AU661129B2 - Benzimidazoles - Google Patents
Benzimidazoles Download PDFInfo
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- AU661129B2 AU661129B2 AU36796/93A AU3679693A AU661129B2 AU 661129 B2 AU661129 B2 AU 661129B2 AU 36796/93 A AU36796/93 A AU 36796/93A AU 3679693 A AU3679693 A AU 3679693A AU 661129 B2 AU661129 B2 AU 661129B2
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- benzimidazol
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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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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A61K31/42—Oxazoles
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Description
P/00/0 1 1 2 Regut.J8tof 3.2
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECII3CAT ION FOR A STANDARD PATENT
ORIGINAL
TO BE COMPLETED BY APPLICANT ame of Applicant: DR KARL THIOMAE GMBH Actual Inventors: Vive Ries; Norbert Hauel; Berthold Narr; Jacques Van Meel; Wolfgang Wienen; Michael Entzeroth *Address for Service: CALLINAN LAWRIE, 278 High Street, Kew, 3101, Victoria, Australia Invention Title: "BENZIMIDAZOLES" The following statement is a full description of this invention, including the best method of performing it known to me:la flenzinidazoles T:Ihe present invention relates to new benziinidazoles, processes for their preparation and pharmaceutical comnpositions containing them.
EP-A-468470 discloses benzimidazoles which are valuable angiotensin-antagonists.
It has been found that certain novel benzimidazoles have particularly valuable pharmacological properties as angiotens in-II-antagonists.
Thus, viewed from one aspect, the present invention **:*provides compounds of formula I;
R
CN
134 (wherein R, denotes a hydrogen, fluorine, chlorine or bromine atom or a fluoromethyl, difluoromethyl, trifluoromnethyl or alkyl group: R, denotes an imidazol-2-yl group optionally substituted in the 1-position by the group wherein R, denotes a phenyl or phenylalkyl group, in which the phenyl nucleus may be mono- or disubstituted by alky?., hydroxy or alkoxy groups and the 2 substituents may be identical or different, a C 3 -7cycloalkyl group or a C 1 alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertible in vivo into a carboxy group, by a trifluoromethyl, carbox l, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or from position 2 by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino or morpholino group, a 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl group optionally substituted in the 1-position by a
C
1 _.-alkyl group, an imidazolium-2-yl group substituted in the 1- and 3positions by groups Rb, which groups may be identical or different, wherein S Rb denotes a phenylalkyl group in which the phenyl S'nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different, or Rb denotes a
C
i 6 -alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertible in vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, ;an oxazol-2-yl or thiazol-2-yl group, whilst the above-mentioned imidazolium-2-yl groups may each additionally be substituted in the 4 and/or positions by a C-.s-alkyl or by a phenyl group (the substituents being identical or different) or an npropylene or n-butylene bridge may be attached via the 4 and/or 5 positions, or the above-mentioned imidazol-2-yl, oxazol-2-yl or i q thiazol-2-yl groups are each substituted in the 4 or 3 position by a phenyl group and may additionally be substituted by a Ci_ 5 -alkyl group in the remaining 4 or position or ar each substituted in the 4- and by a C.-s-alkyl group, or an n-propylene or n-butylene bridge may be attached, via the 4 and/or 5 positions, to the above-mentioned imidazol-2-yl, oxazol-2-yl or thiazol-2-yl groups, if R s represents a group which can be metabolised into a carboxy group in vivo (with the exception of an alkoxycarbonyl group having a total of 2 to 5 carbon atoms) or a 2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl group or Ra denotes a phenyl or phenylalkyl group wherein the phenyl nucleus is mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different, or a CI..-alkyl group in which the alkyl moiety is substituted by a group which can be metabolised in vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or, from position 2, by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino or morpholino group, wherein in each case an n-propylene or n-butylene bridge may be attached via the 4 and/or 5 positions, 0e an oxazolin-2-yl or imidazolin-2-yl group substituted in the 4-position by the groups R 9 and RIo and in the position by the group wherein an imino group may additionally be substituted by Ra or by an R 8 CO- (R 9 CR0) NRa-CO- group, wherein Ra is as hereinbefore defined, and
R
8
R
9 and RIo, which may be identical or different, denote hydrogen atoms, C-.s-alkyl groups or phenyl groups;
R
3 denotes a C 1 -s-alkyl group, a C 3 5 -cycloalkyl group, a -4
C,
1 4 -alkoxy or Cl 1 4 -alkylthio grouip; zu-d
R
4 denotes a hydrogen atom or a group of formula R -CH 2 wherein Rs denotes a group metabolically convertable j.vivo~ into a carboxy group, or denotes a carboxy, cyano, 2,S-dihydro-5-oxo-l,2,4-oxadiazol-3-yl, lHtetrazolyl, 1-triphenylmethyl-tetrazolyl or 2triphenylmethyl- tetrazolyl group; whilst unless otherwise specified any alkyl or alkoxv group contains 1 to 3 carbon atoms, and the phrase group metabolically zonvertable jin yvvo :into a carboxy group" as used herein denotes the esters 00: thereof of formulae 00 CO OR', CO 0- (HCR"I) 0- CO R" and CO 0- (HCR"I) 0- CO OR" wherein RI denotes a straight-chained or branched C 1 6 -alkyl group, a CS-7-cycloalkyl group, a benzyl, I-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, R"I denotes a hydrogen atom or a methyl group and denotes a straight-chained or branched C 16 -alkyl group, a C.- 7 -cycloalkcyl group, a phenyl, benzyl, 1phenylethyl, 2-phenylethyl or 3-phenylpropyl group) and Methyl 4'-t(2-n-propyl-4-methyl-6-(5,6,7,8tetrahydro-benzinidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2 -carboxylate 41- 2-n-Propyl-4-met-hy. 8-tetrahydrobenzimidazol-2-yl) -lH-benzimi&-. -l-yl] -methyl]. biphenyl-2-carboxylic acid tetrahydro-benzimidazoliumiodide-2-yl) -lH-benzimidazol- 1-yl]. -moethyl] -biphenyl-2-carboxylic acid tetrahydrobenzimidazol-2-yl) -KlH-benzimidazol--l-yl] methyl] -biphenyl-2-carboxylic acid 41- L2--n-Propyl-4-methyl-6- 8-tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yll -methyl] (lHtetrazol-5 -yl) biphenyl tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yll] methyl] (lH-tetrazol-5-yl) biphenyl tetrahydro-benzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) -biphenyl 41- 2-Ethyl-4-methyl-6- (1-rnethyl-5, 6,7, 8tetrahydro-benzimidazol-2-yl) -1H-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 41- [12-Ethyl-4-methyl-6- (1-phenyl-5,6, 7,8tetrahydro-benzimidazol-2-yl) -1H-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 6tetrahydr-o-benzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] -biphenyl-2--carboxylic acid 41-(iL2-n-Propyl-4-methyl-6-(l-erhI~yl-5,6,7,8tetrahydrobenzinidazol-2-yl) -lH-benzitnidazol-l--yl] methyl] -biphenyl-2-car-boxylic acid-sesquiihydrate tetrahydrobenzimidazol-2-yl) H-benzimidazol-l-yl] methyl] -biphenyl-2-carboxcylic acid 4'-[[2-n-Propyl-4-methyl-6-(1-isobutyl-5,6,7,8t(-etrahydrobenzitidazol-2-yl) -lH-benzitnidazol-l-yl] methyl] -biphenyl-2-carboxylic acid (rn) [2-n-Propyl-4-methyl-6- (l-carboxynetbhyl- 8"-tetrahydrobenzinidazol-2-yi) -lI--benziinidazol-lyl] -methyl] -biphenyl-2-carboxylic acid-semihydrate 4'-[[2-Cyclopropyl-4-methyl-6--(l-methyl-5,6,7,8tetrahydrobenziinidazol-2-yl) -lH-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid-semihydrate 4'-[H2-cyclopropyl-4-methyl-6-(l-methyl-5,6,7,8tetrahydrobenziini-*Lazol-2-yl) -lH-benzimidazol-1-yl] methyl] (lH-tetrazol-5-yl) biphenyl tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 4'-L(2-ethoxy-4-methyl-6-(l-methyl-5,6,7,B- -7 tetrahydrobenzimidazol-2-yl) -2H-benzimidazol- l-yl] methyl) (lH-tetrazol-5-yl) biphenyl 4'-([2-ethyl-4-methyl-6-Cl-±sopropyl-s,6,7,8tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] (lH-tetrazol-5-yl) biphenyl 4'-[L2-n-propyl-4-methyl-6-(l-isopropyl-5,6,78,tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl' methyl] -biphenyl-2-carboxylic acid 4'-[t2-n-propyl-4-methyl-6-(l-isopropyl-5,6,7,8tetrahlydrobenzimidazol-2-yl) -li-benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) biphenyl 4 t -1[2-ethyl-4-methyl-6-Cl-isobutyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 4'-[[2-ethyl-4-methyl-6-(l-isobutyl-5,G,7,8tetrahydrobenziaidazo.-2-yl) -lH-benzimidazol-1-yl] methyl] Cy) 4'-[[2-n-propyl-4-methyl-6-(l-isobutyl-5,6r7,8tetrahydrobenzimidazol-2 -yl) -lH-benzimidazol-l-yl] methyl] 4'-H[2-n--propyl-4-methyl-G-Cl-carboxytnethyl-5,6,7,8tetr-ahydrobenziinidazol-2-yl) -lHI-benzimidazol-1-yl] methyl] tetrahydro-benzimidazol-2-yl) -lH-benzirnidazol-l-yl] methyl] (lH-tetrazol-5-yl) -biphenyl and the 3-isomers, the 3-isomer mixtures and the salts thereof.
-8 Examples of the definitions of groups RI, R 2 R3 and R.
mentioned above are as follows:
R
1 may denote a hydrogen, fluorine, chlorine or bromine atom or a fluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl or isopropyl group;
R
2 may denote the imidazol-4-on-2-yl, l-methyl-5, dihydro-imnidazol-4-on-2-yl, 1-ethyl-S. cyclopentano-dihydro-imidazol-4-on-2-yl, l-n-propyl-5, spiro-cyclopentano-dihydro-imidazol-4-on-2-yl, I- 5-spiro-cyclopentano-dihydro-imidazol-4-on- 2-yl, 4, 5-dimethyl-oxazol-2-yl, 2-yl, 4-methyl-5-n-propyl-oxazol-2-yl, 4-rr butyl-oxazol-2-yl, 4-methyl--5*-n-pentyl-oxazol-2-yl, 4ttethyl-5-phenyl-oxa7.ol-2-yl, 4, 5-diethyl-axazol-2-yl, 4ethyl-5-n-propyl-oxazol-2-yl, 2-yl, 4-ethyl-5--n-pentyl-oxazol-2-yl, oxazol-2-yl, 4,5-di-n-propyl-oxazol-2-yl, n-butyl-oxazol-2-yl, 4-n-propyl-5-n-penityl-oxazol-2-yl, 4-n-propyl-5-phenyl-oxazol-2-yl, 5-methyl '-ethyloxazol-2-yl, 5-methyl-4-n-propyl-oxazol-2-*yl, diphenyl-oxazol-2-yl, 5,6,7, 8-tetrahydro-benzoxazol-2yl, 4,5-dimethyl-thiazol-2-yl, 4-methyl-S-ethyl-thiazol- 2-yl, 4-methyl-5-n-propyl-thiazol-2-yl, phenyl-thiazol-2-yl, 4,5-diethyl-thiazol-2-yl, 4-ethyl- 5-n-propyl-thiazo'L-2-yl, 4-ethyl-5-pnhenyl-uhiazol-2-yl, 4,5-di-n-propyl-thiazol-2-yl, thiazol-2-yl, 4-n-propyl.-5-phenyl-tiazol-2-yl, diphenyl-thiazol-2-yl, 5,6,7,8-tetrahydro-benz-thiazol- 2-yl, 4-methyl-oxazolin-2-yl, 4-ethyl-oxazolin-2-yl, 4n-propyl-oxazolin-2-yl, 4-isopropyl-oxazolin-2-yl, 4-nbutyl-oxazolin-2-yl, 4-isobutyi-oxazolin-2 -yl, 4-benzyloxazolin-2-yl, 4-phenyl-oxazolin-2-yl, 4,4-dimethyloxazolin-2-yl, 4-methyl-5-phenyl-oxazolin-2-yl, 4,4dimethyl-5-n-propyl-oxazolin-2-yl, 9oxazolin-2-yl, 4-methyl-imidazolin-2-yl, 4,S-dimetlaylirnidazoliri-2-yl, 4, 5-tetramethylene-irnidazolin-2-yl, 4methyl-imidazol-2-yi, 4,5-dimethyl-imidazol-2-yl, 1,4,5trimethyl-imidazol-2-yl, 1-etbhyl-4, 2-yl, 1-n-propyl-4,5-dimethyl-imidazol-2-yl, 1isopropyl-4,5-dimethyl-inidazol-2-yl, 1-n-butyl-4,5dimethyl-inidazol-2-.yl, 1-isobutyl-4,5-dimethylimidazol-2-yl, 1-cyclopropyl-4, 5-dimethyl-imidazol-2-yl, 1-cyclobutyl-4, 5-dimethyl-imidazol-2-yl, 1-cyclopentyl- 4, 5-dimethyl-imidazol-2-yl, 1-cyclohexyl-4, imidazol-2-yl, 1-cyclohepcyl-4, 5-dimethyl-imidazol-2-yl, 1-benzyl-4, 5-dimethyi.-imil-.azol-2-yl, 1- (2 -phenyl -ethyl) 4, 5-dimethyl-imidazo.-2-yl-, 1-carboxymethyl-4, dimethyl-imidazol-2-yl, 3-tnetbhoxycarbonylmetbyl-4, dimethyl-imidazol-2-yli, 1-ethoxycarbonylmethyl-4, dimethyl-imidazol-2-yl, 1-n-prop~oxycarbonylmethyl-4, c.itethyl-imidazol-2-yl, 1-isopropoxycarbonylmethyl-4, dimeth.yl-irnidazol-2-yl, 1-atninocarbonyltnethyl-4, dirnei~yl-imidazol-2-yl, 1-methylaminocarbonylmethyl-4, diehliiao*-l dimethyl-imidazol-2-yl, 4dimethyl-imidazol-2-.yl, 1- propylaminobnlehl 4, nymhl45-dimethyl-imidazo--*l 1ioropylnincarbonylmetbyl-4, 5-dimethyl 5-ime o1-2y1 ia-l-2- 1diEthylaminocarbonylmethyl-4, 5-dimethyl-aidazol-2-y, 1-die thylamiamicarbonylmethyl-4,5dimethyl imidazol-2y-dI -dipr oplrplinarbonylmethhy 5-d4,e5 -dimdal -2 imidazol-2-yl, 1-N-methyl-ethylaminocarborxylmethyl-4, dimethyl**imidazol-2-yl, 1- (2-carboxy--ethyl) dime thyl -imidazol -2 1- (2 -methoxycarbonyl -ethyl) -4,5 dimethyl-imidazol-2-yl, 1- (2 -ethoxycarbonyl -ethyl) -4,5 dimethyl-imidazol-2-yl, 1- (2 -r-propoxycarbony-1-ethyl) 4, 5-dimethyl-icnidazol-2-yl, 1- (2-isopropoxycarbonylethyl) -4,5-dimethyl-imidazol-2-yl, 1- (2-aminocarbonylethyl) 5-ditnethyl-itnidazol-2-yl, 1- (2methylaminocarbonyl -ethyl) 5-dimethyl-imidazol-2-yl, 1- (2 -ethylatninocarboryl -ethyl) 5-dimethyl-itnidazol-2- 10o v1, 1- (2-n-propylarninocarbonyl-ethyl) 4, itidazol-2-yl, 1- (2-isopropylaminocarbonylethyl) dimethyl-imidazol-2-yl, 1- (2-dimethylaminocarbonylethyl) -4,5-dimethyl-inidazol-2-yl, 1-(2diethylaminocarbonyl-ethyl) 5-dimethyl-imidazol-2-yl, 1- (2-di-n-propylaminocarbonyi -ethyl.)-4, imidazol-2-yl, 1- (2-diisopropylaminocarbonyl-ethyl) dimethyl-itaidazol-2-yl, 1- (2-N-methyl-ethylaminocarbonyl-ethyl) -4,5-dim~ethyl-irnidazol-2-yl, 1- (3carboxy-propyl) -4,5-dimethyl-imidazol-2-yl, 1- (3methoxycarbonyl-propy.) 5-di'methyl-imidazol-2-yl, I- (3-ethoxycarbonyl-propyl) 5-dimethyl-imidazol-2-yl, 1- (3-n-propoxycarbonyl-propyl) 5-dimethyl-imidazol-2-yl, 1- (3-isopropoxycarbonyl-propyl) 5-dimethyl--imidazol-2yl, 1.-(3-arinocarbonyl-propyl) 5-ditnethyl-imidazol-2yl, -methylamninocarbonyl-propyl) imnidazol-2-y., 1- (3-ethylaminocarbonyl-propyl) dimethyl-iruidazol-2-vl, 1- (3-n-propylatninocarbonylpropyl) -4,S-dimethyl-imidazol-2-yl, 1- (3isopropylaminocarbonylpropyl) 5-dimethyl-itnidazol-2yl, 1- (3-dimethylaminocarbonyl-propyl) imidazol-2-yl, 1- (3-diethylaminocarbonyl-propyl) dimethyl-imidazol-2-yl, 1- (3-di-n-propylaminocarbonylpropyl) -4,5-dimethyl-itnidazol-2-yl, 1- diisopropylaminocarbonyl-propyl) 2-yl, 1- (3-N-methyl-ethylaminocarbonyl-propyl) dimethyl-imidazol-2-yl, l-(2,2,2-trifUluoroethyl) dimethyl-imidazol-2-yl, 1- (2-hydroxyethyl) imidazol-2-yl, 1- (3-hydroxypropyl) imidazol-2-yl, 1- (4-hydroxybutyl) 2-yl. 'L-(2-tnethoxyethyl) -4,5-ditnethyl-intidazol-2-yl, 1- (3-tethoxypropyl)-4,5-dimethyl-imidazol-2-yl, 1- (4tnethoxybutyl) -4,5-ditnethyi-irnidazoi-2-yl, 1- (2ethoxyethyl) -4,5-ditnethyl-irnidazol-2-yl, 1- (3ethoxypropyl) -4,5-dimethyl-imidazci-2-yl, 1- (4ethoxybutuyl) -4,5-dimethyl-itnidazol-2-yl, 1- (2isopropoxyethyl) -4,5-dirnethy'L-imidazol-2-yl, 1-(3-n- 11 propoxypropyl) -4,5-dimetiiyl-imidazol-2-yl, 1- (4isopropoxybutyl) -4,5-dimethyl-imidazol-2-yl, 1- (2pyrrolidinoethyl) -4,5-dimethyl-imidazol-2-yl, 1- (3pyrrolbidinopropyl) 5-dimethyl-imidazol-2-yl, 1- (4pyrrolidinobutyl) -4,5-dimethyl.-imidazol-2-yl, 1- (2piperidinoethyl) S-dimethyl-imidazol-2-yl, 1- (3piperidinopropyl) 5-dimethyl-imidazol-2-yl, 1- (4piperidinobutyJ4 5-dimethyl-imidazol-2-yl, 1- (2morpholinoethyl) S-dimethyl-imidazol-2-yl, 1- (3morpholinopropyl) 5-dimethyl-itnidazol-2-yl, 1- (4morpholinobutyl) S-dimethyl-imidazol-2-yl, 1-phenyl- 4, 5-dimethyl-imidazol-2-yl, 1-benzyl-4, imidazol-2-yl, 1- (1-phenylethyl) 2-yl, 1- (2-phenylethyl) -4,5-dimethyl-imidazol-2-yl, 1- (1-phenyipropyl) -4,5-5imethyl-imidazol-2-yl, 1- (2phenyipropyl) 5-dimethyl-itnidazol-2--yl, 1- (3phenyipropyl) -4,5-dimethyl-irnidazol-2-yl, 1-methyl-4,5diethyl-itnidazol-2-yl, 1,4,5-triethyl-imidazol-2-yl, Iethyl-4-isopropyl-5-methyl-imidazol-2-yl, 1-ethyl-4isobutyl-5-methyl-itnidazol-2-yl, 1-n-propyl-4-isopropyl- 5-methyl-imidazo.--2-yl, 1-n-propyl-4-isobutyl-5-methylimidazol-2-yl, 1,4-diisopropyl-5-methyl-imidazol-2-yl, 1-isopropy1-4-isobutyl-5--met-hyl-imidazol-2-yl, 1- (2dimethylamino-ethyl) -4-isopropyl-5-tnethyl-irnidazol-2-yl, 1- (2-dirnethylamino-ethyl) 2-yl, 1- (3-direthylamino-propyl) itnidazol-2-yl, 1- (3-dimethylamino-propyl) methyl-imidazol-2-yl, 1,5-dimethyl-4-ethyl-imidazol-2- 4-isopropyl-itnidazol-2-vl, 1,5-dimethyl-4-isobutylimidazol-2-yl, 1,5-dimethyl-4-phenyl-inidazol-2-yl, Irethyl-4,5-diphenyl-irnidazol-2-yl, 1-ethyl-4,5-diphenylimidazol-2-yl, 1-n-propyl 4, 5-diphernyl-imidazol-2-yl, 1isopropyl-4, 5-diphenyl-im.dazol-2-yl, 1-carboxymethyl- 4, 5-diphenyl-imidazol-2-yl, 1-methoxycarbonylmethyl-4, diphenyl-imidazol-2-yl, I-ethoxycarbonylmethyl-4, diphenyl-irnidazol-2-yl, 4,5-trimethylene-itnidazol-2-yl, 12 1-methyl-4,5-trimethylene-imidazol-2-yl, 5,6,7,8tetrahy'dro-benzimidazol-2-yl, tetrahydro-benzimidazol-2 -yl, tecrahydro-benzimidazol-2-yl, tetrahydro-benzimidazol-2 -yl, tetrahydro-benzimidazol-2 -yl, tetrahydro-benziiidazol-2 -yl, tetrahydro-benzimidazol-2 -yl, tetrahydro-benzinidazol-2 -yl, tetrahydro-benzimidazol- 2-yl, tetraliydro-benzimidazol-2-yl, tetrahydro-benzimidazol-2-yl, tetrahlydro-benzimnidlazol- 2-yl, tetrahydro-benzinidazol-2 -yl, tetrahydro-benzimidazol-2- -yl, tetruhydro-benzitnidazol- 2-yl, 1-metiiyl-5, 6,7,8- I-etbhyl-5, 6,7,8- 1-n--propyl-5, 6,7,8- 1-isopropyl-5, 6,7,8- 1-n-butyl-5, 6,7,8- 1-isobutyl-5, 6,7,8- 1-n-pentyl-5, 6,7,8- 1-n-hexyl-5, 6,7,8- -cyclopropyl-S, 6,7,8- 1-cyclobutyl-5, 6,7,8- 1-cyclopentyl-5, 6,7,8- 1-cyclohexyl-5, 6,7,8- 1-cycloheptyl-5, 6,7,8- 1-carboxymethyl-5, 6,7,8- 1-methoxycarbonylmethyl C 4*
S
S
S
C.
