2-yl, 5-aminocarbonyl-l-methyl-benzimidazol-2-yl, 5-dimethylaminosulphonyl-1-methyl-benzimidazol-2-yl, 5-methoxycarbonyl-l-methyl- benzimidazol-2-yl, 5-methylaminocarbonyl-l-methyl-benzimidazol-2-yl, 5-dimethylaminocarbonyl-l-methyl-benzixnidazol-2-yl, 4 ,6-difluoro-l-methyl-benzimidazol-2 yl, 5-acetyl-l-methyl-benzimidazol-2-yl, 5,6-dihydroxy-l-methyl-benzimidazol-2-yl, imidazo[1,2-a]pyridin-2-yl, 5~methyl-imidazo[i,2-a]pyridin-2-yl, 6-methyl-imidazo[1,2-a]-pyridin-2-yl, 7-methyl-imidazo[1,2-a]-pyridin-2-yl, 8-methyl-imidazo[1,2-a]pyridin-2-yl, 5,7-dimethyl-imidazo[l,2-a]pyridin-2-yl, 6-aminocarbonyl-imidazo[1,2-a]pyridin-2-yl, 6-chloro-imidazo[1,2-a]-pyridin-2-yl, 6-bromo-imidazo[l,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[l,2-a]pyrimidin-2-yl, 5,7-dimethyl-imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, l-methyl-imidazo[4,5-b]pyridin-2-yl, 1-n-hexyl-imidazo[4,5-b]pyridin-2-yl, 1-cyclopropyl-imidazo[4,5-b]pyridin-2-yl, l-cyclohexyl-imidazo[4,5-b] pyridin-2-yl, 4-methyl-iinidazo[4, 5-b]pyridin-2-yl, 6-methyl-iinidazo[4,5-b]pyridin-2-yl, 1,4-dime thy 1-imidazo[4,5-b]pyridin-2-yl, 1,6-dimethyl-imidazo[4,5-b] pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, 1-methyl-imidazo[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[2,1-b]thiazol-6-yl, 2-phenyl-imidazo[2,l-b]thiazol-6-yl, 3-phenyl-imidazo[2,1-b]thiazol-6-yl, 2,3-dimethyl-imidazo[2,1-b] thiazol-6-yl, 2, 3-triraethylene-imidazo[2 ,1-b]thiazol-6-yl, 2,3-tetramethylene-imidazo[2,1-b]thiazol-6-y1, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1, 2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[4,5-c]pyridin 2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, imidazo[4,5-d]pyridazin-2 yl, imidazolidin-2,4-dion-3-yl, 5-methyl-imidazolidin-2,4-dion-3-yl, 5-ethyl-imidazolidin-2,4-dion-3-yl, 5-n-propyl-imidazolidin-2,4-dion-3-yl, 5-benzyl-imidazolidin-2,4-dion-3-yl, 5-(2-phenylethyl)- sn 5 imidazolidin-2,4-dion-3-yl, 5-(3-phenylpropyl)-imidazolidin-2,4-dion-3-y1, 5,5-tetramethylene-imidazolidin-2,4-dion-3-y1, 5,5-pentamethylene-imidazolidin-2,4-dion-3-yl, 5,5-hexamethylene-imidazolidin-2 f 4-dion-3-yl, l-methyl-imidazolidin-2,4-dion-3-yl, l-benzyl-imidazolin-2,4-dion-3-yl, 4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-ethyl-4, 5-dihydro-2H-pyridazin-3-on-6-y1, 2-n-propy1-4,5-dihydro-2H-pyridazin-3-on-6-y1, 2-isopropyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-benzyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-(2-phenylethyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2-(3-phenylpropyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl, 4-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 5-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 5,5-dimethyl-4,5-dihydro-2H-pyridaz in-3-on-6-yl, 4,5-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2,4-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2,5-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2,4,5-trimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2,4,4-trimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2,5, 5-trimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl, 2H-pyridazin-3-on-6-yl, 2-methyl-pyridazin-3-on-6-yl, 2-ethyl-pyridazin-3-on-6-yl, 2-n-propyl-pyridazin-3-on-6-yl, 2-isopropyl-pyridazin-3-on-6-yl, 2-benzyl-pyridazin-3-on-6-yl, 2-(2 phenylethyl)-pyridazin-3-on-6-yl, 2-(3-phenylpropyl)-pyridazin-3-on-6-yl, 4-methyl-pyridazin-3-on-6-yl, 5-methyl-pyridazin-3-on-6-yl, 4,5-dimethyl-pyridazin-3-on 6-yl, 2,4-dimethyl-pyridazin-3-on-6-yl, 2,5-dimethyl-pyridazin-3-on-6-yl, 2,4,5-trimethyl-pyridazin-3-on-6-yl, aminocarbonylamino, methylaminocarbonylamino, dixnethylaminocarbonylamino, N-methylaminocarbony 1-methylamino, N-(dimethylaminocarbonyl)-methylamino, N-dimethylaminocarbony1-ethylamino, N-dimethylaminocarbony 1-isopropylamino, N-(dimethylaminocarbonyl)-n-pentylamino, N-methylaminocarbony1-ethylamino, N- 2415 methylaminocarbony1-n-pentylamino, N-methylaminocarbony 1-n-hexylamino, N-methylaminocarbonyl-n-octylamino, N-methylaminocarbony1-cyclohexylamino, ethylaminocarbonylamino, N-ethylaminocarbony1-methylamino, N-ethylaminocarbonyl-ethylamino, N-ethylaminocarbony1-n-hexylamino, N-ethylaminocarbonyl-n-heptylamino, N-ethylaminocarbony1-cyclohexylamino, diethylaminocarbonylamino, N-(diethylaminocarbonyl)-methylamino, N-(diethylaminocarbonyl)-ethylamino, N-(diethylaminocarbonyl)-n-butylamino, N-(diethylaminocarbonyl) -n-hexylamino, N-(diethylaminocarbonyl)-n-octylamino, isopropylaminocarbonylamino, N-isopropyl-aminocarbony1-methylamino, n-butylaminocarbonylamino, N-(n-butylaminocarbony1)-methylamino, N-(n-butylamino-carbonyl)-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-(n-butyl)-aminocarbonyl)-n-hexylamino, N-(n-pentylaminocarbony 1 ) -methylamino, N-(n-pentylaminocarbony1)-ethylamino, N-(n-hexylaminocarbony1)-ethylamino, n-hexylaminocarbonylamino, n-heptylaminocarbonylamino, n-octylaminocarbonylamino, N-(n-hexylaminocarbony1)-n-butylamino, N-(n-hexylaminocarbony1)-n-pentylamino, N-(n-hexylaminocarbony1)-n-hexylamino, N-(n-hexylamino-carbonyl)-cyclohexylamino, di-(n-hexyl)-aminocarbonyl-amino, N-(di-(n-hexyl)-aminocarbonyl)-methylamino, N-((n-hexyl)-methylaminocarbonyl)-amino, cyclohexylamino-carbonylamino, N-cyclohexylaminocarbonyl-methylamino, N-cyclohexylaminocarbony1-ethylamino, N-cyclohexylaminocarbony 1-n-butylamino, N-cyclohexylaminocarbony1-isobutylamino, N-cyclohexylaminocarbony1-n-pentylamino, N-cyclohexylaminocarbony1-n-hexylamino, N-cyclohexylaminocarbonyl-cyclohexylamino, N-(ethyl- 2415 15 cyclohexylaminocarbony1)-methylamino, N-(propyl-cyclohexylaminocarbony1)-methylamino, N-(n-butyl-cyclohexylaminocarbony1)-methylamino, allylaminocarbonylamino, benzylaminocarbonylamino, N-benzylaminocarbony1-isobutylamino, phenylaminocarbonyl-amino, pyrrolidinocarbonylamino, pyrrolidinocarbony1-methylamino, piperidinocarbonylamino, hexamethylene-iminocarbonylamino, morpholinocarbonylamino, 3,4,5,6-tetrahydro-2-pyrimidon~l-yl, 3-methyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-ethyl-3,4,5,6-tetrahydro- 2-pyrimidon-l-yl, 3-n-propyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-isopropy1-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-n-butyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-isobutyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-n-pentyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-n-hexy1-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-cyclopentyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-cyclohexyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-cycloheptyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-benzyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3 ,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-ethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-n-propyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-isopropyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(2-phenylethyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl or 3-(3-phenylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl group; and R3 may represent a hydrogen atom, a methyl, ethyl, n-propyl, isopropy1, n-butyl, isobutyl, tert.butyl, n-pentyl, 1-methy1-buty1, 2-methyl-butyl, 3-methyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto or n-butylmercapto group. 24 1 5 1 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 C,.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 5-position 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 C24( 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, 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[l,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[l,2-a]pyrazin- 2-yl, imidazo[1,2-b]-pyridaz in-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, an Ry-NRj-CO-NRj- group (wherein Rs represents a hydrogen atom, a C,.5-alkyl group, a cyclohexyl or benzyl group, R<s represents a hydrogen atom, a Cj.6-alkyl group, an allyl, cyclohexyl, benzyl or phenyl group, R7 represents a hydrogen atom or a C|.3-alkyl group or and R7 together with the nitrogen atom between them represent an unbranched C4.6-alkyleneimino group or a morpholino group or Rs and Rj together represent a C2.3-alkylene group) ; or R, represents a hydrogen atom or in the 5-, 6- or 7-position R, represents a fluorine, chlorine or bromine atom or a CM-alkyl or a trif luoromethyl 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[l,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-y1, imidazo[l,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazofl,2-b]-pyridazin-2-yl, imidazo[4,5-c]- 24 * ^ I V- £ 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 1-position by a alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a C10 alkyl group, with the proviso that where (i) Rx represents a hydrogen atom, R3 represents an n-propyl group and R4 represents a carboxy or 1H-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 5- or 6-position, and where (ii) Rx represents a hydrogen atom, R3 represents a methyl, ethyl or n-butyl group and R4 represents a lH-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 6-position, and where (iii) Rx represents a hydrogen atom, R3 represents an n-butyl group and R4 represents a carboxy group, then R2 cannot represent a benzimidazol-2-yl group in the 6-position, and where (iv) Ri represents a hydrogen atom, R3 represents an n-propyl group and R4 represents a carboxy group, then R2 cannot represent a l-methyl-benzimidazol-2-yl group in the 6-position substituted in the 5-position by a fluorine atom, by a methyl or trif luoromethyl group or in the 6-position by a methyl group, or a l-n-butyl-benzimidazol-2-yl group in the 6-position, and where (followed by page 22a) ¥ I ^ ' Zl ? n - 22a - V (v) Rj represents a hydrogen atom, R3 represents an n-butyl group and R4 represents a carboxy group, then R2 cannot represent a l-n-butyl-5-trifluoromethyl-benzimidazol-2-yl or l-n-hexyl-5-methyl-benzimidazol-2-yl group in the 6-position, and where (vi) Rx represents a hydrogen atom, R3 represents an ethyl or n-butyl group and R4 represents a carboxy group, then R2 cannot represent a 1-methylbenz-imidazol-2-yl group in the 6-position; R3 represents a C^s-alkyl group or a C3.5-cycloalkyl group; and R4 represents a carboxy or lH-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 Rx in the 4-position represents a chlorine atom, or a Cx^-alkyl or a trifluoromethyl group, and (followed by page 23) 241515 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 5-position 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 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[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[£,5-c]pyridin-2-yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[l,2-a]pyrazin- 2-yl, imidazo[1,2-b]-pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, 24 15 15 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-NR<5-CO-NR5- group (wherein Rs represents a hydrogen atom or a C,.s-alkyl, cyclohexyl or benzyl group, Rj represents a hydrogen atom, a C^-alkyl group or an allyl, cyclohexyl, benzyl or phenyl group, R7 represents a hydrogen atom or a C,.3-alkyl group or R<s and R7 together with the nitrogen atom between them represent an unbranched C^-alkyleneimino group or a morpholino group or Rs and Ra together represent a C2.3-alkylene group); or R, represents a hydrogen atom or in the 5-, 6- or 7-position R, represents a CM-alkyl group or a *4-1 trifluoromethyl group, and R2 represents a benzimidazol-2-yl group optionally substituted in the 1-position by a C^g-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-tetrahydro-imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo [4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo [1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl, 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, or an imidazol-4-yl group substituted in the 1-position by a Cx.3 alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a Ci.3 alkyl group, with the proviso that where (i) R.! represents a hydrogen atom, R3 represents an n-propyl group and R4 represents a carboxy or 1H-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 5- or 6-position, and where (ii) Rx represents a hydrogen atom, R3 represents a methyl, ethyl or n-butyl group and R4 represents a lH-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 6-position, and where (followed by page 25a) 24 ' ^ 25a (iii) Ri represents a hydrogen atom, R3 represents an n-butyl group and R4 represents a carboxy group, then R2 cannot represent a benzimidazol-2-yl group in the 6-position, and where (iv) Rx represents a hydrogen atom, R3 represents an n-propyl group and R4 represents a carboxy group, then Rz cannot represent a 1-methyl-benzimidazol-2-yl group in the 6-position substituted in the 5-position by a fluorine atom, by a methyl or trifluoromethyl group or in the 6-position by a methyl group, or a l-n-butyl-benzimidazol-2-yl group in the 6-position, and where (v) Rx represents a hydrogen atom, R3 represents an n-butyl group and R4 represents a carboxy group, then R2 cannot represent a l-n-butyl-5-trifluoromethyl-benzimidazol-2-yl or l-n-hexyl-5-methyl-benzimidazol-2-yl group in the 6-position, and where (vi) Rx represents a hydrogen atom, R3 represents an ethyl or n-butyl group and R4 represents a carboxy group, then R2 cannot represent a 1-methylbenz-imidazol-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 lH-tetrazolyl group; wherein, unless otherwise specified, each alkanoyl, (followed by page 26) ?A 1 5 1 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 R, 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 5-position by a benzimidazolyl or tetrahydrobenzimidazolyl group, a C2.5(alkanoyl) amino group 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 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,.3-alkyl group and optionally 24 '/ 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, imidazo [1,2-a]pyrimidin-2-yl or imidazo[2,1-b]thiazol-6-yl group, an imidazol-4-yl group substituted in the 1-position by a C10 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 Rx represents a hydrogen atom or in the 5-, 6- or 7-position Rx represents a methyl group, and R2 represents 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 R2 represents an imidazo[1,2-a]pyridin-2-yl group, or an imidazol-4-yl group substituted in the 1-position by a Cj.3 alkyl group, with the proviso that where (i) Rj represents a hydrogen atom, R3 represents an n-propyl group and R„ represents a carboxy or 1H-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 5- or 6-position, and where (ii) Rj represents a hydrogen atom, R3 represents a methyl, ethyl or n-butyl group and R4 represents a lH-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 6-position, and where (followed by page 27a) - 27a - (iii) Rj represents a hydrogen atom, R3 represents an n-butyl group and R4 represents a carboxy group, then R2 cannot represent a benzimidazol-2-yl group in the 6-position, and where (iv) Rx represents a hydrogen atom, R3 represents an n-propyl group and R4 represents a carboxy group, then R2 cannot represent a l-methyl-benzimidazol-2-yl group in the 6-position substituted in the 5-position by a fluorine atom, and where (v) Rx represents a hydrogen atom, R3 represents an ethyl or n-butyl group and R4 represents a carboxy group, then R2 cannot represent a 1-methylbenz-imidazol-2-yl group in the 6-position; R3 represents a C-^s-alkyl group or a C3_5-cycloalkyl group; and R4 represents a carboxy or lH-tetrazolyl group; wherein, unless otherwise specified, each alkanoyl, alkyl or alkoxy moiety contains 1 to 3 carbon atoms and (followed by page 28) -r ' if i -28 - 24 1 5 each cycloalkyl moiety contains 3 to 7 carbon atoms; and the isomers, isomer mixtures and addition salts thereof.
Even more 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 benzimidazol-2-yl group optionally substituted in the 1-position by a Cx^-alkyl group and optionally substituted in the phenyl nucleus by a fluorine atom, or R2 represents an imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[l,2-a]-pyridin-2-yl, imidazo[1,2-a]-pyrimidin-2-yl or imidazo[2,1-b]thiazol-6-yl group, and R3 represents a Cj.s-alkyi group or a C3.s-cycloalkyl group, and R4 represents a carboxy or lH-tetrazolyl group) and the isomers, isomer mixtures and addition salts thereof. (followed by page 28a) 24 1 5 1 - 28a - The present invention particularly encompasses the following compounds: 41 - [ [2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'- [ [2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 41 -[[2-n-propyl-4-methyl-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■-t [2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'- [ [2-n-butyl-6-(isopropylcarbonylamino)-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'- [ [2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-l-yl]-methyl] -biphenyl-2-carboxylic acid; 41 -[[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 41 -t [2-cyclopropyl-4-methyl-6-(l-methylbenzimidazol-2- (followed by page 29) yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4' - [[2-n-propyl-4-methyl-6-(l-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 4•—[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-y1)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 41 -[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-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) benz imidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid; 4'-[[2-ethyl-4-methyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl) -biphenyl; 41-[[2-n-buty1-4-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)-biphenyl; • 41-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 41-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 41-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 41-[[2-n-propyl-4-methyl-6-(l-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; or 41 -[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; or the isomers, isomer mixtures and addition salts thereof.
Especially preferred compounds according to the invention include: 41-[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; or 41 -[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; or the isomers, isomer mixtures thereof.