S
5* 5,6,7, 8-tetrahydro-benzimidazo-2-yl, 1ethoxycarbonylmethyl-5, 6,7, B-tetrabhydro-benzimidazol-2yl, 1- n-propoxycarboriylmethyl-5, 6,7, 8-tetrahydrobenziTiidazol-2-yl, 1-isopropoxycarbonylmethyl-5, 6,7,8tetrahydro-.benzimidazol-2 -yl, 1-aminocarbonylmethyl- 5,6,7, 8-tetrahydro-benzimidazol-2-yl, I- 6, 7,8- tetrahydrobenzimidazol-2-yl, 1-ethylam~inocarbonylmethy-5, 6,7,8tetrahydro-benzimidazol-2-yl, 1-npropylaminocarbonylmethyl-5, 6, 7, 8-tetrahydrobenzimidazol-2-yl, 1-isopropylaminocarbonylmethyl- 6,7,B-tetrahydro-benzimidazol-2-yl, 1dimethylaminocarbonylmethyl-5,6,7, 8-tetrahydrobenzirnidazol-2-yl., 1-diethylaminocarbonylmethyl-5,6,7,8tetrahydro-benzimidazol.-2-yl. 1-di-ripropylaminocarbonylmethyl-5,6,7, 8-tetrahydrobenzimidazol-2-yl, 1-diisopropylaminocarbonrylmethyl- 6,7,8-tetrahydro-benzixL-iazol-2-yl, 1-N-methylethylaminocarbonylmethyl-5,G,7, 8-tetrahydrobenzimidazol-2-yl, 1-(2-carboxy-ethyl) -5,6,7,8tetrahydro-benzimidazol-2-yl, 1- (2-methoxycarbonyl- 13 ethyl) -5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2ethoxycarbonyl -ethyl) 5, 6,7, 8 -tetrahydro-benz itidazol -2 yl, 1-(2-n-propoxycarbonyl-ethyl) -5,G,7,8-tetrahydrobenzimidazol-2-yl, 1- (2-isopropoxcycarbonyl-ethayl) 5,6,7,8-tetrahydro-benzimidazol-2-yl, 1-(2arvinocarbonyl -ethyl) 6,7, 8-tetrahydro-benzimnidazol-2yl, 1- (2 -methylaminocarbonyl- ethayl) 5, 6,7, 8 -tetrahydro benziraidazol-2-yl, 1- (2 -ethy-iaminocarbonyl -ethyl) 5,6,7,8-tetraaydro-benzitnidazol-2-yl, 1-(2-npropylaminocarbonyl-ethyl) 8-tetrahydrobenzimidazol-2-yl, 1- (2 -isopropylaminocarbonyl -ethyl) 5,6,7,8-tetrahydro-benzimnidazol-2-yl, 1- (2dimethylaniinocarbonyl- ethyl) 6,7, 8-tetrahydrobenzimidazol-2-yl, 1- (2 -diethylaminocarbonyl- ethyl) 5,G,7,8-tetrahydro-benzimidazol-2-yl, 1- (2-di-npropylatninocarbonyl-ethyl) 8-tetrahydrobenzitnidazol-2-yl, 1- (2 -diisopropylaminocarbonyl -ethyl) 5,6,7,8-tetrahydro-benzimidazol-2-yl, 1- (2-~tN-ethylethylaminocarbonyl-ethyl) 8-tetrahydroberizimidazol-2-yl, 1- (3-carboxy-propyj4 -5,6,7,8tetrahydro-benzimidazol-2-yl, 1- (3-methoxycarbonylpropyl) -5,G,7,8-tetrahydro-benzimidazol-2-yl, 1- (3ethoxycarbonyl-propyl) 8-tetrahydro-benzimidazol- 2-yl, 1- (3-n-propoxycarbonyl-propyl) 8-tetrahydrobenzirnidazol-2-yl, 1- (3-isopropoxycarbonyl-propyl) 5,6,7,8-tetrah.ydro-benzimidazol-2-yl, 1- (3aminocarbonyl -propy.) 5, 6,7, 8 -tetrahydro -benz itidaz ol -2 yl, 1- (3-rethylaminocarbonyl-propyl) 8-tetrahydrobenzimidazol-2-yl, 1- (3-ethylatinocarbonyl-propyl) 5,6,7,8-tetrabhydro-benzimidazol-2-yl, 1- (3-npropylatninocarbonyl-propyl) 8-tetrahydrobenzimidazol-2-yl, 1- (3-is-)propylatninocarbonyl-propyl) 5,6,7,8-tetrahydro-benzimidazol-2-yl, dinethylaminocarbonyl-propyl)-5,6,7, 8-tetrahydrobenzimidazol-2-yl, 1- (3-diethylaminocarbonyl-propy-) 5,G,7,8-tetrahydro-benzimidazol-2-yl, 1- (3-di-npropylaminocarbonyl -propyl) 5,6, 7, 8 -te trahydro 14 ben2:iridazol-2-yl, 2.-(3-diisopropylaminocarbonylpropyl) -5,6,7,8-tet..-ahydro-benzitnidazol-2-yl, 1- (3-Nmethyl-ethylaninocarbonyl-propyl) 6, 7, 8 -tetrahydrobenzirnidazol-2-yl, l-(2,2,2-trifluoroethyl)-5,6,7,8tetr-alydro-benzimidazol-2-yl, 1-phenyl-5,6,7,8tetrahydro-benzimidazol-2-yl, 1-benzyl-5, 6,7,8tetrahydro-benzimidazol-2-yl, 1-(i-phenylethyl) -5,6,7,8tetrahydro-berizimidazol-2-yl, 1- (2-phenylethyl) -5,6,7,8tetrahydro-benzimidazol-2-yl, 1- (I-phenylpropyl) 5,6,7,8-tetrahydro-benzimidazol-2-yl, 1- (2phenyipropyl) 8-tetrahydro-benzimidazol-2-yl, 1- (3 -phenyipropyl) 8-tetrahydro-benzimidazol-2-yl, 1, 3-dimethyl-5, 6,7, 8-tetrahydro-benzimidazolium-2-yl, 1, 3-diethyl-5, 6,7, 8-tetrahydro-benzimidazolium-2-yl, 1, 3-di-n-propyl-5, 6,7, 8-tetrahydro-benzimidazolium-2-yl *~em or 1, 3-dibenzyl-5, 6,7, 8-tetrahydro-benzimidazolium-2-y1 group;
R
3 may denote a methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, l-methyl-n-propyl, tert.butyl, npentyl, 1-methyl-n-butyl, 2-methyl-n-butyl, cyclopropyl, 'GOVOcyclobutyl, cyclopentyl, methoxcy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio or isobutylthio group; and Rs may denote a carboxy, cyano, IH-tetrazolyl, 1tripiienylmethyl-tetrazolyl, 2 -triphenyitnethyltetrazolyl, methoxycarbonyl, echoxycarbonyl, npropyloxycarbonyl, isopropyloxycarbonyl, nbutyloxycarbonyl, isobutyloxycarbonyl, tert .butyloxycarbonyl, n-pentyloxycarbonyl, isoamyloxycarbonyl, n-hexyloxycarbonyl, cyc lopentyloxyfcarbonyl, cyc lohexyloxycarbonyl, benzyloxycarbonyl, 1 -phenylethyloxycarbonyl, 2phenylethyloxycarbonyl, 3 -phenyipropyloxycarbonyl, methoxymethoxycarbonyl, cinnamyloxycarbonyl, 15 acetoxymethoxycarbonyl, propioriyloxytnethoxycarbonyl, nbutyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, n-pentanoyloxymethoxycarbonyl, isopentanoyloxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, nhexanoyloxymethoxycarbonyl, cyclopentanoyloxymetbhoxycarbonyl, cyclohexanoyloxymethoxycarbonyl, phenylacetoxytuethoxycarbonyl, 1-phenylpropionyloxymethoxycarbonyl, 2 -phenyipropionyloxyme thoxycarbonyl, 3 -phenylbuty2.yloxytnethoxycarbonyl, benzoyloxymethoxycarbonyl, I-acetoxyethoyxycarbonyl, I-propionyloxcyethoxycarbonyl, 1-nbutyryloxyeth-oxycarbonyl, 1.-isobutyryloxyethoxycarbonyl, 1- n-pentanoy'loxyethoxycarbonyl, 1-i sopentanoyloxyethoxycarbonyl, 1-pivaloyloxyethoxycarbonyl, 1-nhexanoyloxyethoxycarbonyl, 1-cyclopentanoyloxyethoxycarbonyl, 1-cyclohexanoyloxyethoxycarbonyl, 1phenylacetoxyethoxycarbonyl, 1- (1-phenylpropionyloxy) ethoxycarbonyl, 1- (2 -phenyipropionyloxy) -ethoxyncarbonl., 1- (3-phenylbutyryloxy) -ethoxycarbonyl, 1benzoyloxyethoxycarbonyl, methoxycarbonyloxytnethoxycarbonyl, ethoxycarbonyloxymethoxycarbonyl, npropyloxycarbonyloxymethoxycarbonyl, isopropyloxycarbonyloxymethoxycarbonyl, nbuyoycroylxmthxcrbnl isbutyloxycarbonyloxymethoxcarbonyl, isotbutyloxycarbonyloxymethoxycarbonyl, n perttyloxycarbonyloxymethoxycarbonyl, n pentyloxycarbonyloxymethoxycarbonyl, n isoayloxycarbonyloxymethoxycarboryl, n hexonyloxycarbnyloxymethoxycarbonyl, cyclopentyloxycarbonyloxymethoxycarbonyl, cycohyloxycarbonyloxymethoxycarboyl, I benyleoxycarbonyloxymethoxycarbonyl, 1phenylethoxycarbonyloxymethoxycarbonyl, 2 phenylethpyoxycarbonyoxymethoxycarbonyl, 3 cinnamyloxycarbony.oxytnethoxycarbonyl, 1- 1G (methoxycarbonyloxy) -ethoxycarbonyl, 1- (ethoxycarbonyloxy) -ethoxycarbonyl, 1- (npropyloxycarbonyloxy) -ethoxycarbonyl, I- (isopropyloxy-carbonyloxy) -ethoxycarbonyl, 1- (nbutyloxycarbonyloxy) -ethoxycarbonyl, 1- (isobutyloxycarbonyloxy) -ethoxycarbonyl, 1- (tert .butyloxycarbonyloxy) -ethoxycarbonyl, 1- (npentyloxycarbonyloxy) -ethoxycarbonyl, 1- (isoamyloxcycarbonyloxy) -ethoxycarbonyl, 1- (nhexyloxycarbonyloxy) -ethoxycarbonyl, 1- (cyclopentyloxy-carbonyloxy) -ethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) -ethoxycarbonyl, 1- (benzyloxycarbonyloxy) -ethoxycarbonyl, 1- (1- 0* phenylethoxycarbonyloxy) -ethoxycarbonyl, 1 phenylethoxycarbonyloxy) -ethoxycarbonyl, 1- (3phenylpropyloxycarbcnyloxy) -ethoxycarbonyl, 1- V (cinnamyloxycarbonyloxy) -ethoxycarbonyl, aminocarbonyl, tnethylaminocarbonyl, ethylaminocarbonyl, npropylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-npropylaminocarbonyl, diisopropylaminocarbonyl, N-methyl ethylaminocarbonyl, N-ethyl- isopropylaminocarbonyl or 2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl group.
Preferred co~mpounds according to the invention include those of formula I wherein R, denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group or a C 1 3 -alkyl group;
R
2 denotes an imidazol-2-yl group optionally substituted in the 1-position by the group Ra,, wherein Ra denotes a phenyl group, a P:enYl(Cl--alkyl) group, a Cs-,-cycloalkyl group or a CI-s-alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertable in 17 viva into a carboxy group, or by a trifluoromethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group or from position 2 by a hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, pyrrolidino, piperidino or morpholino group, a 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl group, an imidazolium-2-yl group substituted in the 1- and 3position by groups Rb, which may be identical or different, wherein Rb denotes a Ci.
3 -alkyl or phenyl(C,.
3 -alkyl) group, 09
S.
pow an oxazol-2-yl or thiazol-2-yl group, whilst the above-mentioned imidazolium-2-yl groups may each additionally be substituted in the 4 and/or positions by a C,.4-alkyl or by a phenyl group (the substituents being identical or different) or an nbutylene bridge may be attached via the 4 and/or positions, or the above-mentioned imidazol-2-yl, oxazol-2-yl or thiazol-2-yl groups are each substituted in the 4 or position by a phenyl group and may additionally be substituted by a C 1 4 -alkyl group in the remaining 4 or position or are each substituted in the 4 and 5 position by a Cl.4-alkyl group, or an n-butylene bridge may be attached, via the 4 and/or positions, to the above-mentioned imidazol-2-yl, oxazol- 2-yl or thiazol-2-yl groups, if Rg represents a group which can be metabolised into a carboxy group in vivo (with the exception of an alkoxycarbonyl group having a total of 2 to 5 carbon atoms) or a 2,5-dihydro-5-oxo- 18 1,2,4-oxadiazol-3-yl group, or Ra denotes a C 1 _s-alkyl group in which the alkyl moiety is additionally substituted by a group which may be metabolised in vivQ into a carboxy group, by a trifluoromethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, or dimethylaminocarbonyl group or from the 2-position by a hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, pyrrolidino, piperidino or morpholino group, wherein in each case an n-propylene or n-butylene bridge may be attached via the 4 and/or 5 positions, an oxazolin-2-yl or imidazolin-2-yl group substituted by the groups R 9 and R1,, wherein an imino group may additionally be substituted by Ra, wherein R 8
R
10 and Ra each represent a hydrogen atom or a C 1 .4-alkyl group; 6* o*
R
3 denotes a C 2 alkyl group, a C3..-cycloalkyl group, a
C
2 4 -alkoxy or C2- 4 -alkylthio group; and
R
4 denotes a 4-biphenylylmethyl group subsituted in the 2'-position by the group Rs, wherein Rs denotes a group metabolically convertable in vivo into a carboxy group, or denotes a carboxy, cyano, IH-tetrazolyl, l-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group; whilst the expression "a group metabolically convertable in vivo into a carboxy group" as used hereinbefore denotes, for example, the esters thereof of the formulae CO OR', CO -0 (HCR") 0 CO and CO 0 (HCR") 0 CO OR"' wherein R' denotes a straight-chained or branched C 1 .4-alkyl 19 group or a CS.
7 -cycloalkyl group, R" denotes a hydrogen atom or a methyl group, and Rutl denotes a straight-chained or branched C, 1 4 -alkyl group or a CS- 7 -cycloalkyl group; and Methyl 4'-[t2-n-propyl-4-methyl--6-(5,6,7,8tetrahydro-benzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylate 4'-([2-n-Propyl-4-.methyl-G-(5,6,7,8-tetrahydrobenzimidazol-2-yl) -lH-Lenzimidazol-l-yl] -methyl] biphenyl-2-carboxylic acid 4'-[12-n-Propyl-4-methyl-6-(1,3-dimethyl-5,6,7,8tetrahydro-benzimidazoliumiodide-2-yl) -lH-benzimidazoll-yl] -methyl] -biphenyl-2-carboxylic acid 4'-([2-n-Propyl-4-methyl-6-(l-methyl-5,6,7,8tetrahydrobenzimidazol-2>yl)-IH-benzimidazol-1-yl] Ce) 4'-([2-n-Propyl-4-metliyl-6-Cs,6,7,8-tetrahydrobenzimnidazol-2-yl) -lH-benzimidazol-l-yl] -methyl] (lHbiphenyl 4'-([2-n-Propyl-4-methyl-6-(l-methyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] (1H-tetrazol-5-yl) biphenyl 4'-[12-Ethyl-4-methyl-6-(l-methyl-5,6,7,8tetrahydro-benzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) -biphenyl 4'-(12-Ethyl-4-methyl-6-(l-methyl-5,6,7,8tetrahydro-benzimidazol-2 -yl) -lH-benzimidazol -yl] 20 methiyl] -biphenyl-2-carboxylic acid 4-1E2-Ethyl-4-methyl-6-(1-phenyl-5,6,7,8tetrahydro-benzimidazol-2-vl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 4'-[12-n-Propyl-4-methyl-6-(l-phenyl-5,6,7,8tetrahydro-benzimidazol-2-yl) -lH-benzirnidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 4'-L[2-n-Propyl-4-methyl-6-(1-benzyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid 4'-([2-n-Propyl-4-methyl-6-(l-ethyl-5,6,7,8tetrahydrobenzituidazol-2-yl) -lH-benzimidazol--.yl] methyl] -biphenyl-2-carboxylic acid-sesquihydrate (m 0[2Ehl4mtyS6(-sp., 15678 terhdobniiao* Sv)lHbniiazl1yl tetrahydrobenzimidazol-2-vl) -1H-benziinidazol-1-yl] methyl] -biphenyl-2-carboxylic acid 4'-1C2-n-clpropyl-4-ethyl--(l-obtyl-5,6,7,8tetrahydrobenzinidazol-2-yl) -IH-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid-eiyrt 4-[2-cyclopropyl-4-methyl-6-(l-methyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -1H--benziLmidazol-1-yl] methyl] (lH-tetrazol-5-yl) biphenyl 21 4'-tL2-ethoxy-4-methyl-6-(l-methyl-5,6,7,8tetrahyrdrobenzirnidazol-2-yl) -lH-b(-*nzimidazol-l-yl] methyl3 -biphenyl-2-carboxylic acid 4'-t[2-ethoxy-4-methyl-6-(l-methyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] (lH-tetrazol-5-yl) biphenyl 4'-C[2-ethyl-4-methyl-6-(l-isopropyl-5,6,7,Btetrahydrobenaziiidazol-2-yl) -lH-benzimidazol-l-yl] methyl] (1H-tetrazol-5-yl) biphenyl 4'-K[2-n-propyl-4--methyl-6-(l-isopropyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid 4'-([2-n-propyl-4--methyl-6-(:--isopropyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH--benzimidazol-l-yl] methyl] (w .2ehl--mty--liobtl5678 tetrahydrobenzimidazol-2-yl) -lH--benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 4'-[12-ethyl-4-methyl-6-(l-isobutyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) biphenyl 4 t -[t2-n-propyl-4-methyl-6-(1-isobutyl-5,6,7,Btetrahydrobenzimidazol-2-yl) -1H-benzimidazol-l-yl] methyl] 4'-1(2-n-propyl-4-methyl-6-(1-carboxymethyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] (aa) t l-[(2-Ethyl-4-methyl-6-(I-ethyl-5,6,7,8- 22 tetrahydro-benzimidazol-2-yl) -H-benzimidazol--yl] methyl]-2- (lH-tetrazol-5-yl) -bipheny and the 3-isomers, the 3-isomer mixtures and the salts thereof.
Particularly preferred compounds according to the invention include those of formula I above wherein
R
3 and R 4 are as hereinbefore defined;
R
2 is in the 6-position and has the meanings given above; and R in the 4-position denotes a fluorine, chlorine or bromine atom, a trifluoromethyl group or a CI.