Viewed from another aspect, the process for preparing compounds thereof which process comprises and addition salts invention provides a of formula I and salts at least one of the following steps: a) cyclising compound of formula II (wherein R1 and R2 are as defined hereinbefore, one of the groups X1 or Y., represents a group of formula 11(a) 11(a) and the other group X, or Y, represents a group of the formula 11(b) Z, Z2 II (b) - NH - X C - R3 (wherein R8 represents a hydrogen atom or an R3CO- group, R3 and R4 are 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. C1.6) alkyl groups or Z, and Z2 together represent an oxygen or sulphur atom, an optionally C^j-alkyl substituted imino group, an alkylenedioxy or alkylenedithio group, each having 2 or^ 3 carbon atoms)) /%J- 241 - 31a - and any corresponding N-oxide thus obtained is reduced; b) reacting a compound of formula III (III) followed by page 32 /V1 \ 32 (wherein Rj to Rj are as defined hereinbefore) with a biphenyl compound of formula IV / Z, (IV) (wherein R4 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 p-toluenesulphonyloxy group); c) (to prepare compounds of formula I wherein R, represents a carboxy group) converting a compound of formula 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; (v) d) (to prepare compounds of formula I wherein R4 represents a IH-tetrazolyl group) cleaving a protecting group from a compound of formula VI 241515 33 (VI ) (wherein Ru R2 and R3 are as defined hereinbefore, and R4" represents a IH-tetrazolyl group protected in the 1- or 3-position by a protecting group) ; e) (to prepare compounds of formula I wherein R, represents a IH-tetrazolyl group) reacting a compound of formula 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[i,2-a]-pyridin-2-yl, imidazo[l,2-a]pyrimidin-2-y 1, imidazo[1,2-c]-pyrimidin-2-yl, imidazo[l, 2-a]pyrazin-2-yl, imidazo-[1,2-b]pyridazin-2-yl or imidazo[2,l-b]thiazol-6-yl groups) reacting a compound of formula VIII (VII) 24 1 5 15 34 V R D A nh2 (VIM) (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 dialkylamino-sulphonyl 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 (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); (IX) 2415 15 g) (to prepare compounds of formula I wherein R2 represents one of the benzimidazol-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, imidazo[4,5-d]pyridazin-2-yl or purin-8-yl groups) cyclising a compound of formula X 1 1 VA, 1 2 (X) (wherein none, one or two of the groups A,, BIf C, or Dt represents a nitrogen atom and the remaining groups A,, B,, C, or D, represent methine groups; 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 dialkylamino-sulphonyl 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 RI3-NH- group and the other X2 or Y2 group represents a group of formula X(a) /'■ 41515 X(a) (wherein R,, R3 and R4 are as defined hereinbefore; one of the groups R13 or R14 represents a hydrogen atom and the other RI3 or R14 group represents a hydrogen atom, a C^-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. Cj^) alkyl groups or Zj 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 C,.3-alkyl <jroup 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 R,, 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 - NHRI5 (XIII) (wherein Ri5 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 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.
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, 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 2415 15 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 3-isomers is preferably obtained which can if desired subsequently be resolved into the corresponding 1- and 3- isomers, preferably by chromatography using a substrate such as silica gel or aluminium oxide.
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 241515 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 R,' 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 R/ 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 24 1 5 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, triphenylmethyl, 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 140°C.
The reaction of step (e) is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150°C, preferably at 125°C. 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 9 A 15 •wij i ^ 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 241515 43 X in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of formula 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 HOOC- (XI ) Oh 1 K 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 p-toluenesulphonic 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 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 IH-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 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 subsequent 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 o-aaino-nitro compound r followed by reduction of the nitro group and cyclisation of the subsequently obtained o-diamino-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 lH-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-propyl-5-(imidazo[l,2-a]pyridin-2-yl)-3H-benzimidazole is obtained by reacting p-amino-acetophenone with butyric acid chloride, followed by nitration, bromination, cyclisation with 2-aminopyridine to form the 6-n-butanoylamido-3- (imidazo[1,2-a]pyridin-2-yl)-nitrobenzene, which is subsequently converted into the desired compound by cyclisation, after reduction of the nitro group, or 2-n~propyl-4-methyl-6- (1-methy lbenz imidazol-2-yl) -m-benzimidazole may be obtained by nitration of methyl 3-methyl-4-n-butanoylamido-benzoate, subsequent reduction of the nitro group and cyclisation to yield 2-n-propyl-4-methyl-6-methoxycarbonyl-lH~benzimidazole, which is then 341515 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, oj-dihaloalkane 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-buty1-7-[3-(imidazol-l-yl)-propyloxy] -4-methyl-benz imidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid; B = 4'-[[2-n-butyl-7-[3-(benzimidazol-l-yl)-propyloxy]-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid trifluoroacetate; C = 4'-[[2-n-butyl-4-methyl-7-[4-(tetrahydro- benzimidazol-l-yl)-butoxy]-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid; D = 4'-[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-ylJ-methyl]-bipheny1-2-carboxylic acid; E = 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 2415 1 5 4'-[[2-n-propyl-4-methyl-6-(l-oxo-isoindolin-2-yl)-benz imidazol-l-yl]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl; 4'-[[2-n-propyl-4-methyl-6-(butanesultam-l-yl)-benz imidazol-l-yl]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl; 4'-[[2-n-buty1-6-(2,3-dimethylmaleic acid imino)-4-methyl-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid semihydrate; 4' - [[2-n-buty1-6-(isopropylcarbonylamino)-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-[[2-n-butyl-4-methyl-6- (morpholinocarbonylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylie acid; 4'-[[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid semitrifluoroacetate; 4' -[[2-n-buty1-7-[3-(imidazol-l-yl)-propyloxy]-4-methyl-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 4'-[(2-cyclopropyl-4-methy1-6-(1-methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid; 4'-[(2-n-propyl-4-methyl-6-(l-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; 4'—[(2-n-propyl-4-methy1-6- 2415 15 (imidazofl,2-a]pyrimidin-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; p = 4' -[ (2-n-propyl-4-iuethyl-6- (5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxy1ic acid; q = 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[l,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-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-bipheny1-hydrochloride; and S = 4'-[[2-n-propyl-4-methy1-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid.
Description of method: Angiotensin Il-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 MgC.l2, 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 [,25I]-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 / /, k 1 - ~y a J I corresponding IC50 value is obtained from the dose-activity curve.
In the test described, substances A to S show the following ICJ0 values: Substance IC50 [nM] A 510.0 B 52.0 C 130.0 D 3.7 E 14.0 F .0 G 1.2 H .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 .0 S 7.8 In addition, compounds D, E, F, G, H, M and O 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 i •• r: i R 1 i V.' | v«j» 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 °4 '5 15 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, bulimia, disorders of cognitive function or other central nervous system disorders.
The dosage required 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 7 5 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, propylene-glycol, cetylstearyl alcohol, carboxyxuethylcellulose 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 24 1 5 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. 2415 15 Example 1 4' - [[2-n-Buty1-7-[5-(imidazol-l-yl)-pentyloxy]-4-methyl-benzimidazol-l-yl] -methyl] -biphenyl-2-carboxylic 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 Cj^gl^Oj x H20 ( 5 5 0 . 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-3-on-6-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methy1-6-(4,5-dihydro-2H-pyridaz in-3-on-6-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4'-[[2-ethy1-4-methy1-6-(4,5-dihydro-2H-pyridazin-3-on- 241515 6-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4'-[ [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-methy1-6-(cyclohexylaminocarbony1-amino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4' -[[2-n-butyl-4-methyl-6-(cyclohexylaminocarbonyl-amino)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4' - [[2-n-propyl-4-methyl-6-(methylaminocarbonyl-methylamino)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4' -[[2-n-propy1-4-methy1-6-(n-pentylaminocarbony1-methylamino)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4' -[f 2-n-propy1-4-methy1-6-(n-pentylaminocarbonylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methy1-6-(n-butylaminocarbony1-methylamino)-benz imidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4' - [ [2-n-propy1-4-methy1-6-(benzylaminocarbonylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4' -[[2-n-propy1-4-methy1-6-(allylaminocarbonylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylie acid 4'-[[2-n-propyl-4-methy1-6-(cyclohexylaminocarbony1-methylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'~[[2-n-propyl-4-methyl-6-(dimethylaminocarbonyl-methylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propy1-4-methy1-6-(cyclohexylaminocarbony1-n-butylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-cyclohexylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-benzylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propy1-4-methy1-6-(n-hexylaminocarbony1-cyclohexylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propy1-4-methy1-6-(cyclohexylaminocarbony1-ethylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methy1-6-(dimethylaminocarbony1-n-pentylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4' - [ [2-n-propyl-4-methyl-6- (pyrrolidinocarbonylami.no) -benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonyl-methylamino)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4' - [[2-n-propyl-4-methyl-6-(piperidinocarbonylamino)-benz imidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(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-methyl-benzimidazol-l-yl] -methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-7-[3-(imidazol-l-yl) -propyloxy]-4-methyl- benzimidazol-l-yl] -methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 69.4% of theory, Melting point: 208-210°C Cj2HJ4N40J (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]-4-methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid trifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4'- % '■ 1 5 [[2-n-butyl-7-[3-(benz imidazol-l-yl)-propyloxy]-4- methyl-benzimidazol-l-y1]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87.8% of theory, Melting point: 221-223°C C36H36N403 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-methyl-benzimidazol-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-methyl- benzimidazol-l-yl ]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 68.5% of theory, Melting point: 126-128°C C33H36N4°3 X H2° (554.68) Calculated: C 71.46 H 6.91 N 10.10 Found: 71.63 7.02 9.98 Mass spectrum: m/e = 53 6 Example 5 4'-[[2-n-Butyl-7-[2-(benzimidazol-l-yl)-ethoxy]-4-methyl-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-methyl-benzimidazol-l-yl] -methyl] -bipheny 1-2 -carboxy late and trifluoroacetic acid in methylene chloride. 241515 Yield: 78.1% of theory, Melting point: 167-169°C C35H34N403 (558.68) Calculated: C 75.25 H 6.13 Found: 75.03 6.17 Example 6 4'-[[2-n-Butyl-7-[5-(benzimidazol-l-yl)-pentyloxy]-4-methy1-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-buty1-7-[5-(benz imidazol-l-yl)-pentyloxy]-4-methyl-bensimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 7 4' -[[2-n-Butyl-7-[4-(benzimidazol-l-yl)-butyloxy]-4-methyl-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-methy1-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 8 4'-[ [2-n-Butyl-4-methyl-7-[4-(tetrahydrobenzimidazol-1-yl)-butyloxy]-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-buty1-4-methy1-7-[4-(tetrahydrobenz imidazol-l-yl)-butyloxy] -benzimidazol-l-yl] -methyl ] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene N 10.03 9.95 2415 15 chloride.
Yield: 86% of theory, Melting point: 229-231°C C37H42N403 (590.76) Calculated: C 75.23 H 7.17 N 9.48 Found: 75.34 7.06 9.38 Example 9 4'-[ [2-n-Propy1-4-methy1-6-(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-methyl-6-(l-methylbenzimidazol-2-yl)- benzimidazol-l-yl]-methyl]-bipheny1-2-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-propy1-4-methy1-6-(1-n-propylbenz imidazol-2-yl) -benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4' -[[2-n-propyl-4-methyl-6-(1-n-hexylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4' -[[2-n-propy1-4-methy1-6-(l-cyclopropylbenziroidazol-2-yl) -benziraidazol-l-yl]-methyl]-biphenyl-2-carboxy1ic acid 4'- [ [2-n-propy1-4-methy1-6-(1-cyclohexylbenzimidazol-2-yl) -benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 241515 Example 10 4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-l-yl]-methy1]-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-propy1-4-methy1-6-(1-methylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-cyano-biphenyl in 50 ml of dimethylformamide and the mixture is stirred for 24 hours at 140°C. Then water is added and the precipitate is removed by suction filtering. The crude product thus obtained is purified by chromatography over silica gel (300 g of silica gel, methylene chloride + 6% ethanol).
Yield: 900 mg (51% of theory), Melting point: 228-230°C CjjHjoNg (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: 4'-[[2-n-propy1-4-methy1-6-(l-n-hexylbenzimidazol-2-yl) -benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methy1-6-(1-cyclobutylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl) -biphenyl 4'-[[2-n~propyl-4-methyl-6-(l-cyclohexylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-4-methy1-7-[2-(imidazo1-1-yl)-ethoxy]-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl 241515 4'-[[2-n-buty1-7-[3-(imidazol-l-yl)-propyloxy]-4-methyl-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl) -biphenyl 4'-[[2-n-buty1-7-[4-(imidazol-l-yl)-butyloxy]-4-methyl-benzimidazol-l-yl] -methyl] -2-(lH-tetrazol-5-yl) -biphenyl 4'" -[ [2-n-buty 1-4-methy 1-7-[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]-4-methy1-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-4-methyl-7-[3-(benzimidazol-l-yl)-propyloxy]-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-7-[4-(benzimidazol-l-yl)-butyloxy]-4-methyl-benzimidazol-l-y1]-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-5-yl)-biphenyl 4'-[[2-n-butyl-7-[2-(4,5,6,7-tetrahydrobenzimidazol-l-yl)-ethoxy]-4-methyl-benzimidazol-l-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'**[ [2-n-buty 1-4-methy 1-7-[3-(tetrahydrobenzimidazol-1-yl)-propyloxy]-benzimidazol-l-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-7-[4-(tetrahydrobenzimidazol-l-yl)-butyloxy]-4-methyl-benzimidazol-l-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-n-buty1-4-methy1-7-[5-(tetrahydrobenzimidazol-l-yl) -pentyloxy ] -benzimidazol-l-yl ] -methyl)-2-(1H-tetrazol-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-yl)-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-(cyclohexylaminocarbonyl-amino)-benzimidazol-l-yl]-methy1]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2~n-propyl-4-methyl-6-(methylaminocarbony1-methylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonyl-methylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[ [2-n-propy1-4-methy1-6-(n-pentylaminocarbonylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propy1-4-methy1-6-(n-butylaminocarbony1-methylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propy1-4-methy1-6-(benzylaminocarbonylamino)-benz imidazol-l-yl]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(allylaminocarbonylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-t[2-n-propy1-4-methy1-6-(cyclohexylaminocarbonyl-methylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propy1-4-methy1-6-(dimethylaminocarbonylmethyl-amino)-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-n-butylamino)-benz imidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' -[[2-n-propyl-4-methyl-6-(methylaminocarbony1-cyclohexylamino)-benzimidazol-l-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4' -[[2-n-propy1-4-methy1-6-(methylaminocarbony1-benzylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [ [2-n-propyl-4-methyl-6-(n-hexylaminocarbony1-cyclohexylamino)-benzimidazol-l-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4' -[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-ethylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methy1-6-(dimethylaminocarbonyl-n-pentylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4[2-n-propyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonyl-methylamino)-benz imidazol-l-yl]-methyl]—2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propy1-4-methy1-6-(piperidinocarbony1-methylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [[2-n-propy1-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 11 4'-l(2-n-Propyl-4-methyl-6-phthalimino-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl- 4-jnethyl-6-phthalimino-benzimidazol-l-yl) -methyl]-2- cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 6.8% of theory, Melting point: sintering from 160°C C33H27N702 (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-methy1-6-phthalimino-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-((2-n-butyl-4-methyl-6-phthalimino-benzimidazol-l-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide. Yield: 7.1% of theory, 241515 Melting point: sintering from 150°C C34H29N702 (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-y1)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl- 4-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 170°C C33H29N70 (539.60) Calculated: C 73.4 5 H 5.42 N 18.17 Found: 73.20 5.41 18.33 Example 14 4'~[12-n-Butyl-4-methy1-6-(l-oxo-isoindolin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-butyl- 4-methy1-6-(l-oxo-isoindolin-2-y1)-benzimidazol-l-yl]- methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 21.0% of theory, Melting point: sintering from 165°C Cj4H31N70 (553.70) Calculated: C 73.76 H 5.64 N 17.71 Found: 73.58 5.33 17.41 2415 15 Example 15 4'-[[2-n-Propyl-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-propyl- 4-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 C29HjiN702S (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 4'-[[2-Ethyl-4-methyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-ethyl-4-methy1-6-(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 C28H29N702S (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-butyl-4-methyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide. 2A 1 5 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-propy1-4-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-ethy1-6-(butanesultam-l-yl)-benzimidazol- 1-yl ]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-ethyl-4-ethyl-6-(butanesultam-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 C29H3,N702S (541.70) Calculated: C 64.30 H 5.77 N 18.10 S 5.92 Found: 64.30 5.51 17.99 5.59 Example 20 4'-[ [2-ri-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-propyl-4-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 C3,H35N702S (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)-benzimidazol-l-yl]-methyl]-2- (lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-ethyl-4-isopropyl-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 C3oH33N702S (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-propy1-4~trifluoromethyl-6-(butanesultam-l-yl)-benzimidazol-l-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Yield: 17.0% of theory, Melting point: 199-203°C C29H28F3N702S (595.70) Calculated: C 58.48 H 4.74 N 16.46 Found: 58.28 4.43 16.22 Example 23 4' -[[2-n-Propy1-4-methy1-6-(N-benzenesulphony1-methylamino)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-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 C32H3iN702S (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-methy1-6-(N-benzenesulphonyl-methylamino) -benzimidazol-l-yl]-methyl]-2-(lH-tetrazol- -yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-buty1- 4-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 CjjHJJN^S (591.70) Calculated: C 66.98 H 5.62 N 16.57 Found: 66.71 5.38 16.39 24 15 15 The following compounds are obtained analogously to Example 24: 4'-[[2-ethy1-4-methy1-6-(4,5-dihydro-2H-pyridaz in-3-on-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [ [2-n-propy 1-4-methy 1-6- (4, S-dihydro^H-pyridazin-S-on-e-yl) -benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [[2-n-buty1-4-methy1-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [[2-ethy1-4-methy1-6-(3-benzy1-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 25 4'-[[2-n-Buty1-4-methy1-6-(1-methylbenzimidazol-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 CmH32N402 (528.70) Calculated: C 77.25 H 6.10 N 10.60 Found: 77.10 5.98 10.46 Example 26 4'-[[2-n-Buty1-4-methy1-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-buty1- 4-methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l- yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 41.0% of theory, Melting point: 235-237°C C34H32Ng (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: 4'-[[2-n-buty1-4-methy1-6-(l-ethylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-buty1-4-methy1-6-(l-cyclopropylbenz imidazol-2-yl)-benzimidazol-1-y1]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[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-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 27 4'-[[2-n-Propy1-4-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-propyl- 241D 1 t) 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 14 0°C (sintering) C30H3iN7O (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-butyl-4-methy1-6-(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) C31H33N70 ( 5 19 . 