3 -alkyl group; and the 3-isomers, the 3-isomer mixtures and the salts thereof.
More particularly preferred compounds according to the invention include those of formula I above wherein R 2 in the 6-position denotes one of the imidazolyl groups mentioned above; and the 3-isomers, the 3-isomer mixtures and salts thereof.
The present invention particularly relates to the following compounds of formula I: 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8tetrahydrobenzimidazol-2-yl) -H-benzimidazol-l-yl methyl] -biphenyl-2-carboxylic acid; (b -t2-r-propyl-4-methyl 6- (1-methyl-5, 6,7,8- 23 tetrAydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl--2-carboxylic acid; tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] tetrcahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid; 4'-[[2-ethyl..4-methyl-G-(l-phenyl-5,G,7,8tetrF.hydrobenzi4midazol-2-yl) -1H-benzimidazol-l-yl] :methyl] -biphenyl-2-carboxylic acid; 4'-([2-n-propyl-4-methyl-G-(1-carboxymethyl-5,.G,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] .~::methyl] -biphenyl-2-carboxylic acid; 4 t -L[2-ethyl-4-methyl-G-(l-ethyl-5,G,7,8-tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] -methyl] (lH- -biphenyl; [12-n-prapyl-4-miethyl-G-(4,4-dimethyl-ox-azoiin-2yl) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2-carbonylic acid; Ci) 4'-f[2-n-propyl-4-methyl-6-(1,5-dimethy"L-4-phenylimidazol-2-yl) -lH-benzimidazol-l-yll -methyl] -biphenyl-2carboxylic acid; and 4'-([2-n-propyl-4-methyl-6-(4-isopropyl-1,5dimethl l-imidazol-2-yl) -lH-benzimidazol-l-yl] -methyl] biphenyl-2- carboxylic acid; and the salts thereof.
24 Viewed trom a further aspect, the invention provides a process for the preparation of compounds of the invention, said processing comprising at least one of the following steps: a) (to prepare compounds of formula I wherein R 2 denotes an oxazol-2-yl, thiazol-2-yl or imidazol-2-yl group, in which an n-butylene bridge is added via the positions and additionally the imino group in the imidazole ring may be substituted by a Cl.--alkyl group, by a phenyl(CI.
3 -alkyl) group or by a phenyl group) reacting a compound of formula II
N
HN-CX- R 2N
I
4
(II)
(wherein
R
1 R3 and R 4 are as hereinbefore defined and X denotes an oxygen or sulphur atom or an imino group optionally substituted by a C 1 .6-alkyl group, by a phenyl(Ci.3-alkyl) group or by a phenyl group) with an ahaloketone of formula III z
(III)
(wherein Z denotes a halogen atom such as a chlorine atom); b) (to prepare compounds of formula I wherein R 2 denotes 25 one of the imidazol-2-yl groups mentioned hereinbefore optionally substituted in the 1-position by the group Ra) reacting a compound of formula IV
(IV)
(wherein RI, R 3 and R 4 are as hereinbefore defined and
R
2 denotes one of the above-mentioned oxazol-2-yl groups) with an amine of formula V
H
2 N R 6 (wherein
R
6 has the meanings given for Ra hereinbefore or denotes a hydrogen atom); c) (to prepare benzimidazoles of formula I denotes a group of the formula:
R.
wherein
R
4 reacting a compound of formula VI 26
N
R~ R 3
N
(VI)
(wherein
R
1 R3 and R 4 are as hereinbefore defined and has the meanings given for R. hereinbef ore, with the exception of the imidazol-2-yl and imidazolin-2-yl groups unsubstituted in the 1-position) with a biphenyl *to**compound of formula VII 0**R *2 C2D
(VII)
(wherein R. is as hereiribefore defined and denotes a nucleophiJlic leaving group such as. a halogen.
atom, e.g. a chlorine, bromine or iodine atom, or a **substituted stilphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or ptoluenesuiphonyloxy group); d) (to prepare a compound of formula I wherein R 5 denotes a carboxy group) converting a compound of formula VIII 27 0 *0*0 ~0 0 *0* 0 0 0 *0 0 0 0*0 *00* ~0 *0 0 0 *00 *0
N
(VI II) (wherein R3., R 2 and R3 are as hereinbef ore def ined and
R
5 1 denotes a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenilysis) into a compound of formula I by hydrol~ysis, thermolysis or hydrogenolys is; e) (to prepare compounds of formula I wherein R 2 denotes a 5, 5-spiro--cyclopentano-dihydro-imidazol-4-on-2-yl group) treating a benzimidazole of formula IX
R
N
2 R-tC H84
(IX)
(wherein RI, R3 and R 4 are as hereinbef ore defined and
R
2 denotes an imidazol-2-yl group in which an nbutylene group is attached via the 4,5-position) with a base in the presence of air and light; f) (to prepare a compound of formula I wherein Rs denotes a iR-tetrazolyl group) cleaving a protective group from a compound of formula X 28
(X)
(wherein RI, R 2 and R3 are as hereinbefore defined and Rs" denotes a 1H-tetrazolyl or 2H-ietrazolyl group protected in the 1- or 2-position by a protecting group); g) (to prepare a compound of formula I wherein Rs denotes a IH-tetrazolyl group) reacting a compound of formula XI
*R
R RCN 2 S H
(XI)
(wherein
R
2
R
3 and R4 are as hereinbefore defined) with may be substituted in the 1-position by a phenylalkyl group (whilst the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different), or by a
C
1 6 -alkyl group, whilst the alkyl group may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, or by a trifluoromethyl, Z 6T^ carboxyl 29 carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, or R 2 denotes one of the imidazolium-2-yl groups mentioned hereinbefore) reacting a compound of formula XII
R
R N R R
H
2
(XII)
(wherein R, and R3 are as hereinbefore defined,
R
2 represents one of the imidazol-2-yl groups unsubstituted in the 1-position mentioned for R 2 hereinbefore and Rs"' denotes a carboxy group or a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, or a 1H-tetrazolyl or 2Htetrazolyl group protected by a protecting group) with a compound of formula XIII Z3 R7 (XIII) (wherein
R
7 denotes a phenylalkyl group (whilst the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different), or a C 1 .6-alkyl group, whilst the alkyl group may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, and Z3 denotes a nucleophilic leavig group such as a halogen 30 atom, e.g. a chlorine, bromine or iodine atom) and subsequently, if necessary, cleaving any protecting group used; i) (to prepare compounds of formula I wherein R 2 represents one of the imidazol-2-yl groups mentioned hereinbefore substituted by the groups R 8
R
9 and R 10 but wherein R 9 or R 10 must denote a hydrogen atom) reacting an aminoketone of formula XIV 9 9*9*
S..
6 **9S *9 99 9 9 5
(XIV)
(wherein RI, R 3
R
4
R
8
R
9 and R 10 are as hereinbefore defined but
R
9 or Rio must denote a hydrogen atom, and Ra' has the meanings given for Ra hereinbefore or denotes a hydrogen atom) with an ammonium salt of a lower aliphatic carboxylic acid; j) (to prepare compounds of formula I wherein R 2 denotes one of the oxazolin-2-yl or imidazolin-2-yl groups mentioned hereinbefore) dehydrating a compound of formula XV
(XV)
(wherein RI, R3, R4, R 8 R, and R 10 are as hereinbefore defined and 31 Y denotes a hydroxy or HINR, group wherein R, is as hereinbefore defined); k) (to prepare compounds of formula I wherein R 2 denotes one of the imidazolin-2-yl groups mentioned hereinbefore) reacting a compound of formula XVI 9*
I
I I
'C
I
I I A *I Ca
I
C
C
I .9 9 *9I* a
C
I I I. C
(XVI)
(wherein
R
1
R
3 and R 4 are as hereinbefore defined and
R
2 denotes one of the oxazolin-2-yl groups mentioned for R 2 hereinbefore, substituted LY groups R 9 and Rr 0 with an amine of formula XVII
H
2 N- (R 8 CH) (R 9
CR
1 O) -NH 2 (XVI I) (wherein R13, R 9 and RIO are as hereinbef ore defined) 1) (to prepare compounds of formula I wherein R 2 denotes on~e of the oxazol-2-yl groups mentioned hereinbef ore stituted by groups Ra, R 9 and RIO) dehydrating an aminoketone of formula XVIII
R
O R 9N
R
8 -0N-
N
00 (XVI II) 32 (wherein
R
1
R
3
R
4 1 R 8
R
9 and Rjj are as hereinbef ore def ined but wherein R 9 or R10 must denote a hydrogen atom); m) (to prepare compounds of formula I wherein R 2 denotes one of the imidazol-2-yl groups mentioned hereinbefore, substituted by the groups R 9 and R 10 dehydrogenating a compound of formula XIX
N
CN 3 HH4 0S (XIX) (wherein
R
1
R
3 and R 4 are as hereinbefore defined and
R
2 111 1 denotes one of the imidazolin-2-yI groups mentioned for R 2 hereinbefore, substituted by the groups
*'R
8
R
9 and R 10 but wherein R 9 or R3.
0 must denote a *0 hydrogen atom); ~cn) (to -)repare compounds of formula I wherein R C denotes a 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group) reacting an amidoxime of formula XX
R
1
N
R 2 3(XX)
NHN
OH
2 2 (wherein
N-OH
R
2 and R23 are as hereinbefore defined) optionally prepared in the reaction mixture, with a compound of formula XXI 33 Z4 CO OR, 1
(XXI)
(wherein
Z
4 denotes a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, and
R
1 denotes an alkyl, aryl or aralkyl group, preferably a lower alkyl group such as a methyl, ethyl, n-propyl or isopropyl group) and subsequently cyclisizing an acylated amidoxime thus obtained; o) converting a compound of formula I thus obtained into a salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound; and p) performing a process as defined in any one of steps to above on a corresponding protected compound and subsequently removing the protecting group used.
The reaction of step is preferably carried out in the presence of a suitable solvent such as dimethylformamide, diethyleneglycoldimethylether, triethyleneglycoldimethyl-ether or sulpholane,optionally in the presence of a base such as potassium carbonate, pyridine, triethylamine, N-ethyldiisopropylamine or N-ethyl-dicyclohexylamine, at temperatures between 0 and 250C.
If X in formula II denotes an oxygen or sulphur atom, the reaction is preferably carried out in a solvent having a boiling point above 150 0 C or in a melt at temperatures between 150 and 250"C, preferably at temperatures between 175 and 225*C.
If X in formula II denotes an optionally alkylsubstituted imino group the reaction is preferably 34 carried out in the presence of a corresponding amine as solvent, e.g. in the presence of liquid ammonia, methylamine, ethylamine, n-propylamine or isopropylamine, at temperatures between 0 and 100"C, preferably at temperatures between 20 and The reaction of step is expediently carried out in an excess of the amine used and preferably in the presence of a corresponding formamide of formula HCONHR, as solvent, optionally in a pressurised vessel at elevated temperatures, e.g. at temperatures between 100 and 250°C, preferably at temperatures between 175 and 225 0
C.
During the reaction of step any substituted carboxy group present in the group R 4 is simultaneously converted into a carboxy group or any substituted tetrazolyl group 0* present is converted into a 1H-tetrazol-5-yl group.
i ::The reaction of step is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethylsulphoxide, 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 0
C.
The reaction of step preferably produces a mixture of the 1- and 3-isomers which may subsequently, if desired, be resolved into the corresponding 1- and 3isomers, preferably by chromatography using a carrier such as silica gel or aluminium oxide.
In step functional derivatives of the carboxy group such as optionally 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. a tert.butylester, may be converted into a carboxy group by thermolysis and esters with aralkanols, e.g. a benzylester, may be converted into a carboxy group by hydrogenolysis.
The hydrolysis of step is conveniently carried out in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid, optionally in the presence of a reaction accelerator such as hexadecyl-tributyl-phosphonium bromide, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between -10 0 C and 120"C, e.g. at Stemperatures between ambient temperature and the boiling temperature of the reaction mixture.
If Rs' in a compound of formula VIII 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 en acid such as sulphuric acid, which may also be simultaneously used as solvent, at temperatures between 0 and If Rs' in a compound of formula VIII 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 trifluoroacetic acid, p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric 36 acid, preferably at the I .Ling temperature of the solvent used, e.g. at temperatures between 40 0 C and 100°C.
If Rs' in a compound of formula VIII represents, for example, a benzyloxycarbonyl group, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50*C, e.g. at ambient temperature, and 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 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 S" atom by a hydrogen atom.
The reaction of step is conveniently carried out in the presence of a base such as sodium hydrdxide or potassium hydroxide, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between -10 0 C and 120*C, e.g. at temperatures between ambient temperature and Lh- boiling temperature of the reaction mixture.
During the reaction of step any ester group present in the group R 4 is simultaneously converted into a carboxy group.
Suitable protecting groups for use in step include, for example, the triphenylmethyl, tributyl tin or triphenyl tin groups.
37 The cleaving of a protective group used in step is preferably carried out in the presence of a hydrohalic acid, preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia, in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, at temperatures between 0 and 100*C, but preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and 150 0 C, preferably at temperatures between 120 and 140°C The reaction of step is preferably carried out in a solvent such as benzene, toluene or dimethylformamide, at temperatures between 80 and 150 0 C, preferably at 125 0 C. Conveniently, either the hydrazoic acid is liberated during the reaction from an alkali r'tal azide, e.g. from sodium azide, in the presence of a weak acid such as ammonium chloride, or a tetrazolide salt obtained in the reaction mixture during the reaction with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which is also preferably produced in the reaction mixture by reacting aluminium chloride or tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric acid or 2N sulphuric acid.
The reaction of step is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or benzene optionally in the presence of an acid binding agent, such as sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride, potassium tert.butoxide, triethylamine or pyridine, whilst the latter two may 38 simultaneously be used as solvents, preferably at temperatures between 0 and 100 0 C, e.g. at temperatures between ambient temperature and If the reaction of step is carried out in the presence of an excess of the compound of formula XIII used, a corresponding imidazolium-2-yl compound of formula I is obtained at the same time.
The subsequent cleaving of a protecting group is preferably carried out by hydrolysis, thermolysis or hydrogenolysis.
The hydrolytic cleaving of a protecting group used is Spreferably carried out in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid, optionally in the presence of a reaction accelerator such as hexadecyl-tributyl-phosphonium bromide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10 0 C and 120*C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
The thermolytic cleaving of a protecting group such as the tert.butyloxycarbonyl group is preferably effected in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 0 C and 100*C.
The hydrogenolytic cleaving of a protecting group such 39 as the benzyloxycarbonyl group is effected 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 dimeLhylformamide, preferably at temperatures between 0 and 50°C, e.g. at ambient temperature, and a hydrogen pressure of 1 to 5 bar.
The reaction of step is conveniently carried out with an ammonium salt of a lower aliphatic carboxylic acid such as ammonium acetate or ammonium propionate, preferably in the presence of a solvent such as glacial acetic acid or propionic acid at elevated temperatures, but preferably at the boiling temperature of the reaction mixture, e.g. at temperatures between 100 and 150 0
C.
The dehydration of step is conveniently carried out in the presence of a dehydrating agent such as phosphorusoxychloride, sulphuric acid, polyphosphoric acid or thionyl chloride, the latter preferably being used as solvent at the same time, at elevated temperatures, e.g. at the boiling temperature of the dehydrating agent used, e.g. at temperatures between 105 and 150 0
C.
The reaction of step is conveniently carried out in a solvent such as toluene, dimethylformamide or dimethylsulphoxide, but preferably in an excess of the amine of formula XVII used, at elevated temperatures, e.g. at temperatures between 100 and 150°C. However, the reaction is preferably carried out without a solvent.
The dehydration of step is conveniently carried out in the presence of a dehydrating agent such as phosphorusoxychloride, phosphoric acid or sulphuric 40 acid, which is preferably used as solvent at the same time, at elevated temperatures, e.g. at the boiling temperature of the dehydrating agent used, e.g. at temperatures between 105 and 150 0 C. During the reaction with phosphorus-oxychloride any tert.butylester present can simultaneously be cleaved.
The dehydrogenation of step is conveniently carried out in the presence of a dehydrogenating agent such as palladium/charcoal, barium manganate or selenium dioxide, in a suitable solvent such as toluene or methylene chloride at elevated temperatures, e.g. at the boiling temperature of the solvent used, e.g. at temperatures between 110 and 150°C.
The reaction of step is conveniently carried out in S: a solvent such as methylene chloride, chloroform, tetrahydrofuran, dioxane or acetonitrile preferably in the presence of an inorganic base, such as sodium or S assium carbonate, or an organic base such as iiethylamine or pyridine whilst the latter two may simultaneously also be used as solvent at temperatures between 0 and .o The subsequent cyclization of a thus obtained acylated amidoxime is conveniently carried out in an organic solvent such as benzene, toluene, xylene, tetrahydrofuran or dioxane at elevated temperatures, e.g. at temperatures between 50 and 100 0 C, preferably at the boiling temperature of the solvent used.
The necessary starting amidoxime is conveniently prepared by reaction of a corresponding nitrile of formula XI with hydroxylamine in the presence of a solvent such as methanol, ethanol, methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or dioxane in the presence of a suitable base such as 41 sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, sodium methoxide, sodium ethoxide or sodium hydride at temperatures between 50 and 100°C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, amino or alkylamino groups may be protected during the reaction by conventional protecting groups which may be cleaved after the reaction.
Examples of suitable protecting groups for a hydroxy group include trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, benzyl and tetrahydropyranyl groups and suitable protecting groups for an amino, alkylamino or imino group include acetyl, benzoyl, ethoxycarbonyl and benzyl groups.
The optional subsequent cleaving of a protecting group used 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 acid or sulphuric acid or in the presence of an alkali metal base 'such as i.i: sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100*C, preferably at the boiling 9.'e 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 0
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 separated, preferably by 42 chromatography using a carrier such as silica gel or aluminium oxide.
The compounds of formula I obtained may be converted into the acid addition salts thereof, more particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Suitable acids for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and 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 salts thereof. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of formulae II to XXI used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature.
Thus, for example, compounds of formulae II, IV, VI, VIII, IX, X, XI and XII may be obtained by acylation of a corresponding o-phenylenediamine and subsequent cyclisation or by acylation of a corresponding o-aminonitro compound, subsequent reduction of the nitro group and cyclisation, whilst an NH-benzimidazole can optionally be converted by alkylation with a corresponding biphenyl derivative into a compound which is correspondingly substituted in the 1-position, with optional subsequent cleaving of any protecting group used.
43 The conversions of oxazol-2-yl compounds of formula IV into imidazol-2-yl compounds substituted in the 1position, as described in this application, may be carried out analogously to the synthesis of 1H-imidazole described in Angew. Chem. 71: 761 (1959) (conversion of oxazoles into 1H-imidazcies using formamide/ammonia).
The oxazk< s of formulae IV, VI, VIII, X and XI may be prepared by acylation of a corresponding a-aminoketone with a corresponding carboxylic acid chloride or carboxylic acid anhydride followed by cyclisation analogously to J. Chem. Soc. 95: 2167 (1909) and Synthesis 1970, 648, using as condensation agents strong acids such as sulphuric acid, phosphoric acid, hydrofluoric acid or POC1 3 A starting compound of formula XV is conveniently obtained by acylation of a corresponding 3-amino-alcohol and a compound of formula XVI is obtained by cyclisation of a compound of formula XV thus obtained.
The acylated a-aminoketones mentioned above can also be converted directly into the corresponding substituted imidazoles by treatment with ammonium acetate in glacial acetic acid analogously to Chem. Ber. 106: 2415 (1973) Starting compounds of formulae XIV and XVIII may be obtained by acylating a corresponding a-amino-acetone with a corresponding activated benzimidazole carboxylic acid, to obtain the desired a-amino-acetone from the corresponding a-amino acids according to Dakin/West (see Chem. Soc. Rev. 17: 91 (1988)).
A starting compound of formula XIX may be obtained by acylating a corresponding P-amino-alcohol with a corresponding activated benzimidazole carboxylic acid, the resulting compound subsequently being cyclised and 44 then reacted with a corresponding ethylenediamine.
The compounds of formula I and the physiologically acceptable salts thereof have valuable pharmacological properties. They are angiotensin-antagonists, particularly angiotensin-II-antagonists.
Those compounds of formula I wherein R 5 denotes a group metabolically convertable in vivo into a carboxy group, or denotes a carboxy or lH-tetrazolyl group, have particularly valuable pharmacological properties, since they are angiotens in- antagonists, mnore particularly angiotensin-IT-antagonists. The other compounds of formula I wherein R 4 denotes a hydrogen atom or Rs :denotes a cyano, 1-triphenylmethyl-tetrazolyl or 2triphenylmethyl-tetrazolyl group are valuable intermediates for preparing the compounds mentioned above.