70) Calculated: C 71.65 H 6.40 N 18.87 Found: 71.44 6.23 18.59 Example 29 4'-[[2-n-Propyl-4-methy1-6-(2-oxo-piperidin-l-yl)-benz imidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-l-yl) -benz imidazol-l-yl]-methyl]-2-(2-triphenylmethyl-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 CjoH^RJO (505.60) Calculated: C 71.26 H 6.18 N 19.39 Found: 71.51 6.39 19.09 Example 3 0 4'-[[2-n-Propy1-6-(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-propyl-6-(imidazof1,2-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 C31H26N402 (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-buty1-6-(6-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-6-(5,7-dimethyl-imidazo[1,2-a]pyridin-2 yl) -benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylie acid 4' - [[2-n-propyl-6-(6-aminocarbonyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-butyl-6-(6-chloro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid 4' - [[2-n-propy1-6-(imidazo[1,2-a]pyridin-2-y1)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid m 515 4'-[[2-n-propy1-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid 4'-[[2-n-butyl-6-(2,3-dimethyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid Example 31 4'-[[2-n-Butyl-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-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol- l-yl] -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 41.0% of theory, Melting point: 193-195°C C32H28N4°2 (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)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propy1- 6- (imidazo[1,2-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 241515 The following compounds may be prepared analogously to Example 32: 4' - [[2-n-propyl-6-(7-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propy1-6-(5-methyl-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [[2-n-buty1-6-(6-bromo-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' - [[2-n-propyl-6-(5,7-dimethyl-imidazo[1,2-a]pyrimidin-2-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 4'—[[2-n-propy1-6-(2-phenyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 3 3 4'—[[2-n-Buty1-6-(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-butyl- 6-(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 C32H2gNg (524.60) Calculated: C 73.26 H 5.38 N 21.36 Found: 73.09 5.32 21.20 Example 34 4'-[[2-n-Propy1-4-methy1-6-(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-propyl-4-methyl-6-(imidazo[l,2-a]pyridin-2-yl)-benzim.idazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 38.0% of theory, Melting point: 19 5-197°C (after evaporation and without recrystallisation) Melting point: 299-303°C (methylene chloride/ethanol = 20:1) C32H28N402 (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]-bipheny1-2-carboxy lie acid 4'-[[2-n-butyl-4-methyl-6-(7-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4[[2-n-butyl-4-methyl-6-(6-methy1-imidazo[1,2-a]-pyridin-2-y1)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4'-[[2-n-propy1-4-methy1-6-(5-methy1-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[t2-n-propyl-4-methy1-6-(5,7-dimethy1-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]- 241515 biphenyl-2-carboxylic acid 4'-[[2-ethyl-4-methyl-6-(6-aminocarbony1-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4'-[[2-ethyl-4-methy1-6-(6-chloro-imidazo[1,2-a]pyridin-2-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-propyl- 4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 21.0% of theory, Melting point: sintering from 181°C C32H28Ng (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-methyl-6-(5-methy1-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol- -yl)-biphenyl 4'-[[2-n-propy1-4-methy1-6-(imidazo[l,2-a]pyrimidin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 241515 Example 3 6 4'-[[2-n-Buty1-4-methy1-6-(imidazo[1,2-a]pyridin-2-yl)-benz imidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-4-methyl-6-(imidazo[1,2-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 Cj3H30N4O2 (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-l-yl] -methyl]-bipheny1-2-carboxylie acid 4' -[[2-n-propyl-6-(pyrrolidin-2-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid 4'-[[2-n-propy1-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-buty1-6-(quinolin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylie acid 4' -[[2-n-propyl-6-(isoquinolin-3-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid 4'-[[2-ethyl-6-(isoquinolin-3-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 24 1 5 Example 37 4'-[[2-n-Buty1-4-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-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl] -methyl] -2-cyano-biphenyl and sodium azide in d imethy1f ormam ide.
Yield: 26.0% of theory, C33H30N8 (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-propyl-6-(pyrrolidin-2-on-5-yl)-benzimidazol-l-yl] -methyl] -2- (lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-6-(pyrrolidin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-6-(piperidin-2-on-6-yl)-benzimidazol-l-yl ]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-butyl-6-(piperidin-2-on-6-yl)-benzimidazol-l-yl ]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl 4'-[[2-n-propyl-6-(piperidin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl 4'-[[2-n-butyl-6-(piperidin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl 4'-[[2-ethyl-6-(pyridin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 2415 15 4' - [[2-n-propyl-6-(pyridin-2-y1)-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-propy.1-6-(quinolin-2-yl) -benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-buty1-6-(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 4'-[[2-n-Butyl-4-methyl-6-(2,2-dimethylpropionylamino) -benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(2,2-dimethylpropionylamino)-benzimidazol-l-yl]-methyl]-biphenyl-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-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-buty1-7-[2-(tetrahydrobenzimidazol-l-yl)-ethoxy]-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene 24 15 15 chloride.
Yield: 81% of theory, Melting point: 236-237°C C35H38N403 (562.71) Calculated: C 74.71 H 6.81 Found: 74.51 6.79 Example 40 4'-[[2-n-Butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-l-yl) -pentyloxy]-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-l-yl)-pentyloxy]-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 41 4'-[[2-n-Butyl-7-[3-(tetrahydrobenzimidazol-l-yl) -propyloxy]-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-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]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 42 4'-[[2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid N 9.96 9.98 Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-propyl-4-methyl-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) C31H27Ns02 (501.60) Calculated: C 74.23 H 5.43 N 13.96 Found: 74.10 5.31 13.66 Example 43 4'-[[2-n-Propy1-4-methyl-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-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 43% of theory, Melting point: 192-195°C (after evaporation and without recrystallisation) Melting point: >300°C (methylene chloride/ethanol -20:1) C30H26N„O2S (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-propy1-4-methyl-6-(3-methy1-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4' -[[2-n-propyl-4-methyl-6-(2,3-dimethy1-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 1 5 15 4'-[[2-n-buty1-4-methy1-6-(2,3-trimethylene-imidazo-[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propy1-4-methy1-6-(2,3-tetramethylene-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4' -[[2-ethy1-4-methy1-6-(2-pheny1-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Example 44 4'-[[2-n-Propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[[2-n-propyl- 4-methyl-6-(imidazo[2,1-b]thiazol-6-yl) -benzimidazol-l-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 21% of theory, Melting point: amorphous, sintering from 196°C C30H26NgS (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-tetrazol- -yl)-biphenyl 4' -[[2-n-butyl-4-methyl-6-(2,3-dimethyl-imidazo[2,1-b] -thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-buty1-4-methyl-6-(2,3-trimethylene-imidazo-[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[[2-ethy1-4-methy1-6-(2,3-tetramethylene-imidazo-[2,1-b]thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'—[[2-n-propy1-4-methy1-6-(2-phenyl-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 45 4'-[[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-propyl-4-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 C32H28Ng (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: 4' - [[2-ethyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-y1)-biphenyl 4'-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-l-yl]-methy1]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propy1-4-methy1-6-(1-n-hexy1-benz imidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)- 241515 biphenyl 4' - [[2-n-propy1-4-methyl-6-(l-cyclopropy1-benzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[[2-n-propyl-4-methyl-6-(l-cyclohexyl-benzimidazol-2-yl) -benzimidazol-l-yl]-methy1]-2-(lH-tetrazol-5-yl)-biphenyl Example 4 6 4'-[[2-n-Propyl-4-methyl-6-(benzimidazol-2-yl) -benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)- benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 43% of theory, Melting point: 239-242°C C32H28N402 (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]-bipheny1-2-carboxylie 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-(l-n-hexyl-benzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid 4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid 4'-[[2-n-propyl-4-methyl-6-(l-cyclohexyl-benzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylie acid Example 47 4[[2-n-Butyl-7-[3-(imidazol-l-yl)-propyloxy]-4-methyl-benzimidazol-l-yl ]-methyl]-2-(lH-tetrazo1-5-yl)-biphenyl Prepared from 4'-[[2-n-butyl-7-[3-(imidazol-l-yl)- propyloxy]-4-methyl-benzimidazol-l-yl]-methyl]-2-(1- triphenylmethyl-tetrazol-5-yl)-biphenyl by cleaving the 1-triphenylmethyl group by means of ethanol/hydro- chloric acid.
Yield: 89.8% of theory, Melting point: 83-87°C c32H34N8° x 1-5 H2° (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-4-methyl-benzimidazol-l-yl]-methyl)-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'- [ [6-(N-benzenesulphonylmethylamino)-2-n-butyl-4-methyl- benzimidazol-l-yl]-methyl]-biphenyl-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 Example 49 4'-[[6-(N-Benzenesulphonyl-n-pentylamino)-2-n-butyl-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'- [[6-(N-benzenesulphonyl-n-pentylamino)-2-n-butyl-4- methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 81.8% of theory, Melting point: 232-233°C C37H41N304S (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-methyl-benzimidazol-l-yl] -methyl ] -biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'- [[2-n-butyl-6-(isopropylcarbonylamino)-4-methyl- benzimidazol-l-yl ]-methyl]-bipheny1-2-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)-4-methy1-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylie acid-semihydrate Prepared analogously to Example 1 from tert.butyl 4'- [[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methy1- benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 88.9% of theory, Melting point: 321-322°C C32H3iN304 x 0.5 H20 (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-4-methy1-benzimidazol-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-propyl-4-methy1- benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 75.4% of theory, Melting point: 329-331°C C3,H29N304 x 0.5 H20 (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]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 95.7% of theory, Melting point: 112-114°C (amorphous) C28H»N3°3 x CFjCOOH x 0.5 HjO (578.59) Calculated: C 62.28 H 5.40 N 7.26 Found: 62.57 5.4 6 7.21 Example 54 4' - [ [ 2-n-Butyl-4-methyl-6- (morpholinocarbonylami.no) -benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'- [[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)- benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 80.9% of theory, Melting point: 279-281°C C31Hj4N404 (526.64) 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)-4-methy1-benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylic acid semitrifluoroacetate Prepared analogously to Example 1 from tert.butyl 4'- [[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4-methyl- benzimidazol-l-yl]-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 76.9% of theory, Melting point: 288-289°C C33H38N403 x 0.5 CF3C00H (595.70) Calculated: C 68.55 H 6.51 N 9.41 Found: 69.08 7.02 9.65 Ml 5 15 Example 56 4'-[[2-n-Propyl-4-isopropyl-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-propyl- 4-isopropyl-6-(l-oxo-isoindolin-2-yl)-benzimidazol-l- yl] -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 14% of theory, Melting point: amorphous C35H33N70 (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-Propy1-5-(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-propyl-5-(imidazo[1,2-a]pyridin-2-yl)- benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 32% of theory, Melting point: 250-253°C C31H26N402 (486.60) Calculated: C 76.52 H 5.39 N 11.52 Found: 76.28 5.47 11.27 Example 58 4' - [(2-n-Propyl-4-ethy1-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example l from tert.butyl 4'-[(2-n-propy1-4-ethy1-6-(1-methylbenzimidazol-2-yl)- I •* 5 1 w « benzimidazol-l-yl)-methyl]-biphenyl-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-propyl- 4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-l- yl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 15% of theory, Melting point: 215-217°C CMH32NS (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-(1-methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylie acid Prepared analogously to Example l from tert.butyl 4'- [(2-cyclopropyl-4-methyl-6-(l-methylbenzimidazol-2-yl)- benzimidazol-l-yl)-methyl)-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 52% of theory, Melting point: 244-246°C C33H2„N402 (512.60) Calculated: C 77.32 H 5.51 N 10.93 Found: 77.75 5.71 10.94 n f / -i 1515 Example 61 4' - [ (2-Cyclopropy1-4-methy1-6-(1-methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2- cyclopropyl-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 CjjHjgNg (536.65) 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-(l-methylbenzimidazol-2-yl) -benzimidazol-l-yl) -methyl]-bipheny 1-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'- [ (2-cyclobutyl-4-methyl-6- (1-methylbenzimidazol-2-yl) - benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 63% of theory, Melting point: 189-191°C C34H30N4O2 (526.60) Calculated: C 77.55 H 5.74 N 10.64 Found: 77.35 5.92 10.40 2 M 5 Example 63 4'—[(2-Cyclobuty1-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'—[(2— cyclobuty1-4-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 C^HjoNg (550.70) Calculated: C 74.16 H 5.49 N 20.35 Found: 74.12 5.74 20.67 Example 64 4'-[(2-n-Propyl-4-methyl-6-(l-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(l-methyl-5-fluoro-benzimidazol 2-yl)-benzimidazol-l-y)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 34% of theory, Melting point: 250-252°C C33H29FN402 (532.60) 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: 4'-[(2-n-propy1-4-methy1-6-(pyridin-2-yl)-benzimidazol-l-yl) -methyl]-bipheny1-2-carboxylie acid 4'-[(2-n-propyl-4-methyl-6-(quinolin-2-yl)-benzimidazol-l-yl) -methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propyl-4-methyl-6-(isoquinolin-3-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid 4' — [(2-n-propyl-4-methyl-6-(isoquinolin-l-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Example 65 4' — [(2-n-Propy1-4-methy1-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propy1- 4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol- 1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 16.5% of theory, Melting point: from 275°C (decomp.) C31H27N9 X H20 (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: 4'-[(2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazol-l-yl) -methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[(2-n-propyl-4-methyl-6-(quinolin-2-yl)-benzimidazol-l-yl) -methyl] -2- (lH-tetrazol-5-yl) -biphenyl 4'-[(2-n-propyl-4-methyl-6-(isoquinolin-3-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[(2-n-propyl-4-methyl-6-(isoquinolin-l-yl)- benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 66 4' - [(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-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) C„H32N402 (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-butyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4' -[(2-ethyl-4-methy1-6-(5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylic acid Example 67 4' -[(2-n-Propy1-4-methy1-6-(5,6,7,8-tetrahydro-imidazo-(1,2-a]pyr idin-2-y1)-benz imidazol-1-y1)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2- £ 'v 1 5 1 5 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-buty1-4-methy1-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl) -benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl 4'-[(2-ethy1-4-methy1-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Example 68 4'-[(2-n-Propy1-4-methy1-6-(1-methy1-6-fluoro-benzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-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]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 76% of theory, Melting point: 243-245°C C33H29FN402 (532.60) Calculated: 74.42 H 5.49 N 10.52 Found: 74.74 5.52 10.77 Mass spectrum: m/e = 532 241515 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 C32H26C1N303 (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-(l-methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-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 C32H27CN402 (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 241515 Example 71 4'-[(2-n-Propyl-4-chloro-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl hydrochloride Prepared analogously to Example 10 from 4'-[(2-n-propy1- 4-chloro-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l- yl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 54.8% of theory, Melting point: sintering from 204°C C32H27C1N8 x HC1 (595.55) Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate = 1:1 and 1% glacial acetic acid) Calculated: C 62.55 H 4.71 N 18.85 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-propy1- 4-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 C32H26C1N70 ( 5 6 0 . 08) 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: 241515 4'—[(2-n-propy1-4-methy1-6-(4-methyl-imidazol-2-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Example 73 4'-[(2-n-Propyl-4-chloro-6-(cyclohexylaminocarbonylamino) -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]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 75% of theory, Melting point: 222-224°C C31H33C1N403 (54 5.09) 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-Propyl-4-methyl-6-amidino-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid hydrate a) Methyl 4'-[(2-n-propyl-4-methyl-6-amidino- benzimidazol-l-vl)-methvl1-biphenvl-2-carboxvlate 2.1 g (5 mMol) of methyl 4'-[(2-n-propyl-4-methyl-6-cyano-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 241515 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-l- vl)-methyl1-biphenvl-2-carboxvlic acid 0.51 g (1.0 mMol) of methyl 4'-[(2-n-propyl-4-methyl-6-amidino-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate are dissolved in 6 ml of tetrahydrofuran. 2.8 ml of 1.4 M agueous 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.) C26H26N402 x H20 (426.53) 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-propyl-4-methyl-6-(3-methyl-imidazol-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylic acid 7 '15 1 Example 75 4'-[(2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid a) 3-Methvl-4-butvrvlamino-5-nitro-acetophenone 32.6 g (148 mmol) of 3-methyl-4-butyrylamino-acetophenone are added in batches at -15°C to 300 ml of fuming nitric acid with stirring, and stirred for a further 30 minutes at -15°C. The reaction mixture is then poured onto 3 litres of ice, with stirring, the crude product precipitated is suction filtered, washed with 400 ml of water, dried and purified by recrystallisation from ethanol/diethylether (1:1).
Yield: 23.8 g (61.0% of theory), Rf value: 0.32 (silica gel; methylene chloride), Rf value: 0.48 (silica gel; methylene chloride/methanol = 50:1). b) 3-Methvl-4-butvrvlamino-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-4-butyrylamino-5-nitro-S)-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) ',41515 Rf value: 0.84 (silica gel; methylene chloride/methanol = 9:1). c) 2-Butvrvlamino-3-nitro-5-(imidazo-4-vl)-toluene A solution of 6.8 g (20 mmol) of 3-methyl-4-butyrylamino-5-nitro-5)-bromoacetophenone in 2 0 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-Butvrvlamino-3-nitro-5-(l-methyl-imidazol-4-vl)-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-Butvrylamino~3-amino-5-(l-methvl-imidazol-4-vll -toluene 640 mg (2.1 mmol) of 2-butyrylamino-3-nitro-5-(l-methyl- "M 1 51 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) 4'-r 2-n-Propvl-4-methvl-6-(l-methvl-imidazol-4-vl)-benzimidazol-l-vl)-methvll-biphenvl-2-carboxvlic acid A solution of 230 mg (0.44 mmol) of tert.butyl-4'-[(2-n-propy 1-4-methy1-6-(1-methy1-imidazol-4-yl)-benzimidazol-l-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-propy 1-4-methy 1-6-(l-n-hexyl-im.idazol-4-yl) -benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylie acid 24 1 4'—[(2-n-propy1-4-methy1-6-(l-benzyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylie acid 4'-[(2-n-propy1-4-methy1-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylie 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-propyl-4-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 H20 (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-propyl-4-methy1-6-(l-ethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4'-[(2-n-propy1-4-methy1-6-(l-n-hexyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propy1-4-methy1-6-(l-benzyl-imidazol-4-yl) -benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4' -[(2-n-propy1-4-methyl-6-(1-isopropy1-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 4' -[(2-n-propy1-4-methy1-6-(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[1,2-a]pyridin-2-yl)-benzimidazol-l-yl) -methyl]-2-(1H-tetrazol-5-vl^ -biphenyl ___ Prepared analogously to Example 10 from 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-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) C31H30Ng (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-methy1-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-propy1-4-methyl-6-(8-methy1-imidazo-[1,2-a]-pyridin-2-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87% of theory Melting point: 295-297*C Rf-value: 0.34 (silica gel; methylene chloride/ethanol = 9:1) C33H30N4O2 X H20 ( 5 3 2 . 65) Calculated: C 74.41 H 6.05 N 10.52 Found: 74.81 6.05 10.43 Example 79 4'-[(2-n-Propyl-4-methyl-6-(2-pyridy1)-benzimidazol-l-yl) -methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propy1 4-methy1-6-(2-pyridyl)-benzimidazol-l-yl)-methyl]-2- cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 56% of theory, Melting point: from 136°C (decomp.) C30H27N7 X 0.5 H20 (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-methy1-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-vl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propy1 4-methyl-6-(8-methy1-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 Rj-value: 0.36 (silica gel; methylene chloride/ethanol = 9:1) C„HJ0Ng (538.61) mass spectrum: m/e = 538 Example 81 4' -[(2-Ethyl-4-methyl-6-(5,6, 7, 8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxvlic acid Prepared analogously to Example 1 from tert.butyl 4'-[2-ethy1-4-methy1-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 50% of theory, Melting point: > 300"C Rf-value: 0.16 (silica gel; methylene chloride/ethanol = 9:1) Example 82 4'-[(2-n-Propyl-4-methyl-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-vl^-methvll-biphenvl-2-carboxvlic 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]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 84% of theory, Melting point: 285-286'C Rf-value: 0.55 (silica gel; methylene chloride/methanol = 9:1) '.4151 - Ill - Example 83 4' - [(2-n-Propyl-4-methyl-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-vl)-methvll-2-(lH-tetrazol-5-vl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl) -methyl] -2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 18% of theory Melting point: amorphous Rf-value: 0.29 (silica gel; methylene chloride/methanol = 9:1) C31H32Ng (516.66) Mass spectrum: m/e = 516 Example 84 4'-[(2-n-Propy1-4-methyl-6-(l-n-hexyl-imidazol-4-yl) -benzimidazol-l-vl)-methvll-biphenvl-2-carboxvlic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(l-n-hexyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride.