By way of example, the following compounds: A =41- C (2-n-propyl-4-methyl-6- 6,7, 8-tetrahydro-
*V.
benzimidazol-2-yl) -lH-benzimidazol-l-ylil -methyl] biphenyl-2 -carboxylic acid; B 4'-([2-n-propyl-4-methyl-6-(l-methyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid; C =41- C(2-n-propyl-4-methyl-6- (1-methyl-5, 6,7, 8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yll methyl] D =4'-[(2-n-propyl-4-methyl-6-(l-benzyl-5,G,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid; 45 E 4'-((2-ethyl-4-methyl-6-(l-phenyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyrl]-biphenyl-2-carboxcylic acid-hydrate; F =4'-t[2-n-propyl-4--methyl-6-(l-carboxcymethyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid-semihydrate; G 4'-tj12-ethyl-4-methyl-6-(l-ethyl-5,6,7,8tetrahydrobenziuidazol-2-yl) -lH-benzitnidazol-l-yl] methyl] -2-(lH-tetrazol-5-yl) -biphenyl-hydrate; H 4 [t2-n-propyl-4--methyl-6- 4-dimethyl-oxazolin-2yl) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylic acid-di-trifluoroacetate;
OV,
I [(2-n-propyl-4-methyl-6-(1,5-dimethyl-4-phenylimidazol-2-yl) -lH-benzimidazol-l-yl] -methyl] biphenyl-2-carboxylic acid-hydrate; and K =4'-1[2-n-propyl-4-methyl-6-(4-isopropyl-1,5dimethyl-imidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid x 1.25 water were tested for their biological effects as follows: Description of method: Ancriotensin TI-receptor bondinca The tissue (rats lung) is homnogenised in Tris-buffer 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 mMol Tris, 5 Mo MgCl 2 0.21 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 370C with pM 2 5 ]-angiotensin II (NEN, Dreieich, FRG) with increasing concentrations of the test substance in a 46 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 MgC1 2 0.1% BSA, pH 7.40). The bound radioactivity is measured using a gamma-counter. The corresponding IC 5 s value is obtained from the doseactivity curve.
In the test described, substances A to K show the following ICso values: Substance IC 50 [nM] A 12.0 B 3.8 C 2.6 SD E 46.0 F 38.0 G 1.6 H 37.0 I 3.2 K 19.5 S* Moreover, when the above-mentioned compounds were administered in a dose of 30 mg/kg i.v. no toxic side effects, e.g. no negative inotropic effects and no disorders in heart rhythm, were observed. The compounds are therefore well tolerated.
In view of their pharmacological properties, the new compounds and the physiologically acceptable 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 47 infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
The new compounds and the physiologically acceptable salts thereof are also suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of 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, S" Parkinson syndrome, bulimia and dis ae- of cognitive function.
Thus, viewed from a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof together with at least one physiologically acceptable carrier or excipient.
Viewed from a still further aspect the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent having an angiotensin-antagonistic activity.
In particular, the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension and cardiac insufficiency, for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac 48 insufficiency after myocardial infarction and for trectLing diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, in particular for treating pulmonary diseases, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy.
More particularly, the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for alleviating central nervous system disorders.
Viewed from a yet still further aspect the invention provides a method of treatment of the human or non-human animal body to combat hypertension and cardiac insufficiency, 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, in particular to combat pulmonary diseases, arterial restenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
More particularly, the invention provides a method of treatment of the human or non-human animal body to alleviate central nervous system disorders, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
49 The dosage required to achieve these effects in adults is appropriately, when administered intravenously, to 100 mg, preferably 1 to 70 mg, and, when administered orally, 0.1 to 200 mg, preferably 1 to 100 mg, 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, ACE inhibitors, 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/ polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
Additional active substances which may be included in the combinations mentioned above include, for example, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzothiazide, cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosine, atenolol, propranolol, (di)hydralazine-hydrochloride, diltiazem, felodipin, nicardipin, nifedipin, nisoldipin, nitrendipin, captopril, enalapril, lisinopril, cilazapril, quinapril, fosinopril and ramipril. The dosage for these active substances is appropriately of the lowest recommended dose up to 1/1 of the normally recommended dose, for example, 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorothiazide, to 200 mg of ethacrinic acid, 5 to 80 mg of furosemide, 20 to 480 mg of propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipin or 5 to 60 mg of 50 nitrendipin.
The following non-limiting Examples are provided to illustrate the invention. All percentages and ratios are by weight, other than eluant or solvent ratios which are by volume.
a a
*S
0 3( Example 1 Methyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,3-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]-methyl]biphenyl-2-carboxylate a) Methyl 4'-[(2-n-propyl-4-methyl-6-amidino-lHbenzimidazol-l-v1)-methyll-biphenvl-2-carboxylate Hydrogen chloride gas is piped into a solution of 6.2 g (14.6 mMol) of methyl 4'-[[2-n-propyl-4-methyl-6-cyano- 1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate in 750 ml of absolute methanol for 3 hours at ambient temperature and the mixture is stirred for a further 2 hours at ambient temperature. After removal of the solvent the mixture is evaporated down in vacuo, the residue is taken up twice with 50 ml of methanol and ml of ether and evaporated down once more. Then the residue is dissolved in 750 ml of absolute methanol and mixed with 30 g of ammonium carbonate. After 12 hours at ambient temperature, 50 g of silica gel (particle size: 0.06-0.3 mm) are added. After filtration and evaporation of the filtrate the residue is chromatographed on silica gel (particle size 0.032-0.063 mm) using as eluant mixtures of methylene chloride and methanol of increasing polarity 4:1, 3:1 and The uniform fractions are combined and evaporated down.
S. Yield: 4.3 g (57% of theory), Foam, R, value: 0.14 (silica gel; methylene chloride/ethanol 9:1) b) Methyl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-l-yl]methvll-biphenyl-2-carboxylate g (1.0 mMol) of methyl 4'-[(2-n-propyl-4-methyl-6amidino-1H-benzimidazol-l-yl]-methyl]-biphenyl-2- 9T carboxylate, 0.13 g (1.0 mMol) of 2-chloro-cyclohexanone Sand 10 ml of liquid ammonia are heated to 60'C in a bomb S-4 for 15 hours. After cooling and evaporation of the ammonia the residue is dissolved in methanol/methylene chloride and chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluant mixtures of methylene chloride and ethanol of increasing polarity (19:1 and The uniform fractions are combined and evaporated down.
Yield: 0.1 g (19% of theory), Foam, Rf value: 0.50 (silica gel; methylene chloride/ethanol 9:1) Example 2 [2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-IH-benzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid 0.1 g (0.2 mMol) of methyl 4'-[[2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-lyl]-methylj-biphenyl-2-carboxylate and 10 mg (0.02 mMol) of hexadecyl-tributylphosphonium bromide are taken up in 10 ml of hydrobromic acid and heated to 110C for minutes. After cooling, 20 ml of ether are poured over and the mixture is diluted with 10 ml of water.
After extraction the organic phase is separated off.
The aqueous phase is adjusted to pH 7 with ammonia, the precipitate thus formed is suction filtered, washed with water and taken up in methylene chloride/ethanol The solvent is evaporated off, the residue is triturated 6. with ether and dried. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluant methylene chloride/ethanol The uniform fractions are combined and evaporated down. The residue is triturated with ether and dried.
Yield: 64 mg (64% of theory), <gT Melting point: 231-235*C (decomp.)
S
3 2
H
32 N0 2 (504.64) 53 *C Mass sper- um: (M 505 Exauple 3 4'-[[2-n-Propyl-4-methyl-6-(5,5-spiro-cyclopentano)dihydroinidazol-4-on-2-yl)-1H-benzimidazol-l-yl]methyl]-biphenyl-2-carboxylic acid-semihydrate 0-05 g (0.1 mMol) of methyl 4'-C2-n-propyl-4-metyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-lylJ-methyl]-biphenyl--2-carboxylate are dissolved in 4 ml of ethanol, mixed with 2 ml of 1 N sodium hydroxide solution and stirred for 4 days at ambient temperature.
After the addition of 4 ml of water the pH is adjusted to 6 using glacial acetic acid, the precipitate formed is suction filtered, washed with water and dried over potassium hydroxide. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluant methylene chloride/ethanol/glacial zcetic acid (50:1:0.1 and 30:1:0.1). The uniform fractions are combined and evaporated down. The residue is triturated with ether and dried.
Yield: 30 mg (59% of theory), Melting point: 310-3110C (decomp.) .09 2 0 3 2
N
4 0 3 (520.64) Mass spectrum: (M 521 Example 4 Tert.butyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8tetrahydrobenzoxazol-2-yl)-lH-benzimidazol--yl]methyl] -biphenyl-2-carboxylate a) 2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-vl)-l-ben;imidazole 2.17 g (10 mMol) of 2-n-propyl-4-methyl-6-aminocarbonyl- IH-benzimidazole and 10.25 g (77 m.Kol) of 2-chlorocyclohexanone are heated to 190'C for one hour. After cooling to ambient temperature the reaction mixture is triturated with ether and suction filtered. The residue is taken up in water and mixed with concentrated ammonia. Then it is extracted with Methylene chloride, the organic phase is washed with water, dried over magnesium sulphate and evaporated down. The residue is chromatographed on silica gel (particle size: 0,032-0.063 mm) using as eluant mixtures of methylene chloride and ethanol of increasing polarity (50:1, 25:1 and 20:1). The uniform fractions are combined and evaporated down.
Yield: 1.9 g (64% of theory), Foam, R, value: 0.20 (silica gel; ethyl acetate) b) Tert.butyl 4'-[[2-n-propyl-4-methyl.-6-(5,6,7,8tetrahydrobenzoxazol-2-yl) -lHi-benzimidazol--l-yl] methyll1-biphenyl-2-carboxylate 3.3 g (11 mMol) off 2-n-propyl-4-methyl--6-(5,6,7,8tetrahydrobenzoxazol-2-yl) -lH-benzimnidazole are dissolved in 15 ml of dimethylformamide and at 5-10'C 1.5 g (13.2 m~ol) of potassium tert.butoxide are added in batches. After 15 mninutes at 5*C 4.6 g (13.2 mMol) of tert.butyl 4 '-bromomethyl-biphenyl-2-carboxylate are added. After a further 45 minutes: at 5*C the reaction mixture is stirred into 200 ml of water. The precipitate formed is suction filtered, washed with water and taken up in 200 ml of ethyl acetate. The solution is washed with water and with saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The residue is chromnatographed an silica gel (particle size: 0.032-0.063 mm~) using as eluant methylene. chloride/ ethanol The uniform fractions are combined and evaporated down.
Yield: 4.8 g (78% of theory), Foam, Rf value: 0.23 (silica gel; methylene V- Rq;\chloride/ethanol =49:1) Examtle 41-[[2-n-Propyl-4-inethyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benziidazol--yl]-methyl]biphenyl-2-carboxylate g (3.56 mMol) of tert.buty. 4'-[[2-n-propylmethyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lHbenzimidazol-l-yll-methyl]-biphenyl-2-carboxylate, 16 il mMol) of fornamide and 40 ml of ammonia (liquid) are heated to 200 0 C in the bomb for 14 hours. After cooling, the reaction mixture is diluted with water,-the precipitate thus formed is suction filtered. The filtrate is adjusted to pH 6 with glacial acetic acid, the precipitate formed is removed by ce' :trifuging and washf-d with water. The residue is takei up in 50 ml of 2 N hydrochloric acid. By the addition of concentrated aOammonia the pH is adjusted to 6 and the precipitate thus formed is suction filtered, washed with water and dried.
Yield: 1.3 g (72% of theory), Melting point: from 2359C (decomp.) Example 6 4'-[[2-n-Propyl-4-methyl-6-(1,3-dimethyl-5,6,7,8tetrahydrobenzimidazolium iodide-2-yl)-lH-benzimidazoll-yl] -methyl] -biphenyl-2-carboxylic acid o 0.85 g (1.7 mMol) of 4'-j[[2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1ylJ-methyl)-bipheny-2-carboxylic acid are dissolved in 9 ml of dimethylsuiphoxide, mixed with 420 mg (3.7 mMol) of potassium tert.butoxide at 5 0 C and stirred for minutes. After the addition of 570 mg (4.0 mMol) of methyliodide the reaction mixture is heated to 70"C for minutes. After cooling, it is poured onto ice, the precipitate formed is suction filtered and washed with water. The residue is tdken up in 50 ml of e,.hanol, 6G' combined with 12 ml of I N sodium hydroxide solution and stirred for 5 days at ambient temperature. The solvent is evaporated off in vacua, the residue is mixed with ice and acidified with aqueous citric acid The precipitate thus formed is suction filtered, washed with water and dried.
Yield: 470 Mg (42* of theory), Melting point: 240-242'C (decump.) C34H 3 7,N 4
O
2 I (660.61) Calculated: C 51.82 H 5.65 N 8.48 Found: 61.69 51,88 8.72 Examinle 7 4' 12-n-Propyl-4-methyl-6-(1-methyl-5, 6,7,8tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid-hydrate Prepared analogously to Example 5 from tert.buty. 4'- C(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobeizoxazol-2yl) -lH-benzimidazal-.-yl]-methyl]-biphenyl-2-carboxylate and N-methyl formamide/methylamine.
*Yield: 27% of theory, *Melting pont 183-186*C
C
33
H
34
N
4 0 2 X 1H20 (536.68) Calculated: C 73.85 H 6.76 N 10.44 Found: 74.22 6.97 10.48 Examp~le 8 4 2-n-Propyl-4-methyl-6--(5, 6,7,8-tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1i-yl]-methyl]-2-(lHbiphenyl-semnihydrate a) 4'-CC2-n-propyl-4-methyl-6-(5,6,7, tetrahydrobenzoxazol-2-yl) -lH-benzimidazol-1-Yllmethyl- 1-2- Prepared analogously to Example 4b from 2-ri-propyl-4- -49methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl) -1Hbenzimidazole and 4 '-bromomethyl-2-(l-triphenylmetiiylbiphienyl.
Oil, Rf value; 0.67 (silica gel; ethyl acetate) b) 4'-1 £2-n-propyl-4-methyl-6-(5,6,7, 8-tetrahydrobenzimidazol-2-yl) -lH-benzi-midazol-1-yl)-methyl)-2bit~henvl-semihvdrate Prepared analogously to Example 5 from 2-n-propyl-4methyl-6- 6, 7,8-tetrahydrobenzoxazol-2-yl) -l biphenyl and forinamide/ainmonia.
Yield: 70% of theory, Melting point: from 230 9 C (decoinp.)
C
3 2 N. x 0. 5 H20 (537.68) Calculated: C 71.48 H 6.19 N 20.84 *Found: 71.43 6.46 21.20 Examtile 9 4'-[t2-n-Propyl-4-methyl-6-(l-methyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl]methyl 1-2- (1H-tetrazol-5-yl) biphenyl-semihydrate Prepared analogously to Example 5 from 4'-[Ci-n-propyl- 4-methyl-6- 6,7, 8-tetrahydrobenzoxazol-2-yl) -lHbenziniidazol-l-yl 3-methyl) (l-triphenyJlmethylbiphenyl and N-methylformamide/iethylamine.
Yield: 63% of theory, Melting point: from 240*C (decomp.)
C
33
H
34
N
8 x 0.5 H 2 0 (5F..7l) Calculated: C 71.84 H 6.40 N 20.31 Found: 71.63 6.45 20I.64 Example 4 2-n--Propyl-4 -ethyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-lyl]-rethylbiphenyl.
2-carboxylic acid 1.2 g (24 mol) of tert.butyl 2-n-propyl-4-methyl-6- (5,6,7,8-tetrahydrobenzoxazol-2-yl) -H-benzimidazol-lyl]-methyl]-biphenyl-2-carboxylate are dissolved in ml of methylene chloride, mixed with 8.5 ml of trifluoroacetic acid and stirred for 3 hours at ambient temperature. Then the solvent is evaporated off in vacuo, the residue is mixed with ice and made alkaline with conc. ammonia. After one hour the pH is adjusted to 5 by the addition of citric acid. The precipitate thus formed is suction filtered, washed with water and dried. The crude product is purified on silica gel (particle size: 0.032-0.063 rm) using ethyl acetate as aluant. The uniform fractions are combined and evaporated down.
Yield: 33% of theory, Melting point: 229-232*C (decomp.)
C
32
H
31
N
3 0 3 (505.62) Mass spectrum: M4* 505 Example 11 4 '-(2-Ethyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-lH-benzimidazol-1-y13-methyl)-2-(1H- -biphenyl-hydrate a) 2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2y.l.-IH-benimidazole Prepared analogously to Example 4a from 2-ethyl-4methyl-6-aminocarbonyl-lH-benzimidazole and 2-chlorocyclohexanone.
Yield: 60% of theory, Oil, Rf value: 0.17 (silica gel; bthyl acetate) b) 4'-H2-Ethyl-4-methyl--(5,6,7,8-tetrahydrobenzoxazol-2-yl) -1H-benizimidazol-±-yl] -methyl-2- (1- -bip~henyi Prepared analogously to Examnple 4b from 2-ethyl-4metlhyl-6- 8-tetrahydroberizoxazol-2-yl) -lHbenzimidazole and 4 '-bromonmethyl-2-(1-tripheny2lmethyl- -biphenyl.
Yield: 63% of theory, Oil, R'f value: 0..69 (silica gel; ethyl acetate) c) 4'-C[2-Ethyl-4-methyl-6-(-methyl.-5,6,7,Btetrahydrobenzimidazol-2-yl) -lH-benziinidazol-l-yl] methyl-2- Prepared analogously to Example 5 from 4'-[(2-ethyl-4- 6,7,8-tetrahydrobenzoxazol-2-yl) -2Hbenzimidazol---yl] -methyl-2- (2-triphenylmethyl-tetrazol- -biphenyl and N-mnethyl-formamide/methylanine.
Yield: 51% of theory, Melting point: from 1809C (decomp.)
C
3 2H 3
RN
8 X 2 0 (546.69) **Calculated x H 2 0: C 70.31 H 6.27 N 20.50 Found: 70.07 6.55 20.60 Mass spectrum: M+ 528 Examrile 12 4'-j[(2-Ethyl-4-rnethyl-6-(J.-methyl-5,6,7, 8-tetrahydrobenzimidazol-2-yl) -lH-benzimnidazol-l-yl)-methyl)biphenyl -2-carboxylic acid-hydrate a) tert.butyl 4'-(12-ethyl-4-methyl-6-(5,6,7,8tetrahydrobenzoxazol-2-yl) -2H-benz imidazol-l-yl] methyll1-bin-henvI--2-carboxylate Prepared analogously to Example 4b from 2-ethyl-4methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-lH- A4(? benzimidazole and tert.butyl 4'-bromnomethyl-biphefly-2- -52carboxylate.
Yield: 77% of theory, Melting point: 160-162*C b) 2-ethyl-4--methyl-'6-(1-methyl--5,6,7,8tetrahydrobenzimidazol-2-vl) -1I--benzimidazol-J.-yl 3meth 1 -bi hen 1-2-c-arb, )vic acid-hydra-te Prepared analogously to Examnple 5 from tert.butyl 4'- [E2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2yl) -lH-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and N-Methylformamide/methyla-mine.
Yield: 34% of theory, Melting point: 292-3006C (decomp.)
C
3 2H 3 2N4O 2 X 112 (522.66) Calculated x 1,40: C 73.54 H 6-56 N 1,0.72 00Fcund: 73.38 6.76 10.67 Mass spectrum: M~=504 E Camplg 13 4 2-Ethyl-4-methyl-6-(l-phenyl-5, 6,7 ,8-tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] -methyl) biphenyl-2-carboxylic acid-hydrate Prepared analogously to Example 5 from tert.btityl 4'- I(2-ethyl-4--methyl-6-(5, 6,7,8-tetrahydroberizoxazol-2- -1H-benzii'dazol-1-yl) -methyl] -biphenyl-'2-carboxylate and N-formyl-anilide/aniiine.
Yield: 13% of theory, Melting point: 255-257*C (decamp.)
C
37
H
34 N.02 X H 2 0 (584.73) Calculated x H2,0: C 76.00 H 6.20 N 9.58 Found, 76.36 6.18 9.59 Mass spectrum: 566 Example 14 4' 2 -n-Propyl-4-methyl-6-(l-phenyl-5, 6,7, 8-tetrahydrobenzimidaZol-2-yl) -lH--benzimidazol-1-yl) -methyl] biphenyl-2-carboxyl ic acid-semihydrate Prepared analogously to Example 5 from tert.butyl 4'- [[2-n-propyl-4-methyl-6- 6,7, 8-tetrahydrobenzoxazol-2yl) -lH-benzimidazol-l-yl]-methyl1-biphenyl-2-carboxylate and M-formyl -anilide/aniline.
Yield: 23% of theory, Melting point: 258-260'C (decoinp.)
C
38
HAN
4 2 X 1/2 H 2 0 (589.75) Calculated x 1/2 H 2 0: C 77-.39 H 6.32 N 9.50 Found:. 77.03 6.30 9.39 Mass spectrum: W~ 580 Example S. 4 t-t f2-n-Propyl-4-methyl-6-(l-benzyl-5, 6,7,8ltetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-Yl]methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example 5 froim tert.butiyl 4'- C [2-n-propyl-4-methyl-e-(5, 6,7, 8-tetrahydrobenzoxazol-2yl) -lH-benzimidazol-1-yl] -methyl]-biphenyl-2-carboxylate and N-benzyl-formnamide/benzylamine Yield: 54% of theory, Melting point: 256-258'C (decomp.)