Example 85 4'-[(2-n-Propyl-4-methyl-6-(l-benzyl-imidazol-4-yl) -benzimidazol-l-vl)-methvl1-biphenvl-2-carboxvlic acid Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(l-benzyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride. ? 4 * 5 1 Example 86 4'-[(2-n-Propy1-4-methy1-6-(l-n-hexyl-imidazol-4-yl)-benzimidazol-1-vH-methyl1-2-(lH-tetrazol-5-vl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(l-n-hexyl-imidazol-4-yl) -benzimidazol-l-yl)-methyl]-2-cyano-biphenyl and sodium azide in d imethy1f ormamide.
Example 87 4'-[(2-n-Propy1-4-methy1-6-(l-benzyl-imidazol-4-yl)-benzimidazol-l-vl)-methyl1-2-(lH-tetrazol-5-vl)-bipheny1 Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(l-benzyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I, particularly those compounds wherein 1*4 represents a carboxy- or 1H-tetrazolyl 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 KH2P04 2 mg Na2HP04 x 2H20 50 mg NaCl 12 mg Water for injections ad 5 ml Preparation: The buffer substances and isotonic substance are dissolved in some of the water. The active substance is added and, once it has been completely dissolved, water is added to make up the required volume.
Example II Ampoules containing 100 mg of active substance per 5 ml 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 ; A i .■ 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 . 0 mg Polyvinylpyrrolidone 3. mg Magnesium stearate 1. mq 200. 0 mg Preparation: The active substance, CaHP04, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50°C in a circulating air dryer and screened again.
After the lubricant (magnesium stearate) has been added, the granules are compressed in a tablet making machine. > i A :«* 1 Example IV Coated tablets containing 50 mg of active substance Composition: Active substance 50.0 mg Lysine .0 mg Lactose 60. 0 mg Corn starch 34.0 g Gelatin .0 mg Magnesium stearate 1.0 mq 180.0 mg Preparation; The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying the granules are mixed with magnesium stearate and compressed to form tablet cores.
The cores thus produced are covered with a coating by known methods. A colouring may be added to the coating suspension or solution.
Example V Coated tablets containing 100 mg of active substance 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 ma 350.0 mg 241515 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 mg 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. 24151 117 Example VII Oral suspension containing 50 mg of active substance per 5 ml Composition; Preparation: Distilled water is heated to 70°C. Hydroxyethyl-cellulose is dissolved therein with stirring. With the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and active substance are added. The suspension is evacuated with stirring to remove any air. One dose of 50 mg is contained in 5.0 ml.
Example VIII Suppositories containing 100 mg of active substance Composition: Active substance 100.0 mg Solid fat (e.g. lard) 1600.0 mg Active substance Hydroxyethylcellulose Sorbic acid 70% sorbitol Glycerol Flavouring Water ad 50.0 mg 50.0 mg 5.0 mg 600.0 mg 200.0 mg .0 mg .0 ml 1700.0 mg

Claims (16)

241515 - 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. 2415 - 119 - whatxwe cla,m is:" "e-f-ai-gs
1. Compounds of formula (wherein R, in the 4-position represents a fluorine, chlorine or bromine atom or a CM-alkyl, 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 may represent a C^-alkoxy group substituted in the 2-, 3-, 4- cr 5-position by a benzimidazolyl or tetrahydrobenzimidazolyl group, or R2 represents a CM-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 C2J,( alkoxy carbonyl) group, a Chalky lsulphonyl group, a benzoyl, benzenesulphonyl, phenylalkanesulphonyl, naphthalenesulphony1, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl group, in which the above-mentioned phenyl nuclei may k-f *■ 3 h - 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-carboxyphenylcarbonyl-amino 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 totally or partially hydrogenated and may be mono- or disubstituted by alkyl or alkoxy groups whilst the substituents may be identical or different, 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 C1.6 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 \ " 1 '
2. Compounds of general formula I as claimed in claim 1, (followed by page 126) (wherein - 126 - R, in the 4-position represents a fluorine, chlorine or bromine atom, a C^j-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 C^-alkoxy group substituted in the 2-, 3-, 4- or 5-position 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 C2j)(alkoxycarbonyl) 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, a maleic acid imido group optionally mono- or disubstituted by an alkyl or phenyl group, whilst the 241 - 127 - substituents may be identical or different, an amidino group optionally substituted by one or two 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-tetrahydro-imidazo[1,2-a]pyridin-2-y1, imidazo[l,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin- 2-yl, imidazo[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 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 may be substituted in the 2-position by a methyl or benzyl group, 2415 - 128 - an R7-NRj-CO-NR5- group (wherein R5 represents a hydrogen atom, a C,.5-alkyl group, a cyclohexyl or benzyl group, Rj represents a hydrogen atom, a C^-alkyl group, an allyl, cyclohexyl, benzyl or phenyl group, R7 represents a hydrogen atom or a C^-alkyl group or Rj and R7 together with the nitrogen atom between them represent an unbranched C^-alkyleneimino group or a morpholino group or Rs and Rj together represent a C2.3-alkylene group) ; or R, represents a hydrogen atom or in the 5-, 6- or 7-position R, 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,.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-yl, 5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[l,2-c]pyrimidin-2-yl, imidazofl,2-a]pyrazin-2-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, - 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 1-position by a alkyl group or by a benzyl group which may also be substituted in the carbon skeleton by a C,.-, alkyl group, with the proviso that where (i) Rx represents a hydrogen atom, R3 represents an n-propyl group and R4 represents a carboxy or 1H-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 5- or 6-position, and where (ii) Ri represents a hydrogen atom, R3 represents a methyl, ethyl or n-butyl group and R4 represents a IH-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 6-position, and where (iii) Rj represents a hydrogen atom, R3 represents an n-butyl group and R4 represents a carboxy groupj then R2 cannot represent a benzimidazol-2-yl group in the 6-position, and where (iv) Rx represents a hydrogen atom, R3 represents an n-propyl group and R„ represents a carboxy group, then R2 cannot represent a l-methyl-benzimidazol-2-yl group in the 6-position substituted in the 5-position by a fluorine atom, by a methyl or trifluoromethyl group or in the 6-position by a methyl group, or a l-n-butyl-benzimidazol-2-yl group in the 6-position, and where (followed by page 129a) - 129a i (v) Rj represents a hydrogen atom, R3 represents an n-butyl group and R4 represents a carboxy group, then R2 cannot represent a l-n-butyl-5-trifluoromethyl-benzimidazol-2-yl or l-n-hexyl-5-methyl-benzimidazol-2-yl group in the 6-position, and where (vi) Ri represents a hydrogen atom, R3 represents an ethyl or n-butyl group and R4 represents a carboxy group, then R2 cannot represent a 1-methylbenz-imidazol-2-yl group in the 6-position; R3 represents a C^s-alkyl group or a C3.5-cycloalkyl group; and R4 represents a carboxy or IH-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 C10-alkyl or a 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 5-position by a benzimidazolyl or tetrahydrobenzimidazolyl (followed by page 130) i S 1 5 - 130 - 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 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-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2~yl, imidazo[l,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[l,2-a]pyrazin- 2-yl, imidazo[1,2-b]-pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or a carbon attached pyrrolidine, piperidine or pyridine ring in which a phenyl group may be condensed onto the pyridine 241515 - 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 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-NR6-CO-NR5- group (wherein R5 represents a hydrogen atom or a C,.5-alkyl, cyclohexyl or benzyl group, R
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 R2 represents a C3.5-alkoxy group substituted in the 3-, 4- or 5-position by an imidazolyl group, or R2 represents a C2.j-alkoxy group substituted in the 2-, 3-, 4- or 5-position by a benzimidazolyl or tetrahydrobenzimidazolyl group, a C2.5 (alkanoyl) amino group 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-Tn.embered 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,.3-alkyl group and optionally substituted in the phenyl nucleus by a fluorine atom, or R2 represents an imidazo[l,2-a]-pyridin-2-yl group, * 5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl, imidazo[l,2-a]pyrimidin-2-yl or imidazo[2,l-b]thiazol-6- - 134 - yl group, an imidazol-4-yl group substituted in the 1-position by a Ci.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 Ri represents a hydrogen atom or in the 5-, 6- or 7-position Rx represents a methyl group, and R2 represents 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 R2 represents an imidazo[1,2-a]pyridin-2-yl group, or an imidazol-4-yl group substituted in the 1-position by a Cj.j alkyl group, with the proviso that where (i) Rx represents a hydrogen atom, R3 represents an n-propyl group and R< represents a carboxy or 1H-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 5- or 6-position, and where (ii) Rx represents a hydrogen atom, R3 represents a methyl, ethyl or n-butyl group and R4 represents a IH-tetrazolyl group, then R2 cannot represent a 1-methyl-benzimidazol-2-yl group in the 6-position, and where (iii) Ri represents a hydrogen atom, R3 represents an n-butyl group and R, represents a carboxy group, then R2 cannot represent a benzimidazol-2-yl group in the 6-position, and where *9 I (follcwed by page 134a) - 134a - ? f 1 i) (iv) Rx represents a hydrogen atom, R3 represents an n-propyl group and R4 represents a carboxy group, then R2 cannot represent a l-methyl-benzimidazol-2-yl group in the 6-position substituted in the 5-position by a fluorine atom, and where (v) Ri represents a hydrogen atom, R3 represents an ethyl or n-butyl group and R4 represents a carboxy group, then R2 cannot represent a 1-methylbenz-imidazol-2-yl group in the 6-position; R3 represents a C^.s-alkyl group or a C3„5-cycloalkyl group; and R4 represents a carboxy or IH-tetrazolyl group; wherein, unless otherwis.e 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. (followed by page 135) -135 - ! o '/ 5
5. Compounds of formula I as claimed in claim 1, (wherein Rr in the 4-position represents a chlorine atom or a methyl group, and R2 represents 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 R2 represents an imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a)-pyridin-2-yl, imidazotl,2-a] -pyrimidin-2-yl or imidazo[2,1-b]thiazol-6-yl group, and R3 represents a C^-alkyl group or a C3.5-cycloalkyl group, and R4 represents a carboxy or IH-tetrazolyl group) and the isomers, isomer mixtures and addition salts thereof.