C
3 1HN 4
C
2 (594 .77) Calculated: C 78.76 H- 6.44 N 9.42 Found! 78.50 6.49 9.35 Mass spectrum: M* 594 54 Example 16 4 '-F12-n-Propyl-4-nethyl-6-(1-ethyl-5,6,7,8t--etrahydrobenzinidazol-2-yl) -JH-benzimidazol-1-yl]methyl) -biphenyl-2-carboxylic acid-sesquihydrate Prepared analogously to Example 5 from tert.butyl 4'- C L2-n-propyl-4-methyl-6-(5, 6,7 ,8-tetrahydrobenzoxazol-2yl) -lH-benz imidazol-l-yl 3-methyl] -biphenyl-2-carboxylate and N-ethyl-formamide/ethylanine.
Yield: 17% of theory, Melting point: from 228*C (decomp.)
C
34 H36N 4 0 2 X 1.5 H 2 0 (559.71) Caic. x 1. 5 H 2 0: C 72.96 H 7.02 N 10.01 Found: 73.04 6-90 9.77 Mass spectrum: M* 532 4 (2-Ethyl-4-methyl-.6-(1-isopropyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] maethyl] -biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'- C[2-ethyl-4-methyl-6- (5 7,8-tetrahvdrobenzoxazol-2yl) -lH-benzimidazol-l-yl] -methyl]-biphenyl-2-carboxylate and N-isopropyl-formamide/isopropylauine.
Yield: 2% of theory, Melting point: 197'C
C
3 4 2 (532.69) Mass spectrum: M* 532 Example 18 4'-[[2-n-Propyl-4-methyl-6-(l-isobutyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -l1-benzimidazol-1-yl] mnethyl] -biphenyl-2--carboxylic acid Prepared analogously to Example 5 from tert.buty. 4'- [(2-n-propyl-4-methyl-6-(5, 6,7, 8-tetrahydrobenzoxazol-2yl) -lM-berlzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and isobutylamine/water.
Yield: 5% of theory, C36H 40
N
4
O
2 (560.75) Mass spectrum: 561 Example 19 4'-f42-n-Propyl-4-methyl-6-(l,3-dibenzyl-5,6,7,8tetrahydrobenzimidazolium acetate-2-yl) -lH-benzimidazol- :,ee&1-yl 3-methyl] -biphenyl-2-carboxylic acid-seinihydrate :00640Prepared analogously to Example 6 from tert..butyl 4'o 9 L (2-r-propyl-4-methyl-6-(5, 6,7,8-tetrahydrobenzimidazol- 2-yl) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2- **farcarboxylate and benzylbromide/sodium hydroxide 9 solution/glacial acetic acid.
Yield: 76% of theory, Melting point: sintering from 800C
C
46 1- 44
N
4 0 2 x CH 3 COOH x 1/2 H 2 0 (753.95) 9 .Calc. x CH COOH x 1/2 H20: C 76.47 H 6.55 N 7.43 Found: 76.46 6.65 7.76 eve$Mass spectrum: M+ 684 Example 4'-L L 2 -n-Propyl-4-methyl-6-(l-carboxy-methyla,s6,7,8tetrahydrobenzimidazol.2-yl) -lH-benzimidazol-l-yl) methy.] -biphenyl-2-carboxylic acid-semihydrate Prepared analogously to Exazaple 6 from 4'-f[2-n-propyl- 4-methyl-6-(5, 6,7,8-tetrahydrobenzimidazol-2-yl)-lHbenzimidazol-i-yij -methyl) -biphenyl-2-carboxylic acid and ethyl bromoacetate/sodium hydroxide solution.
Yield: 34% of theory, Melting point: 239-242'C
C
34 H3 4 o4 4 X 1/2 H1 2 0 (571.69) Calc. x 1/2 H120: C 71.43 H 6.17 N 9.80 Found: 71-39 6.19 9.81 Mass spectrum: M+ 562 Example 21 4, f2-Cyclopropyl-4-methyl-G- (1-methyl-S 1 6,7,8tetrahydrobenzinidazol,-2-yl) -lH-benzimidazol-l-yl)methyl) -biphenyl-2-carboxylic acid-semihydrate Prepared analogouisly to Example 5 from tert.butyl 4'- [[2-cyclopropyl-4-methyl--6-(5,6,7,8tet..ahydrobenzoxazol-2-yl) -lH-benzimidazol-l-yl methyl) -biphenyl-2-carboxylate and N-methylformamnide/methylamine.
Yield: 50% of theory, Melting point: 285-289*C
C
33
H
32
N
4 0 2 x 1/2 1120 (525.66) Calculated: C 75.40 H 6.33 N 10.66 Found: 75.24 6.44 10.42 Mass spectrum: W~ 516 The following compounds may be obtained analogously to preceding Examples: 4 1 2 -cyclopropyl-4-Methyl-6-(l-methyl5,6,7,8tetrahydrobenzimjidazol-2-yl) -lH-benzimidazol-l-yl] mnethyl]-2- (I-tetrazol-5-yl) biphenyl tetrahydrobenzimidazol-2-yl.)-lH--benz imidazol-l-yl methyl] -biphenyl-2-carboxyljc acid 4'-t[2-ethoxy-4-methyl-6-(l-methyl-5,6,7,8tetrahydrobenzimidazol-2-yl) -lH-benzixnidazol1--yl]methyl) (I-tetrazol-5-yl) biphenyl tetrahydrobenzimidazol-2-yl) -I-benzimidazol-l-y1] methyl] (1H-tetrazol-5-yl) biphenyl 2-n-propyl-4-methyl-6-(1-isopropyl-5,6,7,Stetrahydrobenzinidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -bipheriyl-2-carboxylic acid 4''-[(2-n-propyl'-4-methyl-6-(l-isopropyl-5,6,7,8tetrahydrobenziiidazol-2-yl) -lH-benzimidazol-l-yl 3mfethyl] (lH-tetrazol-5-yl) bipheriyl tetrahydrobenzimidazol-2-yl) -lH--benzimidazvl-l-yl 3- =ethyl] -bipheriyl-2-carboxylic acid tetrahydrobenzimidazol-2-yl) -lH-beIz imidazol-l-yl) methyl] (lH-tetrazol-5-yL) biphenyl 4'-((2-n-propyl-4-methyl-6-(1-isobutyl-5,6,?,8tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl]methyl] (lH-tetrazol-5-yl) biphenyl 4 '-j(2-n-propyl-4-methyl-6-(l-carboxyuethyl- 17l *4 5,6,7, 8-tetrahydrobenzimidazol-2-yl) -lH-ber1zimidazol-lyl ]-methyl] (lH-tetrazol-5-yl) biphenyl (11) 41-[ [2-n-propyl-4-Inetyl-6-(l-methyl-4,5trimaethyl ere- imida zol-2 -yl) H-benzimnidazol- l-yl] methyl] -biphenyl-2-carboxylic acid (12) 4 -1 [2-n-propyl-4-methyl-6-(1-methyl-4, trimethylene-imidazol-2-yl) -1H-berizimidazol-1-'l] methyl] (lH-tetrazol-5-yl) biphenyl E'xample 22 4'-r[2-Ethyl-4-methyl-6-(5,6,7,s-tetrahydrobenzoxazol-2yl) -lN-benzi-midazol-l-yl]-methyl]-2- (lH-tetrazol-5-yl) O. :b ipherlyl Prepared analogously to Example 10 from 4 [2ehl4 methyl-6- 8-tetrahydrobenzoxazol-2-yl) -lHbenzimidazol-l-yl) -methyl] -2-(1-triphenylmethyltetraZol-5-yl)-bipheiyl and hydrochloric acid in methanol.
Yield: 15% of theory, Melting point: 140-1420C (deconp.)
C
31 11 29
N
7 0 (515.63) Mass spectrum: 516 Exam~ile 23 4'-[[2-Ethyl-4-methyl-6-(l-ethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl) -methyl] (l11- -biphenyl-hydrate Prepared analogously to TLxample 5 from 4'-[(2-ethyl-4- 6, 7,8-tetrahydrobenzoxazol-2-yl) -lHbenzimidazol-l-yl] -methyl] (1-triphenylmethyl- -biphenyl and N-ethylformamide/ethylamine,.
Yield: 25% of theory, Meltiiig point; from l80*C (decomp.)
C-
33
"NN
8 x H 20 (560.72) Calculated: C 70.68 H 6.47 N 19.99 Found: 70.46 6.44 19.56 Mass spectrum: M' 542 Example 24 4'-I:[2-n-Propyl--4-methyl-6-(4,4-dimethyl-oxazolin-42-yi) 1H-benzimidazol-1-yl3 -methyl]-biphenyl-2-carboxylic acid di-tri fluo roacetate Prepared analogously to Example 10 from tert-butyl 4'- E2-n-propyl-4-methyl-6-(4,4-dimethlyl-oxazolin-2-y.) -1Hbenzimidazol-1-yl J-methyl]-biphenyl-2-carboxylate and ****trifluoroacetic acid.
,:*Yield: 60% of theory, Melting point: 158-159*C
C
3
,H,
1
N
3 0 3 x 2 CF 3 COOH (709.64) :Calculated: C 57.55 HI 4.69 N 5.92 *Found: 57. 76 4.72 6.02 Mass spectrum: M' 481 gmam le_ 4 t2-n-Propyl-4-nlethyl-6-(1,5-dimethyl-4-phenylimnidazol-2-yl) -1H-benzimidazol-l--yl]-methyl]-biphenyl-2carboxylic acid-hydrate a) Tert.butyl 4'-[[2-n-propyl-4-methyl-6--[N-(1-benzoylethyl) -methylaminocarbonyl] -1H-benz imidazol-l-y)Jmethyll~-biphenvl-:2-carboxylate To a soluition of 1.0 g (2.0 Mol) of tert.butyl 4'-H[2n-propyl-4-methyl -6-chlorocarbonyl--lH-benzimidazol-lyl]-methyl]-biphenyl-carboxylate in 20 ml of methylene chloride are added 20 ml of toluene and 0.44 g (2.2 InMol) of 2-methylamin-propiopheloe. The reaction mixcture is heated to 85*C and 2.0 ml of pyridine are added dropwise within 4 hours. Then the reaction mixture is evaporated down, the residue is mixed with ice water arnd extracted twice with methylene chloride.
The combined organic phases are dried over magnesium sulphate and evaporated down,. The crude product is chromatographed an~ silica gel (particle size: 0.032-0.063 mmn) using as eluant methylene chloride to start with and later mnethylene chloride/ethanol/ammfoflia (50:1:0.25 and 25:1:0.01). The uniform fractions are combined and evaporated down.
Yield: 1.0 g (79% of theory), Foam, Rf value: 0.50 (silica gel; methylene chloride/ethanol =9:1) b) Tert.butyl 4' -([2-n-.propyl-4-inethyl-6-(1,5-diluethyl- 4-phenyl-imidazol-2-yl) -l-benzimidazol-1-yl]imethyllJ-binhenvl-2--carboxylate A solution of 1.0 g (1.5 MMol) of tert.butyl 4'-EI[2-npropyl-4-mnethyl-6-[N-(l-belzoyl-ethyl) iethylaminocarbonyl]-lH-benzimidaz'. l-yl]-methyl) biphenyl-2-carboxy.ate and 1.5 g of ammonium acetate in ml of glacial acetic acid is refluxed for 2.5 hours.
Then the reaction mixture is evaporated down 'to half, the residue is mixed with ice water and extracted twice with ethyl acetate. The con-I-hined organic phases are *0***washed with water, dried over magnesium sulphate and evaporated down. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant methylene chloride with increasing amounts of ethanol 10% and 20t). The uniform fractions are combined and evaporated down.
Yield: 0.68 g (74% of theory), Foam, R, value: 0.40 (silici gel; miethylene chloride/ethanol 19:1) c) (2-n-Propyl-4-methyl-6-(l,5-dimaethyl-4-phenylimnidaZol-2-yl) -lH-benzimidazol-l-yl) -methyl) bipbenyl-2 -carboxyl ic acid-hydrate Prepared analogously to Example 10 from tez-L.butyl 4'- [2-n-propyl-4-methyl-6- (1,5-dimethyl-4-phenyl-imidazol- 2-yl) -lH-benzimidazol-1-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: from 1529C (decomp.)
C
36 H1 33
N
4 0 2 x H70 (572.72) Calculated: C 75.50 H 6.34 N 9.78 Found: 75.95 6.48 9.92 Mass spectrum: W~ 554 Exml 260 f2-n-Propyl-4-methyl-6-(l-methyl-4 imidazl>-2-yl) -1H-benzimidazol-l-yl]-inethyl]-biphenyl-2carboxyl ic acid-sesquihydrate a) Tert..butyl 4 I-f[2-n-propyl-4--methyl-6-(l-methyl-4,5diphenyl-iinidazol-2-yl) -lI-benzimidazol-l-y1 methvll)-bipohenyl-2-carboxylate Prepared analogously to Example 25b from tert-btityl 4V- [[2-n-propyl-4-methyl-6- (l-benzoyl-benzyl) methylamiriocarbonyl] -lH-benzimidazol-l-yl) -methyl)biphenyl-2-carboxylate and am~monium acetate in glacial acetic acid.
Yield: 27% of theory, Rf value: 0. 40 (silica gel; methylene chloride/ethanol 19:1) b) 4' -((2-n-Propyl-4-methyl-6-(l-methyl-4 imidazol-2-yl)-1H-benzimidazol-l-yl}-methyl]biphenyl-2-carboxylic acid-sesquihydrate Prepared analogously to Example 10 from tort.butyl 41- [(2-n-propyl-4-mnethyl-6-(1-mnethyl-4, 2-yl) -lH-benzirnidazol-1-yl)-methyl]-biphenyi-2carboxylate and trifluoroacetic acid.
Yield: 60% of theory, Melting point: 325-3280C (decomp.)
C
41 H36N 4 0, x 1. 5 H 2 0 (643.79) Calculated: C 76.49 H 6.11 N 8.70 Found: 76.53 6.15 8.75 Mass spectrum: W 616 Example 27.
4' 2-n-Propyl-4--methyl-6-(5-methyl-4-isopropylimnidazol-2-yl) -lH-benzimidazol-l-yl) -methyl]-biphenyl-2carboxyl ic acid-dihydrate-acetate 4 C, a) Tert.butyl 4'-j 2-n-propyl-4-mnethyl-6-(5-methyl-4isopropyl-imidazol-2-yl) -lH-benzimidazol-l-yl]methyll -biphenyl-2-carboxylate Prepared analogously to Example 25b from tert.butyl -41- E (2-n-propyl-4-methyl-6- (l-acetyl-2-methyl-n-propyl) methylaminocarbonyl 3-lH-benzimidazol-1-yl) -methyl) biphenyl-2-carboxylate and ammonium acetate in glacial 00 acetic acid.
Yield: 45% of theory, *Oil, Rf value: 0. 10 (silica gel; ethyl acetate/ petroleum ether =2:1) b) 4 2-r-Propyl-4-methyl-6-(5-methyl-4-isopropylimidazoJ.-2-yl) -lH-benzirnidazol-l-y4.3-methyl)biphenyl-2-carbo~cylic acid-dihydrate-acetate Prepared analogously to Example 10 from tert.butyl 41- [[2-n-propyl-4-methyl-6- (5-methyl-4-isopropyl-imidazol- 2-yl) -lH-benzimidazol-l-yll-methyl]-biphenyl-2carboxylate arnd trifluoroacetic acid.
Yield: 75% of theory, Melting point: from 155"c (decomp.)
C
32
H
34
N
4 0 2 X CH 3 COOH x 2 H 2 0 (602.74) Calculated: C 67.75 H 7.02 N 9.30 Found: 67.G9 7.02 9.53 mass spectrum: m' 506 Examp~le 28 V1-[ 2-n-Propyl-4-Inethyl-6-(4-methyl-imidazolin-2-yl) 1H-benzimiclazol-1-yl) -methyl] -biphenyl-2-carboxylio acid-di-tri fluoroacetate a) Tert.butyl 4 2-r-propyl-4-*ethyl-6-(4-methylimfidazolin-2-yl) -lH-benzimidazol-l-ylj -methyl] bi-phenvi -2-carboxylate A mixture of 0.43 g (0.8 in~ol) of tert.butyl 4'-f (2-npropyl-4-methyl-6- 4-dimethyl-oxazolin-2-yl) -lHbenzimidazol-l1-yl -methyl ]-biphenyl-2-carboxyl ate and 0.67 ml (5.8 mMol) of 1,2-diaminopropane is heated to 120 0 C for 48 hours. The yellow solid obtained after cooling to ambient teraperature is stirred..with water for .00 1 hour, suction filtered and dried. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant wiethylene chloride/ ethanol /ammonia (50:1:0.05, 20:1:.0.02 and 7:1:0.07). The uniform fractions are combined. and evaporated down.
Yield: 0.26 g (62% of theory), Foam, Rf value: 0.20 (silica gel; methylene see*chloride/ethanol -9:1 ammonia) b) (2-n-Propyl-4-methyl-6-(4-methyl-imidazolin-2yl) -1H-benziinidazol-1-yl]-methyl]-biphenyl-2carboxylic acid-di-tr f2.uoroacetate Prepared analogously to Example 10 from tert.butyl 4'- C C2-n-propyl-4-methyl-6- (4-nethyl-iidazolin-2-yl) -lHbenzimidazol-l-yl)-methyl) -biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 72% of theory, Melting point: 115-1180C (decomp., sinters from 100*C)
C
29
H
3
ON
4 0 2 x 2 CF 3 COOEI (694.63) A Calculated: C 57.06 H 4.64 N 8.07 72- -64-- Found: 57.02 5.02 8.13 Mass spectrum: M 466 Example 29 4'-[[2-n-Propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol- 2-yl)-lH-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 3.9 g (6.7 mMol) of tert.butyl 4'-[[2-n-propyl-4-methyl- 6-(N-(l-acetyl-2-methyl-n-propyl)-aminocarbonyl]-1Hbenzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate are dissolved in 50 ml of phosphorusoxychloride and stirred for 2.5 hours at 105'C. Then the phosphorusoxychloride is removed, the residue is decomposed with water at and, after cooling, mixed with conc. ammonia. The pH is S" adjusted to 5 by the addition of glacial acetic acid, the precipitate thus formed is suction filtered, washed with water, taken up in methylene chloride/methanol and dried over magnesium sulphate. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant petroleum ether/ethyl acetate/glacial acetic acid (1:1:0.002) and methylene chloride/ethanol/glacial acetic acid (20:1:0,002). The uniform fractions are combined, evaporated down, triturated with ether and suction filtered.
Yield: 2.4 g (71% of theory), Melting point: 222-223'C
C
32 H3N 3 0 3 (507.64) Calculated: C 75.71 H 6.53 N 8.28 Found: 75.61 6.59 8.36 Mass spectrum: M' 507 73 Example 2 -n-Propyl-4-methyl-6-(4-isopropyl-1,5-dimethylimidazol-2-yl) -lH-benzimnidazol-l-yl] -methyl] -biphenyl-2carboxylic acid x 1.25 water Prepared analogously to Example 5 from tert.butyl 4'f[ 2 -n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2yl) -1H-benzimnidazol-1-yl) -methyl] -biphenyl-2-carboxylate and N-methyl-for-mamide/methylamine.
Yield: 38% of theory, Melting point: from 150*C (decomp.) C 3iH3N 4 0 2 x 1..25 1420 (543.20) Calculated: C 72.97 H 7.14 N 10.32 Found: 72.95 7.02 9.94 Mass spectrum: M* 520 Excample 31 4 2-n-Propyl-4-methyl-6-(l-ethyl-4-isopropyl-5methyl-imidazol-2-yl) -2H-berizimidazol-t.-yl] -methyl)bihnyl-2-carboxylic acid Prepared anioqously to Example 5 from tert.butyl 4'- [[2-n-propyl--4-methyl-6- (4-isopropyl-5-methyl-oxazol-2yl) -lH-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylate and N-ethyl-formaimide/ethyldnmlne.
Example 32 4 I.-(2-n-Propyl-4-methyl-6-(l-isopropyl-4-isoprop~'inethyl-imidazol-2-yl) -1H-benzIrnidazol---yl 3-methyl] biphenyl-2-carboxylic acid.
Prepared analogously to Example 5 from tert.butyl 4'f(2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2yl) -lH-benzimida2'ol-l-yl]-methyl]-biphenyl-2-carboxylate and N-isopropyl-formamide/isopropylamine.
-74- Example 33 6 4 [2-n-Propyl-4-methyl--(-cyclohexyl-4iSoproyl5methyl-imaidazol-2-yl) -lH--benzimidazol-1-yl] -mrethyl] biphenyl-2--carboxylic acid Prepared analogously to Example 5 from tert.btutyl 4'- I [2-n-propyl-4-met'hyl-6- (4-isnpropyl-5-methyl-oxazol-2yl) -1H-benzimidazol---yl) -methyl3-biphenyl-2-carboxylate and N-cyclohexyl -forinamide/cyclohexylamine.
Yield: 10% of theory, C381i 4 4N 4 0 2 (588.80) Rf value: 0. 24 (silica gel; methy'lene chloride/ethanol/acetic acid 9:1:0.01) Mass sliectrum: 589 Exampe34 V 4 '-([2-n-Propyi-4-xnethyl-6-[l-(2-dimethylamino-ethyl) -4isopropyl-5-methy3.-imidazol-2-yl) -1H-benzimaidazol-1-yl)methyl] -biphenyl-2-carboxylic acid-setnihydrate Prepared analogously to Example 5 from tert-butyl 41- C (2-n-propyl-4-methyl-6-(4-isopropyl-5-mnethyl-oxazol-2yl) -lH-benzimidazol-1-yl]-methy1)-biphenyl-2-carboxylate and N- (2-dimethylamino-ethyl) -formamide/2-dimaethylaminoethylamiie.
Yield: 48% of theory, Melting point: 192-195*C (decomp.)
C
36 H4 3
N
5 0 2 x 0. 5 M 2 0 (586.79) Calculated: C 73.69 F. 7.56 N 11.93 Found: 73.53 7.55 11.94 Mass spectrum: M' =577 Example 4 [C2-n-Prop-yl-4-rnethy1-6- (1 ,5-dimethyl-4-isobutylimidazol-2-yl) -lH-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'- [(2-n-propyl-4-1nethy1-6-(4-isobutyl-5-methyl-oxazol-2yl) -lH-benzimidazol-1-yl3 -methyl) -biphenyl-2-carboxylate and N-methyl-formamide/mnethylamine.
Yieldt 64% of theory, Melting point 155-157 0 C (decomp.) C 34 E38N 4
O
2 x 0.75 1120 (548,22) Calculated: C 74.49 H1 7.28 N 10.22 Found: 74.45 7.29 10.35 Mass spectrum: KW 534 Example 36 4'-C [2-n-Propyl-4-methyl-6- imidazol-2-y.) -1H-benzimidazol-1-yl] -methyl]-biphenyl-2carboxylic acid x 0.25 water Prepared analogously to Example 5 from tert.butyl 4'- C [2-n-propyl-4-maethyl-6- (4-isobutyl-5-methyl-oxazol-2yl) -lH-benziinidazol-l-yl]-methylj-biphenyl-2-.-arboxylate and N-ethyl-forinamide/ethylamine Yield: 62% of theory, Melting point: 239-2410C
C
3 5 3
H
35 N 3 0 3 X 0.25 H 2 0 (526.17) Caic. X 0.25 1120: C 75.33 Hi 6.80 N 7.99 Found- 75.35 6.75 7.96 Mass spectrum: M' 527 -74 Example 37 6 4'-f f2-n-Propyl-4-rnethyl-6-(l-tert.butyl-4-sobutyl.5methyl-imidazol-2-yl) -IH-benzimidazol-l-yl] -methyl] biphenyl-2--carboxylic acid Prepared analogously to Exampie 5 from tert.butyl 4'- L[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2yl) -lH-benzimidazol-l-yl]-methyl] -biphenyl-2-carboxylate and N-tert.butyl-forsnamide/tert.butylamine.
Example 38 4'-f 12-n-Propyl-4-methyl-6-(l-benzyl-4-isobutyl-5methyl-imidazol-2-yl) -lH-benzimidazol-l-yl] -methyl] biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 41- [[2-n-propyl-4-inethyl-6-(4-isobutyl-5-methyl-oxazol-2yl) -lH-benzimidazol-1-yl] -methyl]-biphenyl-2-carboxylate and N-benzyl-forrmamide/benzylamine.
Example 39 4f[2-n-Propyl-4-methyl-6-[l-(2-morpholiio-ethyl) -4isobutyl-5-methyl-imidazol-2-yl) -lH-benzimidazol-1-yl3- 00. methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'- [f2-n-propyl-4-methyl-6-(4-isobutyl-5-rnethyl-oxazol-2yl) -1H-benzimidazol---yl] -methyl] -biphenyl-2-carboxylate and N- (2-morpholino-ethyl) -formamide/2-inorpholinoethylamine.
Yield: 30% of theory, Melting point: 201-203'c (decomp.)
C
39
H
47
N
5 0 3 (633.85) Calculated: C 73.90 H- 7.47 N 11.05 Found: 73.65 7.45 11.07 '7 Mass spectrum: M+ 633 Example 4'-L [2-n-Propyl-4-methyl-6-[l-(2-methoxy-ethyl) -4i6sobutyl-5-met-.Iyl-imidazol-2-y1)-lH-benzimidazol-' *yl) methyl]-biphenyl-2-carboxylic acid-hydrate Prepared analogously to Example 5 from tert.batyl 4't E2-n-propyl-4--methyl-6-(4-isobutyl-5-methyl-oxazol-2yl) -1H-benzimniAdazol--l-yl}-methyl]-biphenyl-2-carboxylate arnd N- (2-methoxy-ethyl) -for-mamide/2-mettioxy-ethylamine.
Yield: 29% of theory, Melting point: 135-137*C (decomp., sintering from 110-C)
C
36
H
42
N
4 0 3 .x H-0 (596.78) Calculated: C 72.46 H 7.43 N 9.39 Found: 72.10 7.45 9.77 *Mass spectrum: 578 Example 41 4 '-[[2-ri-Propyl-4-mnethyl-6- El- (2-hydroxy-ethyl)-4methyl] -biphenyl.-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'- C [2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2yl) -lH-benzimidazol-l-yl3 -methyl] -biphenyl--2-carboxylate and N- (2-hydroxy-ethyl) -formamide/2-hydroxy-ethylamine.
Exair~le 42 [2-n-Propyl-4-methyl-6-fl-(3-dimethylamilo-propyl)- 4-isobutyl-5-methyl-imidazol-2-yl] -lH-benzimidazol-lyl] -methyl) -biphenyl-2-carboxylic acid Prepared analogously to Example 5 fro~m tert.butyl 4'yl) -lH-benzimidazol-i-ylj -methyl] -biphenyl--2-carboxylate and N- (3-di-methylamnino-propyl) -forimainide/3dimethylaxnino-propylam-ie.
Exa~nple 43 4' L 2 -n-Propyl-4-mnethyl-6-(1-carboxymethyl-4isobutybiphernyl-2-carboxylic acid Prepared analogously to Example 5 from tert-butyl 4'- [2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2yl) -1H-benziluidazol-1-yl]-methyl]-biphenyl-2-.carboxylate and N-forznylglycineethylester/glycineethylester.
Example 44 2-n-Propyl-4-methyl-6-(l-aminocarbonylinethyl-4isobutyl-5-methyl-ijmidazol-2-yl' '-H-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylate Prepared analogously to Example 5 from tert.butyl 4'- £(2-n-propyl-4-maethyl-6- (4-isobutyl-5-methyl-oxazol-2yl) -lH-benzimidazol-l-ylJ -methyl] -biphenyl-2-carboxylat( and N-formyl-glycinamaide/glycinamide.
Example [[2-n--Propyl-4-methyl-6- (2-carbox~y-ethyl) -4isobutyl-5-methyl-iiidazol-2-yl) -lH-benzimidazol---yl] methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert~butyl 4'- [2-n-propyl-4-met-hyi-6-(4-isobutyl-5-methyl-oxazol-2yl) -lH-benzimidazol- t-yl 3-methyl]3-biphenyl--2-carboxylate and ethyl 3-formylamino-propionate/ethyl 3- 01,1-7 :4,aminopropionate.
79 The following may be obtained analogously: 4 C2-n-propyl-4-methyl-6-(l, 5-dimethyl-4-isobutylbiphenyl 4,-f t2-n-propyl-4-methyl-6-(l-n-propyl-4-isobutyl-5methyl-imaidazol-2-yl) -lH-benzimidazol-l-yl]-methyl]-(Hbiphenyl 4 (2-n-propyl-4-methyl-6-(l-(2-dimethylamino-ethy1) -4isobUtyl-5-methyl-imnidazol-2-yl]J-lHi-benzimidazcl-Kl-yljmethyl]- H-tetrazol-5-yl) biphenyl Example 4( VO...Methyl 4 '-([2-n-propyl-4-methyl-6-(4-methyl-imidazol-2yl) -lH-benzimid.azol-l-yl) -methyl]-biphenyl-2-carboxylate A solution of 0.35 g (0.7 mI~ol) of methyl 12-nbezmdzliy]mty]bpey--abxlt in ml of toluene is mixed with 0.16 g palladium (10% on activated charcoal) under nitrogen and the mixture is refluxed for 66 hours. Then the toluene is evaporated off, the residue is taken up in methylene chloride, filtered and evaporated down. The crude product is chromatographed on silica gel (particle size: 0.032- 0.063 mm) using as eluant methylene chloride to start with, later followed by methylene chloride/ethanol/ amm~onia (50:1:0.05, 20:1:0,02, 10:1:0.01 and 5:1:0.005).
The uniform fractions are combined and evaporated down.
Yield: 0.30 g of theory), Mass spectrum: M+ 478 'go ExampLe 47 (2-ri-Propyl--4-methyl-6- 4, 5-tri'netbyl-imidazol-2yl) -1H-benzimidazol-l-ylJ-methylJ-biphenyl-2-carboxylic aCid 0.25 x H 2 0 Prepared analogously to Example 5 from t* .butyl 4t-[(2f-prcpyl-4-miethyl-6-(4 ,5-dimethyl-oxazol-2-yl) -1Hbenzimnidazol---yl] -methyl]-.biphenyl-2--carboxylate and Nrethyl-fornamide/methylamine.
Yield; 61% of theory, Melting point: 217-219'C (decomp.)
C
31
H
32 Nt 4 0 2 X 0.25 H 2 0 (497.13) calculated: C 74.90 H 6.59 N 11.27 Found: 74.84 6.58 11.26 **Mass spectrium: W* 492 Example 48 £[2-n-Propyl-4-methyl-6- -ethyl-4, imidazol-2-yl) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'- [[2-n-propyl-4-methy1-6- 5-dimethyl-oxazol-2-yl) -1Hbenzimidazol-l-yl]-methyl3-biphenyl-2-carboxylate and Nathylformamide/ethylamine.
0...*Example 49 £[2-n-Propyl-4-methyl-6- (l-methyl-4, imidazol-2-yl) -lH-b:enzimidazol-l-yl)-methyl]-2-(lH- -biphenyl Prepared analogously to Example 5 from 4'-[(2-n-propyl- 4-methyl-6- 5-diethyl-oxazol-2-yl) -lH-benzimidazol-lyl3-methyl]-2-(2-triphenylinethyl-tetrazol-5 .yl) -bipheny.
and N-methyl-formiamide/rnethylamine.
Examp~le 4 1 -[:[2-n-Propyl--4-methyl-6- (l-ethyl-4, imidazol-2-yl) -lH-benzimidazol-1-y1] -methyl] (lH- -biphenyl Prepared analogously to Example 5 from 41-(2-n-propyl- 4-muethyl-6- 5-dimethyl-oxazol-2-yl) -lH-benzimidazol-lyl] -methyl] (2-triphenylmethyl-tetrazol-5-yl) -biphenyl and N-ethyl-formanide/ethylamiie.
Example 51 4 '-L[2-n-Propyl-4-methyl-6-(1-isopropyl-4,5-dimnethylimidazol-2-yl) -lH-benzimidazol-1-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'- [[2-n-propyl-4-methyl-6- 5-dimethyl-oxazol-2-yl) -lHbenzimidazol--y.] -methyl) -biphenyl-2-carboxylate and Nisopropyl-formamide/ isopropylamine.
Examnle 52 4' -t 2-n-Propyl-4-inethyl-6-f1- (2-dimethylamino-ethyl) 4, 5-dimethyl-intidazol-2-yl]-lH-benzimidazol-l-yl]methyl] -bipheriyl-2-carboxylic acid Prepared analogously to Example 5 fronm tertbutyl 4"- C [2-n-propyl-4-xnethyl-6-(4,5-dimethyl-oxazol-2-yl) -11benzimidazol-l--yl]-methyl]-biphenyl-2-carboxylate and N- (2-dimethylamino-ethyl) tormamide/2-dinethylamiioethylamine.
Example 53 4 [2-n-Propyl-4-methyl-6-[l-(2-2norpholino-ethyl) dimethyl-imidaZol-2-yl]-H-benzimidazol1..yl] -methyl]biphenyl-2--carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'- [[2-n-propyl-4-methy.-6- 5-dimethyl-oxazol-2-yl) -lHbenzimnidazol-1-ylj -methyl) -biphe-nyl-2-carboxylate and l'- (2-morpholino-ethyl) -formamide/2-morpholino-ethylamine.
Example 54 4 2-n-Propyl-4-rnethyl-6-(l-(2-morpholino-ethyl)-4, diethyl-imidazol-2-yl3jI-H-benziiidazol-1-yl]-methyl3-2- -biphenyl Va...Piepared analogously to Example 5 from 4'-[[2-n-propyl- 4-methyl-6- 5-diethyl-oxazol-2-yl) -lH-benzimidazol-lyl)-methyl]-2-(2-triphenylmetiyl-tetrazol-5-yl) -biphenyl and N-(2-morpholino-ethyl) -formai.ide/2-morpholinoe-thylamine.
Example 4'-L (2-n-Propyl-4-methyl-6-[l-(2-mnethoxy-ethyl)-4,5dimethyl-imidazol-2-yl3-IH-benzimidazol-l-yl]-tethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert~buty. 41- C [2-n-propyl-4-methyl-6-(4 ,5-dimethyl-oxazol-2-yl) -lHbenzimidazol-1-yl]-methyl3-biphenyl-2-carbo.xylate and N- (2-methoxy-ethyl) -formamide/2-methoxy-ethylamine- 9 Example 565 4 2-n-Propyl-4-methiyl-6-(1-(2-methoxy-ethyl)
F-
dimethyl-iinidazo1-2-y. J-lH-benzimidazol-l-yl 2-methyl 3-2- Prepared analogously to Example 5 from 41-t[2-n-propyl- 4-methyl-6- 5-dimethyl-oxazol-2-yl) -lH-benzianidazol-lyl]-inethyl) (2-triphenylmethyl-tetrazol-5-yl) -biphenyl and N- (2-methoxy-ethyl) -formamide/2-methoxy-ethylamine.
Example 57 4 L2-n-Propyl-4-methy1-6-[l-(2-carboxy-ethyl) dimethyl-imidazol-2-yl] -lH-benzimidazol-l-yl] -methyl 1-2biplienyl-carboxylic acid Prepared analogously to Example 5 from tert.butyl 41j (2-n-propyl-4-Methyl-6- 5-dimnethyl-oxazol-2-yl) -lHbenzimidazol-l-yl] -methyl] -1iphenyl-2-carboxylate and ethyl N-formyl-3-aminopropionate/ethy1 3aminopropionate Example 58 4' -([2-n-Propyl-4-methyl-6- (l-methyl- -diethylimidazol-2-yl) -1H-benzimidazol-1-yl]-mnethylj-biphenyl-2carboxylic acid x 0.25 2 Prepared analogously to Example 5 from tert.butyl 4'- [[2-n-propy2.-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-lHbenzimida2ol-l-ylJ-methyl3-biphenyl-2-carboxylate and Nmethyl-formnamide/methylamine.
Yield: 65% of theory, Melting point: 247-249'~C (decontp.)
C
33
H
36
N
4 0 2 X 0.25 H 2 0 (525.18) Calculated: C 75.47 H 7.01 N 10.67 Found: 75.43 7.11 10.68 t~ S S S. t
IS..
I p *5*5 S S
S
*C
I S S
S
~1 *5 S
IS..
p *1 S S
SOS.
-76- Mass spectrum: M* 520 [2-n-Propyl-4-methyl-6-(l-metyl-imidalin..2.yl) 2IH-benzimidazol-.-yl] '-methyl] -biphenyl-2-carboxylic acid Prepared by heating tert..butyl £2-n-propyl-4-methyl- 6- (N-methylamino) -ethylaminocarbonyl] -iHbenziinidazol-l-yl] -methyl] -biphenyl-2-carboxylate in phosphorusoxyc'nloride and isolating analogously to Example Yield: 30% of theory, C29H 30
N
4 0 2 (466.59) Rf value: 0. 50 (methylene chloride/methanol/acetic acid 2:1:0.02) Mass spectrum: =467 Excample 2-n-Propyl-4-methyl-6--[l-(2-dimaethylamino-ethyl) 4, 5-diethyl-imidazol-2-yl]3-1H-benzimidazol-1-yl 3methyl] -biphenyl-2-carboxylic acid-dihydratetrihydrochici-ide Prepared analogously to Example 5 from tert.bu-tyl 4'- [[2-n-propyl-4-metbhyl-6-(4,5-diethyl-oxazol-2-yl) -lHbenzimidazol-l-yl] -methyl] -biphenyl-2-carboxylate and N- (2-dimethylamnino-ethyl) -formamide/2-dimethylaminoethylamine.
Yield: 14t~ of theory, Melting point: 210*C (decomp.)
C
36 H4I 3
N
5
Q
2 x 3 HC. x 2 H 2 0 (723.21) Calculated: C 59.79 H 6.97 N 9.69 Cl 14.71 Found: 59.28 6.92 9.75 14.26 Example 61 41-C 2-n-Propyl-4-m'ethyl-6-[1-(2-morpholino-ethyl) diethyl-imnidazol-2-yl]-H-benzimidazol. U-yl] -methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 5 from tert.butyl 4'- [[2-n-propyl-4-methyl-6-(4, 5-diethyl-oxazol-2-yl) -1Hhenzimidazol-1-yl'-methyl] -biphenyl-2-carboxylate and N- (2-morpholino-ethyl) -formainide/2-morpholino-ethylamine.
Y1ield: 41% of theory, Melting point: from 196*C (decomp.)
CUH
45 NS0 3 (619.82) Mass spectrum: MW 619 4 t- (2-n-Propyl-4-methyl-6-[l-(2-methoxy-ethyl) -4 dietbyl-imidazol-2-yl] -1H-benzimidazol-1-yl]3-'3ethyl) V. biphenyl-2-carboxylic acid hydrate Prepared analogously to Example 5 from tert-butyl 4'benzimidazol-1-yl]-methyl] -bipbhenyl-2-carboxylate and N- (2 -methoxy-ethyl) -forinaiide/2-methoxy-ethylamine.
C
3
SH
40 N,.0 3 x H20 (582.76) Calculated x H 2 0 C 72.14 H 7.27 N 9.61 **Found: 71.99 7.19 9.84 Mass spectrumn: 563 Example 63 4 2-n-Propyl-4-methyl-6-(4,5-diethyl-oxazol-2-Yl]-lHberizimidazol-1-vll-methvll-biphenyl-2-carboxvlic-acid- Prepared analogously to Example 29 from tert.butyl 4'- [[2-n-propyl-4-methyl--6-(N-(l-propionyl-n-propyl) aminocarbonyl] -lH-benzimidazol-1-yl] -methyl] -biphenyl-2carboxylate and phoriasoxychloride.
Yield: 97% of theory, 194 Melting point: 250-255*C
C
32 H3 3
N
3 0 3 (507.64) Calculated: C 75.71 H 6.55 N 8.28 Found: 75.77 6.59 8.46 Mass spectrum: M+ 507 Exaple 4 4 t2-n-Propyl-4-methyl-6-(4,5-diethyl-1H-imidazol-2yl]-1I-benzimidazol-l-yl)-mnethyl]-2-(lH-tetrazol-5-yltiph e n vl Prepared analogously to Example 25b from propyl-4-methyl-6-(N- (l-propionyl-n-propyl) O.ainrocarbonyl]3-lH-benz imidazol.-l-yl 3-methyl 3-2- (2- -biphenyl and amnmonium, acetate/glacial acetic acid.
Yield: 27% of theory, Melting point: 221-223'C *C3 2
"H
34
N
8 X H 2 0 (530.69) Calculated: C 70.05 H 6.61 N 20.42 Found: 70.79 6.98 18.83 Mass spectrum: M' 530 Example 4'-([2-n-Propyl-4-methyl--6-(4,5-dimethyl-oxazol-2-ylj- 1H-benzimidazol-l-yl1-methy-l--biphenvl-2-carbomevlic acid Prepared analogously to Example 29 from tert.butyl 4'- 1(2-n-propyl-4-mncthyl-6-rN-(l-acetyl-ethyl) aminocarbonyl] -lH-benz imidazol-1-yl] -methyl 3-biphenyl-2carboxylate and phosphorusoxychior-ide.
Yield: 88% of theory, Melting point: 259-260'C (decomp.)