6. 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; 4'-[[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl) -benzimidazol-l-yl] -methyl] -.2- (lH-tetrazol-5-yl) -biphenyl; 4 1 - [ [2-n-propyl-4-methyl-6- (l-oxo'-isoindolin-2-yl) -benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 4'-t[2-n-propyl-4-methyl-6-(butanesultam-l-yl)- ^4 ^ 5 - 136 - benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methylbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 41 -[[2-n-butyl-6-(isopropylcarbonylamino)-4-methyl-benzimidazol-l-yl] -methyl]-biphenyl-2-carboxylic acid; 41 -[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-t[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4-methyl-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-[[2-cyclopropyl-4-methyl-6-(l-methylbenzimidazol-2-yl) -benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4'-[[2-n-propyl-4-methyl-6-(l-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 4 1 -[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl) -biphenyl; 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; 4 ' -[[2-n-propyl-4-methyl-6-(5,6,7, 8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl] -2-(lH-tetrazol-5-yl)-biphenyl; *4 1 5 1 - 137 - 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-carboxylic acid; 4'-[[2-ethyl-4-methyl-6-(butanesultam-l-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 41 -[[2-n-butyl-4-methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-yl]-methyl]-2-(1H-tetrazol-5-yl) -biphenyl; 41 -[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; 4'- [ t2-n-propyl-4-methyl-6-(imidazo[1, 2-a] pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; 41 -[[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; 4'-[[2-n-propyl-4-methyl-6-(l-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-l-yl] -methyl]-biphenyl-2-carboxylic acid; or 4'-t[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo [1,2-a]pyridin-2-yl) -benzimidazol-l-yl] -methyl] -biphenyl-2-carboxylic acid; or ^n isomer.^ isomerriixture or addition salt thereof. - 138 - 2& 1 i
7. 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; or 41 -[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid; or an isomer, isomer mixture or addition salt thereof.
8. A pharmaceutical composition containing a compound of formula I according to any one of claims 1 to 7 or a physiologically acceptable addition salt thereof together with one or more inert carriers or diluents.
9. A process for preparing the compounds as claimed in any one of claims 1 to 7, said process comprising at least one of the following steps: a) cyclising compound of formula II (wherein Rx and R2 are as defined in any one of claims 1 to 7, one of the groups Xx or represents a group of formula II (a) ( I I \ II (a) V - 139 - and the other group Xj or Yj represents a group of the formula 11(b) Zx Z2 11(b) \ / - NH - C - R3 (wherein R8 represents a hydrogen atom or an R3CO- group, R3 and R4 are as defined in claims 1 to 7, Zx and Z2/ which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by C^g-alkyl groups or Zx and Z2 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 any corresponding N-oxide thus obtained is reduced; b) reacting a compound of formula III \ H (wherein Ri to R3 are as defined in any one of claims 1 to 7), with a biphenyl compound of formula IV (wherein R4 is as defined in any one of claims 1 to 7, and Z3 represents a nucleophilic leaving group); 140 c) (to prepare compounds of formula I wherein R4 represents a carboxy group) converting a compound of formula V (wherein Rx to R3 are as defined in any one of claims 1 to 7, and R41 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 IH-tetrazolyl group) cleaving a protecting group from a compound of formula VI (wherein Rlf R2 and R3 are as defined in any one of claims 1 to 7; and R4" represents a IH-tetrazolyl group protected in the 1- or 3-position by a protecting group); e) (to prepare compounds of formula I wherein R4 represents a IH-tetrazolyl group) reacting a compound of formula VII (V) (VI) 141 1 (VII) (wherein Rx to R3 are as defined in any one of claims 1 to 7) with hydrazoic acid or a salt thereof; f) (to prepare compounds of formula I wherein R2 represents one of the imidazo[1,2-a]-pyridin-2-yl, imidazo [1,2-a]pyrimidin-2-yl, imidazo[1,2-c]-pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo-[1, 2-b]pyridazin-2-yl or imidazo [2,1-b]thiazol-6-yl groups mentioned in any one of claims 1 to 7) 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, R9 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 or dialkylamino- i f * * (VIM) I . - 142 - 2.4 * j i 5 sulphonyl group, and R10 represents a hydrogen, fluorine or chlorine atom or a methyl, methoxy or hydroxy group; or R9 and R10 attached at adjacent ring positions together represent a propylene or n-butylene group) with a compound of formula IX (wherein Rj., R3 and R4 are as defined in any one of claims 1 to 7 and Z4 represents a nucleophilic leaving group); g) (to prepare compounds of formula I wherein R2 represents one of the benzimidazol-2-yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl, imidazo[4,5-d]pyridazin-2-yl or purin-8-yl groups mentioned in any one of claims 1 to 7) cyclising a compound of formula X 1 1 VA. 1 2 CK D (X) (wherein none, one or two of the groups A1( Blf Cx or Dx represents a nitrogen atom and the remaining groups A1# Bx, Cx or Dj represent methine groups; i i Zl ! 143 - Ru 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 dialkylamino-sulphonyl group; and R12 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 Y, group represents a group of formula X (a) X (a) (wherein Rlf R3 and R4 are as defined in any one of claims 1 to 7; one of the groups R13 or R14 represents a hydrogen atom and the other R13 or R14 group represents a hydrogen atom, a Ci.g-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 C^g-alkyl groups or Z5 and Z6 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; (to prepare compounds of formula I wherein R2 24 ? 5 144 represents a dihydro-pyridazin-3-one or pyridazin-3-one group which may be substituted in the 2-position by a C^-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 Rx, R3 and R4 are as defined in any one of claims 1 to 7; and E represents an ethylene or ethenylene group optionally substituted by one or two C^alkyl groups) , or a reactive acid derivative thereof, with a hydrazine of formula XIII (wherein R15 represents a hydrogen atom or a C^j-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 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. (XII) H2N - NHR15 (XIII) aUG 1334 - 145
10. Use of a compound of formula I as defined in any one of claims 1 to 7 or an isomer or physiologically acceptable salt thereof for the manufacture of a therapeutic composition with an angiotensin antagonistic activity.
11. Use of a compound of formula I as defined in any one of claims 1 to 7 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.
12. Use of a compound of formula I as defined in any one of claims 1 to 7 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.
13. A method of treatment of the 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 1 to 7 or an isomer or salt thereof.
14. A method of treatment as claimed in claim 13 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. 146 %4 1
15. A method of treatment as claimed in claim 13, wherein said body is suffering from depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function or other central nervous system disorders.
16. A compound as claimed in any one of claims 1 to 7 substantially as disclosed in any one of the Examples. PR KARL THOMAE GmbH ^y Wiear Attorneys SON & CAREY ,.i
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