C
30
HZ
9
N
3 0 3 X 0.25 120 (484.09) Calculated: C 74.44 H 6.14 N 8.68 Found: 74.33 6.14 8.69 Mass spectrum: M' 479 Example 66 4 [[2-r-Propyl-4-methyl-6- (1-methyl-S. 6,7,8tetrahydrobenzimidazol-2-yl] -lH--benzimidazol-1-yl] methyl] -2 5-dihydro-5-oxo-l ,2,4 -oxadiazol-3-yl)binhenyl a) 4'-[[2-n-Propyl-4-methy1-6-(l-methyl-5,6,7,8tetrahydrobenz imidazol-2-yl] -1H-benziinidazol-1-yl] methyllr21.hdroxcarbamimidoyl)-bihy___ To a solution of 8.4 g (0.12 Mol) of hydroxylaminehydrochloride in 30 ml of dimethylsulfoxide are added 30ml of a sodium methoxide solution (30% in methanol) at :room temperature. After 10 minutes, 4.5 g (10 ml-lol) of [[2-n-propyl-4-methyl-6- (1-methyl-S 1 6,7,8- .:..tetrahydrobenzimidazol-2-yl]-lH-benzimid zol-1-y1) methyl]-2'-cyano-bipheny. are added to this solution and the suspension obtained is heated to 906c for 12 hours.
After cooling to room temperature the reaction mixture is poured into 200 ml of ice water. The precepitate obtained is suction filtered, washed with water, dissolved in methylene chloride and chromatographed on 6* silica gel (particle size: 0.023-0.063 Imm) using as eluant mixtures of ethyl acetate, ethanol and concentrated ammonia (19:1:0.06, 19:1:0.08, 1.9,1:0.1 and The uniform fractions are combined, evaporated, triturated with ether and dried.
Yield: 1.2 g (25% of theory), Melting point: 221-224*C (decomp.) b) 4'-[2-n-Propyl-4-xnethyl-G-(l-methyl-5,6,7,8tetrahydrobenzimidazol-2-yl] -1H-benzimidazol-1-yl]methyl] -2 5-dihydro-5-oxo-l, 2, 4-oxadiazol-3-yi) binhenyl To a solution of 0.5 g (1 mMol) of 4 4 -[[2-n-propyl-4methyl-6-(l-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl]- TF 1H-benzimidazol-l-yll-methyl]-2'-(hydroxycarbamimidoyl)biphenyl and 0.2.4 Ml (1 Mi~ol) of triethylamine in 40 nl of tetrahyrdrofuran is added a solution i.f 0.1 ml (1 m.Mol) of ethyl chioroformate in 1 ml of methylene chloride at 50C. After 2 hours at room temperature, the precipitate forme is suction filtered. After evaporation of the fill-te the residue obtained is dissolved in 5 ml oi. xy'7ene and refluxc-d for 90 mninutes.
After cooling to room temperature, the reaction mi-,Cture is mixed with 20 ml of ethyl acetate, washed with water and dried over magnesium sulfate. "'i-ter evaporating the organic phase, the obtained residue is chromatographeon silica gel (particle size: 0.032-0.063 mmn) using as eluant methylene chloride with increasing amounts of :ethanol (0 to The unifor. fractions are combined, evaporated, triturated with ether and dried.
Yield: 80 mg (14*t of theory), Melting point: 199*C (decomp.) Rf-value: 0.33 (silica gel; ethyl acetate/ methanol I 3:1) :C34H34N 6
O
2 (558.59) Mass spectruin: 557 The following compound may be obtained analogously to Example 66: 4 [2-n-Propy:V4-methyl-6-(l,4,5-trimethyl-imidazol-2ylJ-lIH-benzimidazol-1-yl]-methyl] -2 -12,4-oxcadiazol1-yl) -biPhenyl In the Examplas of Pharmaceutical Formulations which follow, any suitable compouind of formula I, particularly those compounds wherein R, denotes a group metabolically convertable _in vivo into a carboxy group, or R 5 denotes a carboxy or IH-tetrazolyl group, may be used as the active substance: Example I Ampoules containing 50 mg of active substance per 5 ml Active substance 50 mg
KH
2 PO 2 mg Na 2 HPOQ x 2H 2 0 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 0* Ampoules containing 100 mg of active substance per 5 ml o**o Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglyco3-polypropyleneglycol block polymer 250 mg Water for injections ad 5 ml Preparation: Methyl glucamine is dissolved in some of the water and the active substance is dissolved with stirring and heating. After the addition of solvents, water is added to make up the desired volume.
Example III Tablets containing 50 mg of active substance Active substance calcium phosphate Lactose Corn starch Polyvinylpyrrol idone Magnesium stearate 50.0 mg 70.0 mng 40.0 mg 35.0 mg 3.5 mg 1.5 mg~ 200.0 mg *5
S
S. S
S
S.
S
S
*o Preparation: The active substance, CaHPO 4 lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 501C in a circulating air dryer and screened again.
After the lubricant has been added, the granules are compressed in a tablet making machine.
Example IV Coated tablets containing 50 mg of active substance
S.
S
S.
Sn.
S
Active substance Ly sine Lactose Corn starch1 Gelatin Magnesium stearate 50.0 mg 25.0 mg 60.0 mg 34.0 mg 10.0 mg 1.0 mCT 180.0 mg Preparat ion: The active substance is mixed with the excipients anld 09 moistened with an aqueous gelatin solution. After screening and drying the granules are mixed with magnesium stearate and compressed to form cores.
The cores thus prodced are covered with a coating by kno~-n methods. A colouring may be~ added to the coating suspension or solution.
ql.
)Exampl~Je V Coated tablets containing 100 mg of active substance Active substance Lysine Lactose Corn starch Polyvinylpyrrol.idone Microcrystalline cellulose Magnesium ctearate 100.0 Mg 50.0 mg 86.0 mg 50.0 mg 2.8 mng 60.0 mg 1.2 maf 350.0 mg
S
S
*5 OSeS S S. S S
S
C 5
S
0 *S S. S 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 459C.
Affter drying, it is screened again and the magnesium stearate is added. This mixture is compressed into cr~res.
Tb.o cores thus produced are covered with a coating by known methods. Colourings may be added to theg coating suspension or solution.
Example VI Capsules containing 250 mg of active substance 0 6 Active substance Corn starch I-Tagnesium stearate 250. 0 mg 68. 5 mg 1. 5 mgi 320.0 mg q3 Preparation: The active substance and corn starch are mixed toqetheand 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 I hard gielatin capsules.
Exam'Ple V=T oral suspension containing 50 mg of active substance per Ml Active substance 50.0 mg Hydroxyethylcellulose 50.0 mg :.*Sorbic acid 5.0 mg sorbitol 600.0 mc, Glycerol 200.0 mg *Flavouring 15.0 mg to Water ad 5.0 ml 4 Preparation: The distilled water is heated to 70*C and the hydroxeyethylcellulose is dissolved therein with Go..stirring. With the addition of sorbitol sol1ution and glycerol the mixture is cooled to ambient temperature.
At ambient temperature, sorbic acid, fflavouring 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.
911- Example VIII SuppositorieTs containing 100 mg of active substance Active substance Solid fat 100.0 mg 1600.0 mg 1700.0 mug Preparation: The hard fat is melted. At 40-C the grounid active substance is homogeneously dispersed in the melt. It is cooled to 38 0 C and poured into slightly chilled suppository mnoulds.
a boo *a .400
Claims (1)
- 94. a The claims defining the invention are as follows: 1. Compounds of formula I R -N I H 4 (I) (wherein R, denotes a hydrogen, fluorine, chlorine or bromine atom or a fluoromethyl, difluoromethyl, trifluoromethyl or alkyl group; R, denotes an imidazol-2-yl group optionally substituted S.in the 1-position by the group Ra, wherein Ra denotes a phenyl or phenylalkyl group, in which the phenyl nucleus may be mono- or disubstituted by S* alkyl, hydroxy or alkoxy groups and the substituents may be identical or different, a C3- 7 cycloalkyl group or a C 1 .5-alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertable in vivo into a carhoxy group, by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or from position 2 by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino or morpholino group, a 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl group optionally substituted in the 1-position by a C,-3-alkyl group, 95 an imidazolium-2-yl group substituted in the 1- and 3- positions by groups Rb, which groups may be identical or different, wherein Rb denotes a phenylalkyl group in which the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different, or Rb denotes a C 1 _6-alkyl group in which the alkyl moiety may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, an oxazol-2-yl or thiazol-2-yl group, whilst the above-mentioned imidazolium-2-yl groups may each additionally be substituted in the 4 and/or positions by a Cl-s-alkyl or by a phenyl group (the substituents being identical or different) or an n- propylene or n-butylene bridge may be attached via the 4 and/or 5 positions, or the above-mentioned imidazol-2-yl, oxazol-2-yl or Sthiazol-2-yl groups are each substituted in the 4 or position by a phenyl group and may additionally be substituted by a C 1 _s-alkyl group in the remaining 4 or position or are each substituted in the 4 and 5 position by a Cl. 5 -alkyl group, or an n-propylene or n-butylene bridge may be attached, via the 4 and/or 5 positions, to the above-mentioned imidazol-2-yl, oxazol-2-yl or thiazol-2-yl groups, if Rs represents a group which can be metabolised into a carboxy group in vivo (with the exception of an alkoxycarbonyl group having a total of 2 to 5 carbon atoms) or a 2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl re group, or 96 Ra denotes a phenyl or phenylalkyl group wherein the phenyl nucleus is mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different, or a C 1 6 -alkyl group in which the alkyl moiety is substituted by a group which can be metabolised in vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or, from position 2, by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino or morpholino group, wherein in each case an n-propylene or n-butylene bridge may be attached via the 4 and/or 5 positions, an oxazolin-2-yl or imidazolin-2-yl group substituted in the 4-position by the groups R 9 and R 10 and in the position by the group R 8 wherein an imino group may :additionally be substituted by Ra or by an R 8 CO-(R 9 CR 1 0 NRa-CO- group, wherein Ra is as hereinbefore defined, and RS, R 9 and R10, which may be identical'or different, denote hydrogen atoms, C 1 .s-alkyl groups or phenyl S. groups; R3 denotes a C 1 _s-alkyl group, a C3.s-cycloalkyl group, a C 1 .4-alkoxy or C 1 .4-alkylthio group; and R 4 denotes a hydrogen atom or a group of formula R CH 97 wherein Rs denotes a group metabolically convertable in vivo into a carboxy group, or denotes a carboxy, cyano, 2.5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, lii- tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2- triphenylmethyl-tetrazolyl group; whilst unless otherwise specified any alkyl cr alkoxy group contains 1 to 3 carbon atoms, and the phrase "a group metabolically convertable in vivo into a carboxy group" as used herein denotes the esters thereof of formulae CO OR', to CO 0- (HCR"I) 0 -CO RIII and CO 0- (HCR"I) 0- CO- OR"' wherein RI denotes a straight-chained or branched Cl- 6 -alkyl group, a CS- 7 -cycloalkyl group, a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyrl or cinnamyl group, R"I denotes a hydrogen atom or a methyl group, and to denotes a straight-chained or branched C 16 -alkyl group, a CS- 7 -cycloalkyl group, a phenyl, benzyl, 1- phenylethyl, 2-phenylethyl or 3-phenylpropyl gro'lip); and Methyl 4'-[[2-n-propyl-4-methyl-6-(5,6,7,8- tetrahydro-benzimidazol-2-yl) H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylate 4'-[[2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro- benzimidazol-2 -yl) -lH-benzimidazol-l-yl] -methyl] zpgt biphenyl-2-carboxylic acid 98 41- 2-n-Propyl-4-methyl-6- (1,3-dimethyl-5, 6,7, 8- tetrahydro-benzimidazoliumiodide-2-yl) -lH-benzimidazol- l-yl] -methyl] -biphenyl-2-carboxylic acid 4 1- 2-n-Prapyl--4-methyl-6- (1-methyl--5,6, 7,g8- Letrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 4 1- [[2-n-Propyl-4-methyl-6- 6, 7,8-tetrahydro- benzimidazol-2-yl) -lH-benzimidazol-l-yl] -methyl] (lH- biphenyl Cf) 41- 2-n-Propyl-4-methyl-6- (l-methyl-5, 6,7, 8- tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-ylj methyl] 41- 2-Ethyl-4-methyl-6- (1-methyl-5,6, 7,8- tetrahydro-benzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) -biphenyl V. S 41- [[2-Ethyl-4-methyl-6-Cl1-methyl-5, 6,7,8- be. tetrahydro-benzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid tetrahydro-benzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 41- C(2-n-Propyl-4-methyl-6- (1-phenyl-5,6, 7, 8- tetrahydro-benzimidazol-2-yl) lH-henz imidazol- 1-yl] methyl] -biphenyl-2-carboxylic acid 4 1- 2-n-Propyl-4-methyl-6-Cl1-beizyl-5, 6,7, 8- tetrahydrobenzimidazol-2 yl) -1I--benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 41- 2-n-Propyl-4-methyl-6- (l-ethyl-5,6,7, 8- tetrahydrobenzimidazol-2-yl) -lH--benzimidazol-i-yl] k I 99 methyl] -biphenyl-2-carboxylic acid-sesquihydrate (in) 4'-((2-Ethyl-4-methyl-6-(l-isopropyl-5,6,7,8- tetrahydrobenziinidazol-2-yl) -lH-benzimidazol-l-yl] inethyll -biphenyl-2-carboxylic acid 4'-[[2-n-Propyl-4-methyl-6-(l-isobutyl-5,6,7,8- tetrahydrabenzimidazol-2-yl) -1H-benzimidazol-l-yl] methyl] -biphenyl-2-uarboxylic acid 4'-1 12-n-Propyl-4-methyl-6- Ci-carboxymethyl- 5,6,7,8-tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l- yl] -methyl] -biphenyl-2-carboxylic acid-semihydrate (p 4'-1E2-Cyclopropyl-4-mtethyl-6-(l-tethyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid-seinihydrate 4'-[[2-cyclopropyl-4-methyl-6-(:L-iethyl-5,6,7,8- tetrahydrobenziinidazol-2-yl) -lH-benzimidazol-l-yl] methyl] Cr) 4'-[[2-ethoxy-4-methyl-6-Cl-methyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -bipheteyr-2-carbaxylichacid 4'-[[2-ethoy-4-methyl-6-(l-methroyl-5,,7,- tetrahydrobenzimidazol-2-yl) -lH-benzirnidazol-l-yl] methyl] Ct) 4'-([2-ethryl-4-methyl-6-(l-isopropyl-5,6,7,8- tetrahydrobenzimidazol-2 -yl) -lH-benzimidazol-l -yl] methyl] -biphenyl-2 -carboxylic acid '3 100 4'-[(2-n-propyl-4-methyl-6-(l-isopropyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-1-yl] methyl] (lH-tetrazol-5-yl) bipheny. tetL.rahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] -biphenyl-2--carboxylic acid 4'-[[2-ethyl-4-methyl--6-(l-isobutyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) -lH-benzitnidazol-l-yl] methyl] tetrahydrobenzimidazol-2-yl) -'H-benzimidazol-l-yl] methyl] 4'-[[2-n-propyl-4-mec-hyl-6-(l-carboxymethyl-5,6,7,8- tetrahydrobenzimilazol-2-yl) -lH-benzimidazol-l-yl] methyl] V. 9 Caa) 4'-[(2-Ethyl-4-methyl-6-(l-ethyl-5,6,7,8- tctrahydro-benzimidazol-2 -yl) -lH-benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) -biphenyl and the 3-isomers, the 3-isomer mixtures anda the salts thereof. 2. Compounds of formula I as claimed in claim 1, wherein R, denotes a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group or a C 1 3 -alkyl group; R 2 denotes an imidazol-2-yl group optionally substituted in the 1-position by the group wherein R, denotes a phenyl group, a phenyl(C.. 3 -alkyl) AVF Zlqcgroup, a CS- 7 -cycloalkyl group or a C 1 -5-alkyl group 101 in which the alkyl moiety may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, by a trifluoromethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group or from position 2 by a hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, pyrrolidino, piperidino or morpholino group, a 5,5-spiro-cyclopentano-dihydroimidazol-4-on-2-yl group, an imidazolium-2-yl group substituted in the 1- and 3- positions by groups Rb, which may be identical or different, wherein t Rb denotes a CI 3 -alkyl or phenyl(C-3-alkyl) group, an oxazol-2-yl or thiazol-2-yl group, whilst the above-mentioned imidazolium-2-yl groups may each additionally be substituted in the 4 and/or positions by a C 1 .4-alkyl or by a phenyl group (the substituents being identical or different) or an n- butylene bridge may be attached via the 4 and/or positions, or the above-mentioned imidazol-2-yl, oxazol-2-yl or thiazol-2-yl groups are each substituted in the 4 or position by a phenyl group and may additionally be substituted by a 4 -alkyl group in the remaining 4 or position or are each substituted in the 4 and 5 position by a C 1 4 -alkyl group, or an n-butylene bridge may be attached, via the 4 and/or positions, to the above-mentioned imidazol-2-yl, oxazol- 102 2-yl or thiazol-2-yl groups, if Rs represents a group which can be metabolised into a carboxy group in vive (with the exception of an alkoxycarbonyl group having a total of 2 to 5 carbon atoms) or a 2,5-dihydro-5-oxo- 1,2,4-oxadiazol-3-yl group, or Ra denotes a Cl- 5 -alkyl group in which the alkyl moiety is additionally substituted by a group which may be metabolised in vive into a carboxy group, by a trifluoromethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, or dimethylaminocarbonyl group or from the 2-position by a hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, pyrrolidino, piperidino or morpholino group, wherein in each case an n-propylene or n-butylene bridge may be attached via the 4 and/or 5 positions, .an oxazolin-2-yl or imidazolin-2-yl group substituted by the groups R, and RIO, wherein an imino group may additionally be substituted by Ra, wherein RIO and Ra each represent a hydrogen atom or a C.. 4 -alkyl group; R 3 denotes a C2- 5 -a.kyl group, a C3- 2 -cycloalkyl group, a C 2 -4-alkoxy or C2-4-alkylthio group; and S*0 R4 denotes a 4-biphenylylmethyl group :ubstituted in the 2'-position by the group R 5 wherein 4 b: Rs denotes a group metabolically convertable in vive into a carboxy group, or denotes a carboxy, cyano, 1H-tetrazolyl, 1-tripheilylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group; whilst the expression "a group metabolically convertable in vive into a carboxy group" as used hereinbefore denotes the esters thereof of the formulae 103 CO OR'I, CO (HCRI") CO Rv"' and CO 0 (11CR"I) 0 CO OR"' wherein R' denotes a straight -chained or branched C 1 4 -alkyl group or a Cs- 7 -cycloalkyl group, R"1 denotes a hydrogen atom or a methyl group, and R' denotes a straight- chained or branched C, 1 4 -alkyl group or a C 5 -7-cycloalkyl group; and Methyl 2-n-propyl-4-methyl-6- 7, 8- tetrahydro-benzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylate 41- [[2-n-Propyl-4-methyl-6- 7, 8-tetrahydro- benzimidazol-2-yl) -lH-benzimidazol-l-yllj -methyll biphenyl-2-carboxylic acid 41* 2n Poy eh l -i e h l 5 6 ,8 tetrahydro-benzimidazoliumiodide-2-yl) -lH-benzimidazol- 1-yll -methyl] -biphenyl-2-carboxylic acid 4'-2 -n Propy 1- 4 -methy 1- 6- me thy 1- 5,6, 7,8 tetrahydrobenzimidazol-2-yl) -1H-benzimidazol-l-yll methyl] -biphenyl-2 -carboxylic acid 41- (t2-n-Propyl-4-methyl-6- 6,7, 8-tetrahydro- benzimidazol-2-yl) -lH-benzimidazol-l-yl] -methyl] (lH- biphenyl tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] 104 4'-L[2-Ethyl-4-methyl-6-(l-methyl-5,6,7,8- tetrahydro-benzimidazol-2 -yl) -lH--benzimidazol-1-ylj methyl] (lH-tetrazo.-5-yl) -biphenyl tetrahydro-benzimidazol-2-yl) -lH-benzimidazol- l-yl] methyl] -biDphenyl-2-carboxylic acid 4'-L[2-Ethyl-4-methyl-6-Cl-phenyl-5,6,7,c- tetrahydro-benzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 4'-[L2-n-Propyl-4-methyl-6G-(l-phenyl-5,6,7,8- tetrahydro-benzimidazol-2-yi) -lH-benzimidazol-l-yl] methyl] -biphenyl-2 -carboxylic aciAd 000(k) 4'-[[2-ri-Propyl-4-methyl-6-(l-benzyl-5,6,7,8- Letrabhydrobenzimidazol-2-yl) -lH--benzimidazol-l-vl] methyl] -biphenyl-2-carboxjlic acid 4'-[[2-n-Propyl-4-methyl-6-(l-ethyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid- sesquihydrate (mn) 4'-[L2-Ethyl-4-methyl-6-(l-isopropyl-5,6,7,8- 00 0 tetrahydrobenzinidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 4'-[[2-ri-Propyl-4-methyl-6-Cl-isobutyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid 4 C2-r-Propyl-4-inethyl-G- (l-carboxymethyl- 6,7, B-tetrahydrobenzimidazol-2-yl) -1H-benzimidazol -1- yl] -methyl] -biplienyl-42-carboxylic acid-semihydrate 105 4'-[[2-Cyclopropyl-4-meth-yl-6-Cl-mee-hyl-5,6,7/,s- tetrahydrobenzitnidazol-2-yl) -lH-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid-semihydrate 4'-LI:2-cyclopropyl-4-methyl-6-(l-methyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] Cr) 4'-[[2-ethoxy-4-methyl-6-Cl-methyl-5,6,7,8- tetrahydrobenzimidazol-2 -yl) -1H-benzimidazol- l-yli met.hyl] -bipheriyl-2-carboxylic acid Cs) 4'-f[2-ethoxy-4-etlyl-G-Cl-meth-y1-5,6,7,8- tetrahydrobenzimidazol-2 -yl) -1H-benzimidazol-1-yl] methy'l-2- C1H-tetrazol-.5-yi) biphenyl 4'-[L2-ethyl-4-methyl-6-(1-isopropyl-5,6,7,8- ft f ft.. tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] C1H-tetrazol-5-yl) biphenyl Cu) 4'-([2-n,-propyl-4-methyl-6-Cl-isopropyl-5,6,7,8- tetrahydroberizimidazol-2 -yl) -lH-benzimidazol- 1-yl]- ft f. ftmethyl] -bipheriyl-2-carboxylic acid Cv) 4'-[[2-n-propy1-4-methyl-6-Cl-isopropyl-5,6,7,8- ft.. fttetrahydrobenzimidazo'L-2 -yl) -1H-benzimidazol.-1-yl] methyl] 4 1 -f(2-ethyl-4-methyl-6-(l-isobutyl-5,6,7,8- tetrahydrobenzimidazol-2 -yl) -lH-benzimidazol-l-yl] methyl] -biptienyl-2-carboxylic acid Cx) 4'-[L2-ethyl-4-methyl-6-Cl-isobutyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) -lH-benzimidazol- l-yl] methyl] 106 4'-[[2-n-propyl-4-methyl-6-Cl-isobutyl-5,G,7,8- tetrahydrobenzimidazol-2 -yl) -lH-benz imidazol- l-yl] methyl] 4'-[[2-n-propyl-4-methyl-6-(l-carboxymethyl-5,G,7,8- tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yll methyl] (aa) 4'-[[2-Ethyl-4-methyl-6-(l-ethyl-5,6,7,8- tetrahydro-benzimidazol-2 -yl) -lH-benzimidazol-1-yl] methyl] (lH-tetrazol-5-yl) -biphenyl and the 3-isomers, the 3-isomer mixtures and the salts thereof. 3. Compounds of formula I as claimed in claim 1 or :claim 2, wherein PR 2 is in the 6-position; and R, in the 4-position denotes a fluorine, chlorine or bromine atom, a trifluoromethyl group or a C, 3 alkyl :group; 0. and the 3-isomers, the 3-isomer mixtures arnd the salts thereof. 4. Compounds of formula I as claimed in claim 3, :wherein R 2 in the 6-position denotes an imidazolyl group; and the 3-isomers, 3-isomer mixtures and the salts thereof. Compounds as claimed in claim 1 being: 41[2npoy--mty--5678 tetr-ahydrobenzimidazol-2 -yl) -lH-benzimidazol-l-yl] 107 methyl] -bipheri-l-2-carboxylic acid; tetrahydrobenzimidazol-2-vl) -1H-benzimidazol--yl] methyl] -biphenyl-2-carboxylic acid; 4'-U[2-n-propyl-4-methyl-6-(l-methyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) H-bernzimidazol- 1 -yl] methyl] (1H-tetrazol-5-yl) biphenyl; '2-n-propy1-4-methyl-6-(l-benzyl-5,6,7,8- tetrahydrobenzim-,idazol-2-yl) -lH-benzimidazol-l-ylj methyl] -biphenyl-2-carboxylic acid; 4'-[f2-ethyl-4-methyl-6-(l-phenyl-5,G,7,8- 4* tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid; p. 41-t[2-n-propyl-4-methyl-6-(l-carboxymethyl-5,6,7,8- tetrahydrobenzimidazol-2-yl) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid; 4'-H[2-ethyl-4-methyl-G-(l-ethyl-5,6,7;s8-tetrahydro- ~benzimidazol-2-yl) -1H-berizimidazol-l-yl] -methyl] (1H- -biphenyl; [[2-n-propyl-4-methyl-6- (4,4-dimethyl-oxazolin-2- l) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2-carboxylic acid; 4'-[12--n-propyl-4-methyl-6-(l,5-dimethyl-4-phenyl- imidazol-2-yl) -lH-benzimidazol-1-yl] -methyl] -ba.phenyl-2- carboxylic acid; or 4'-C12-n-propyl-4-methyl-6-(4-isopropyl-1,5- dimethyl-imidazbl-2-yl) -lH-benzimidazol-l-yfl]-methyl] biphenyl-2-carboxylic ac~id; I 108 and the salts thereof. 6. A compound as claimed in any one of claims 1 to being a physiologically acceptable salt of a compound as claimed in any one of claims 1 to 7. A pharmaceutical composition, containing a compound as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps: 9* a) (to prepare compounds of formula I wherein R 2 denotes an oxazol-2-yl, thiazol-2-yl or imidazol-2-yl group, in which an n-butylene bridge is added via the positions and additionally the imino group in the imidazole ring may be substituted by a CI.6-alkyl group, by a phenyl(C 1 _3alkyl) group or by a phenyl group) reacting a compound of formula II HN-CX R3 S N R 4 4* (II) (wherein RI, R 3 and R4 are as defined in any one of claims 1 to and X denotes an oxygen or sulphur atom or an imino group optionally substituted by a C-_.-alkyl group, by a phenyl(C_. 3 -alkyl) group or by a phenyl group) with an a- k 109 haloketone of formula III (III) (wherein Z denotes a halogen atom); b) (to prepare compounds of forraula I wherein R 2 denotes one of the imidazol-2-yl groups mentioned in any one of claims 1 to 5 optionally substituted in the 1-position by the group Ra) reacting a compound of formula IV SO S S *5S* S. S. *s S SS 9 IS S 0 90 S S S S 0Sr N-R3 N 4 (IV) (wherein RI, R3 and R 4 are as defined in any one of claims 1 to and R 2 denotes one of the oxazol-2-yl groups mentioned in any one of claims 1 to 5) with an amine of formula V H2N R6 (wherein R, has the meanings given for Ra in any one of claims 1 to 5 or denotes a hydrogen atom); c) (to prepare compounds of formula I wherein R 4 denotes 110 a group of the formula R -CH 2 reacting a compound of formula VI S.. 0* S. 5. 0SS a. S S S* 0 a S S S S S. S S S S S 55 5 (VI) (wherein R, and R 3 are as defined in any one of claims 1 to 5 and R 4 denotes a hydrogen atom R 2 has the meanings given for R 2 in any one of claims 1 to 5, with the exception of the imidazol-2-yl and imidazolin-2-yl groups unsubstituted in the 1-position) with a biphenyl compound of formula VII R Z,-CH 2 2C (VII) (wherein R s is as defined in any one of claims 1 to 5 and Z 2 denotes a nucleophilic leaving group); d) (to prepare a compound of formula I wherein R denotes a carboxy group) converting a compound of formula VIII ll AT CH 2 (VIII) (wherein RI, R 2 and R 3 are as defined in any one of claims 1 to and Rs' denotes a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a compound of formula I by hydrolysis, thermolysis or hydrogenolysis; s o e) (to prepare compounds of formula I wherein R 2 denotes a 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl group) treating a benzimidazole of formula IX R N R .2 R3 go R (IX) (wherein RI, R 3 and R 4 are as defined in any one of claims 1 to and R 2 denotes an imidazol-2-yL group in which an n- butylene bridge is added via the 4,5-position) with a base in the presence of air and light; f) (to prepare a compound of formula I wherein R denotes a 1H-tetrazolyl group) cleaving a protecting group from a compound of formula X 112 (X) (wherein Ri, R. and R 3 are as defined in any one of claims 1 to and Rs" denotes a 1H-tetrazolyl or 2H-tetrazolyl group protected in the 1- or 2-position by a protecting group); g) (to prepare a compound of formula I wherein R denotes a 1H-tetrazolyl group) reacting a compound of S*formula XI R R (XI) (wherein R1, R 2 and R3 are as defined in any one of claims 1 to and R 4 denotes a cyano group) with hydrazoic acid or a salt thereof; h) (to prepare compounds of formula I in which R 2 denotes one of the imidazol-2-yl groups mentioned in any one of claims 1 to 5, which may be substituted in the 1- position by a phenylalkyl group (whilst the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical 113 or different), or by a C1.-alkyl group, whilst the alkyl group may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, or by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, or R 2 denotes one of the imidazolium-2-yl groups mentioned in claims 1 to reacting a compound of formula XII N R* R (XII) (wherein RI and R3 are as defined in any one of claims to R 2 denotes one of the imidazol-2-yl groups Sunsubstituted in the 1-position mentioned for R 2 in any one of claims 1 to 5 and Rs"' denotes a carboxy group or a group which can be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, or a 1H-tetrazolyl or 2H- tetrazolyl group protected by a protecting group) with a compound of formula XIII Z3 R, (XIII) (wherein R 7 denotes a phenylalkyl group (whilst the phenyl nucleus may be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and the substituents may be identical or different), or a C 1 alkyl group, whilst the alkyl group may additionally be substituted by a group metabolically convertable in vivo into a carboxy group, or by a tlrifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or 114 dialkylaminocarbonyl group, and Z. denotes a nucleophilic leaving group) and subsequently if necessary any protecting group used is cleaved; i) (to prepare compounds of formula I wherein R 2 denotes one of the imidazol-2-yl groups mentioned in any one of claims 1 to 5 substituted by the groups R 9 and R 10 but wherein R 9 or Ro must represent a hydrogen atom) reacting an aminoketone of formula XIV R R a-CO-UC-NR -CO R3 *R H N (XIV) (wherein R P3, R 4 R 8 R 9 and R 1 i are as defined in any one of claims 1 to 5, but R 9 or RIo must represent a hydrogen S" atom, and Ra' has the meanings given for Ra in any one of claims 1 to 5 or represents a hydrogen atom) with an ammonium salt of a lower aliphatic carboxylic acid; j) (to prepare compounds of formula I wherein R 2 denotes one of the oxazolin-2-yl or imidazolin-2-yl groups mentioned in any one claims 1 to 5) dehydrating a compound of formula XV 11W 115 R R R 8 9 N Y -CH-C-NH-CO- R 3 R 10 N R (XV) (wherein R1, R 3 R4, RP, R, and R1 0 are as defined in any one of claims 1 to 5 and Y denotes a hydroxy or HNRa group wherein Ra is as defined in any one of claims I to k) (to prepare compounds of formula I wherein R 2 denotes one of the imidazolin-2-yl groups mentioned in any one of claims 1 to 5) reacting a compound of formula XVI **R N 4 denotes one of the oxazolin-2-yl groups mentioned for R2 in any one of claims 1 to 5 and substituted by the groups R 8 R, and Ro) with an amine of formula XVII H 2 N- (RCH) (RCR 10 -NH 2 (XVII) (wherein R 8 R, and R4. are as defined in any one of claims 1 to .w I 116 1) (to prepare compounds of formula I wherein R 2 denotes one of the oxazol-2-yl groups mentioned in any one of claims 1 to 5 and substituted by the groups R 8 R 9 and R 10 dehydrating an aminoketone of formula XVIII R O R N R-C- -NH-C -R 3 R 0 N 10 1 R 4 (XVIII) (wherein R 1 R 3 R 4 R 9 and Rio are as defined in any one of claims 1 to 5, but wherein R 9 or R 10 must denote a hydrogen atom); m) (to prepare compounds of formula I wherein R 2 denotes :..one of the imidazol-2-yl groups mentioned in any one of o* claims 1 to 5, substituted by the groups R 8 R 9 and R 10 dehydrogenating a compound of formula XIX R N H C R3 (XIX) (wherein RI, R3 and R 4 are as defined in any one of claims 1 to and R 2 denotes one of the imidazolin-2-yl groups mentioned for R 2 in any one of claims 1 to 5 and substituted by the groups Ra, R 9 and RiO, but wherein R 9 or RIO must denote a hydrogen atom); 117 n) (to prepare compounds of formula I wherein Rs denotes a 2,5-dihydro-5-oxo--l,2,4-oxadiazol-3-yl group) reacting an amidoxime of formula XX R R2 R 3 (XX) CH 2 NH -C 2 -OH (wherein N-OH R 1 R 2 and R 3 are as defined in any one of claims 1 to optionally prepared in the reaction mixture, with a compound of formula XXI Z4 CO OR, 1 (XXI) to (wherein Z 4 denotes a nucleophilic leaving group and R1 denotes an alkyl, aryl or aralkyl group) and subsequently cyclising an acylated amidoxime thus obtained; S o) converting a compound of formula I thus obtained into a salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an .inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound; and p) performing a process as defined in any one of steps to above on a corresponding protected compound and subsequently removing the protecting group used. 11. A method of treatment of the human or non-human animal body to combat hypertension and cardiac insufficiency, for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), 118 for the preve ion of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof. 12. A method of treatment as claimed in claim 11 to combat pulmonary diseases, for preventing arterial re- stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy, said method comprising administering to said body a compound as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof. 13. A method of treatment as claimed in claim 11 to alleviate central nervous system disorders, said method comprising administering to said body a compound as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof. C C 14. A compound as claimed in claim 1 or a pharmaceutical composition thereof as herein disclosed in any one of the Examples. DATED this 5th day of May, 1995. DR KARL THOMAE GmbH By Their Patent Attorneys: CAL1,INAN LAWRIE Abstract Benz iMidazoles The invention relates to benziinidazoles of formula I R N N II (wherein R1, RZ, and R 4 are as defined in any one of claims 1 to 5) and the 3-isomer mixtures, tite quaternary N-alkyl salts and the salts thereof. The new compounds have valuable pharmacological properties, particularly an angiotensin-antagonistic activity, preferably anqiotensin-11-antaqonistic activities. 6* at a a a. a a a. .a a a a a. 9*
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4212250 | 1992-04-11 | ||
| DE4212250A DE4212250A1 (en) | 1992-04-11 | 1992-04-11 | New 1-phenyl:benzyl -benzimidazole derivs. with alkylene-bridged heterocyclic gp. - used as angiotensin II antagonists e.g. for treating cardiovascular, pulmonary or CNS disorders |
| DE4224752A DE4224752A1 (en) | 1992-04-11 | 1992-07-27 | Benzimidazoles, medicaments containing these compounds and process for their preparation |
| DE4224752 | 1992-07-27 |
Publications (2)
| Publication Number | Publication Date |
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| AU3679693A AU3679693A (en) | 1993-10-14 |
| AU661129B2 true AU661129B2 (en) | 1995-07-13 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| AU36796/93A Ceased AU661129B2 (en) | 1992-04-11 | 1993-04-08 | Benzimidazoles |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0566020A1 (en) |
| JP (1) | JPH0625234A (en) |
| KR (1) | KR930021734A (en) |
| AU (1) | AU661129B2 (en) |
| CA (1) | CA2093785A1 (en) |
| CZ (1) | CZ62193A3 (en) |
| DE (1) | DE4224752A1 (en) |
| FI (1) | FI931599A (en) |
| HU (1) | HUT64059A (en) |
| IL (1) | IL105356A0 (en) |
| MX (1) | MX9302034A (en) |
| NO (1) | NO931342L (en) |
| NZ (1) | NZ247373A (en) |
| PL (1) | PL298449A1 (en) |
| SK (1) | SK32493A3 (en) |
| TW (1) | TW232016B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4408497A1 (en) * | 1994-03-14 | 1995-09-21 | Thomae Gmbh Dr K | New bi:phenyl-methyl-benzimidazole derivs. |
| DE69718850T2 (en) * | 1996-06-28 | 2003-10-09 | Dow Agrosciences Llc, Indianapolis | Heterocyclic N-acetonylbenzamides and their use as fungicides |
| TWI406850B (en) * | 2007-06-05 | 2013-09-01 | Theravance Inc | Dual-acting benzoimidazole antihypertensive agents |
| JP2011506459A (en) * | 2007-12-11 | 2011-03-03 | セラヴァンス， インコーポレーテッド | Dual acting benzimidazole derivatives and their use as antihypertensive agents |
| CN101798287A (en) * | 2010-03-18 | 2010-08-11 | 北京理工大学 | [(4-methyl-2-propyl-N-methoxyl-substituted benzene alkyl-1H-benzimidazole-6-formamide)-1-yl] methyldiphenyl compound and preparation method thereof |
| EP2935253B1 (en) | 2012-12-21 | 2018-08-01 | Zenith Epigenetics Ltd. | Novel heterocyclic compounds as bromodomain inhibitors |
| JP6599852B2 (en) | 2013-06-21 | 2019-10-30 | ゼニス・エピジェネティクス・リミテッド | Novel substituted bicyclic compounds as bromodomain inhibitors |
| ES2806135T3 (en) * | 2013-06-21 | 2021-02-16 | Zenith Epigenetics Ltd | New bicyclic bromodomain inhibitors |
| CN105593224B (en) | 2013-07-31 | 2021-05-25 | 恒元生物医药科技(苏州)有限公司 | Novel quinazolinones as bromodomain inhibitors |
| CA2966298A1 (en) | 2014-12-01 | 2016-06-09 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
| US10179125B2 (en) | 2014-12-01 | 2019-01-15 | Zenith Epigenetics Ltd. | Substituted pyridines as bromodomain inhibitors |
| JP2017537946A (en) | 2014-12-11 | 2017-12-21 | ゼニス・エピジェネティクス・リミテッドＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｌｔｄ． | Substituted heterocycles as bromodomain inhibitors |
| CA2966450A1 (en) | 2014-12-17 | 2016-06-23 | Olesya KHARENKO | Inhibitors of bromodomains |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU8122791A (en) * | 1990-07-23 | 1992-01-30 | Dr. Karl Thomae Gmbh | Benzimidazoles |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3928177A1 (en) * | 1989-04-08 | 1991-02-28 | Thomae Gmbh Dr K | BENZIMIDAZOLE, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| EP0400835A1 (en) * | 1989-05-15 | 1990-12-05 | Merck & Co. Inc. | Substituted benzimidazoles as angiotensin II antagonists |
| EP0470543A1 (en) * | 1990-08-10 | 1992-02-12 | Dr. Karl Thomae GmbH | Heterocyclic imidazoles, remedies containing them and processes for their preparation |
| SI9210098B (en) * | 1991-02-06 | 2000-06-30 | Dr. Karl Thomae | Benzimidazoles, drugs with this compounds, and process for their preparation |
-
1992
- 1992-07-27 DE DE4224752A patent/DE4224752A1/en not_active Ceased
-
1993
- 1993-03-18 TW TW082101985A patent/TW232016B/zh active
- 1993-04-07 NO NO93931342A patent/NO931342L/en unknown
- 1993-04-07 EP EP93105770A patent/EP0566020A1/en not_active Ceased
- 1993-04-07 MX MX9302034A patent/MX9302034A/en unknown
- 1993-04-08 FI FI931599A patent/FI931599A/en unknown
- 1993-04-08 PL PL93298449A patent/PL298449A1/en unknown
- 1993-04-08 SK SK324-93A patent/SK32493A3/en unknown
- 1993-04-08 NZ NZ247373A patent/NZ247373A/en unknown
- 1993-04-08 CA CA002093785A patent/CA2093785A1/en not_active Abandoned
- 1993-04-08 AU AU36796/93A patent/AU661129B2/en not_active Ceased
- 1993-04-09 JP JP5083492A patent/JPH0625234A/en active Pending
- 1993-04-09 CZ CZ93621A patent/CZ62193A3/en unknown
- 1993-04-09 IL IL105356A patent/IL105356A0/en unknown
- 1993-04-09 HU HU9301056A patent/HUT64059A/en unknown
- 1993-04-10 KR KR1019930006013A patent/KR930021734A/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU8122791A (en) * | 1990-07-23 | 1992-01-30 | Dr. Karl Thomae Gmbh | Benzimidazoles |
Also Published As
| Publication number | Publication date |
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| KR930021734A (en) | 1993-11-22 |
| CZ62193A3 (en) | 1994-01-19 |
| DE4224752A1 (en) | 1994-02-03 |
| MX9302034A (en) | 1994-06-30 |
| HU9301056D0 (en) | 1993-06-28 |
| AU3679693A (en) | 1993-10-14 |
| FI931599A (en) | 1993-10-12 |
| HUT64059A (en) | 1993-11-29 |
| PL298449A1 (en) | 1994-04-18 |
| EP0566020A1 (en) | 1993-10-20 |
| TW232016B (en) | 1994-10-11 |
| NO931342D0 (en) | 1993-04-07 |
| JPH0625234A (en) | 1994-02-01 |
| SK32493A3 (en) | 1994-02-02 |
| CA2093785A1 (en) | 1993-10-12 |
| FI931599A0 (en) | 1993-04-08 |
| IL105356A0 (en) | 1993-08-18 |
| NZ247373A (en) | 1995-06-27 |
| NO931342L (en) | 1993-10-12 |
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