AU660209B2 - Heteroaryl substituted biphenylmethyl benzimidazoles - Google Patents

Heteroaryl substituted biphenylmethyl benzimidazoles Download PDF

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AU660209B2
AU660209B2 AU31962/93A AU3196293A AU660209B2 AU 660209 B2 AU660209 B2 AU 660209B2 AU 31962/93 A AU31962/93 A AU 31962/93A AU 3196293 A AU3196293 A AU 3196293A AU 660209 B2 AU660209 B2 AU 660209B2
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methyl
imidazol
group
biphenyl
benzimidazol
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AU3196293A (en
Inventor
Michael Entzeroth
Norbert Hauel
Berthold Narr
Uwe Ries
Jacques Van Meel
Wolfgang Wienen
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Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

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

Description

P/00/111 Regutation 3.2
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
V6U 209 a. S S
C.
49 0 *90* 0O*0 C C *5 C TO BE COMPLETED BY APPLICANT 'f.jame of Applicant: Actual Inventor(s): :S**o *dress for Service: Jvention Title: *.The following statemei p erforming it known to DR KARL THOMAE GMBH Norbert HAUEL; Berthold NARR; Uwe RIES, Jacques VAN MEEL; Wolfgang WIENEN; and Michael ENTZEROTH CALLINAN LAWRIE, 278 High Street, Kew, 3101, Victoria, Australia i "HETEROARYL SUBSTITUTED BIPHENYLMETHYL
BENZIMDAZOLES"
it is a full description of this invention, including the best method of me:- 1- 59063.579 Heteroaryl Substituted Biphenvlmethyl Benzimidazoles The present invention relates to new benzimidazoles, processes for their preparation and pharmaceutical compositions containing them.
EP-A-392317 describes benzimidazoles which are valuable angiotensin antagonists.
It has now been found that certain new benzimidazoles are even more useful angiotensin antagonists, particularly angiotensin-II-antagonists.
Thus, according to one aspect the present invention provides compounds of formula I:
R
2
N
(wherein R, represents a C 1 .3-alkyl group, a hydrogen, fluorine, chlorine or bromine atom;
R
2 represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a C-_.-alkyl group or by a phenyl group and S"substituted in the 1-position by a CI.7-alkyl group substituted in the 4-, ,AL A/ 6- or 7- position by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, 2 morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxidothiomorpholinocarbonyl group, by a C2- 4 -alkyl group substituted in the 3- or 4position by a hydroxy, alkoxy, alko-cyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxidothiomorpholino.or imidazol-l-yl group, by a C 1 .3-alkyl group substituted by a trifluoromethyl group, by a C3.
7 -cycloalkyl group or by a phenyl group itself optionally mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, or by a C 3 -alkyl group substituted by two phenyl groups, where unless otherwise specified the above-mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms;
R
3 represents a C..
4 -alkyl, C 2 .3-alkoxy, C 2 3 -alkylthio, cyclopropyl or cyclobutyl group; and
R
4 represents a carboxy, cyano, 1H-tetrazolyl, 1triphenylmethyl-tetrazolyl or 2-triphenylmethyl- Stetrazolyl group or a group convertable in vivo into a carboxy group); and the compounds 4'-[(2-n-Propyl-4-methyl-6-(1-(2-phenylethyl)imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylic acid, -3 [(2-n-Propyl-4-tnethyl-G-(2-methyl-oxazol-4'-yl) benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid, (2-n-Propyl-4.-methyl-6- (2-methyl-oxazol-4-yl) benzimidazol-l-yl) -methyl] (1H-tetrazal-5-yl) biphenyl, [(2-Ethoxy-G- (l-isopropyl-imidazol-4-yl) benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) biphenyl, [(2-Ethoxy-6- (l-isopropyl-imidazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid (if) I(2-Ethoxy-G- (l-isopropyl-imidazol-4-yl) benzimidazol-l-yl) -methyl] (1H-tetrazol-5-yl) biphenyl, 4'-[I(2-n-Propyl-4-methyl-6- (1-cycloheptyl-itnidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid, [(2-n-Propyl-4-methyl-6- (1-cycloheptyl-imidazol- 4-yl) -benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) biphenyl, 4'-[(2-n-Propyl-4-methyl-6-(l-(1-n-propyl-n-butyl)imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid, (j 4L(2-n-Propyl-4-methyl-6- (l-n-propyl-n-butyl)imidazol-4-yl) -benzimidazol-l-yl) -methyl] (1K- -biphenyl, 4'-[(2-n-Propyl-4-methyl-6-(l,2-dimethyl-imidazol-4yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic L acid hydrate, 4 4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)biphenyl, 4'-[(2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid, and [(2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)and the salts thereof, particularly, for pharmaceutical use, the physiologically acceptable salts thereof with inorganic or organic acids or bases.
The term "a group convertable in vivo into a carboxy group" may denote, for example, carboxyl esters such as those of formulae CO OR', CO 0 (HCR") 0 CO and CO 0 (HCR") 0 CO OR"' (wherein R' denotes a straight-chained or branched C..g-alkyl group or C-.
7 -cycloalkyl, benzyl, 1-phenylethyl, 2- Sphenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl S* group, S: R" denotes a hydrogen atom or a methyl group, and denotes a straight-chained or branched C 1 alkyl group or a Cs_.-cycloalkyl, phenyl, benzyl, 1phenylethyl, 2-phenylethyl or 3-phenylpropyl group).
The following are examples of the definitions of groups R, to R 4 given hereinbefore: R, may represent a hydrogen, fluorine or chlorine atom, a methyl, ethyl, n-propyl or isopropyl group;
R
2 may represent an oxazol-4-yl, 2-methyl--oxazol-4-yl, 2ethyl-oxazol-4-yl, 2 -n-propyl-oxazol-4-yl, 2 -isopropyloxazol-4-yl, 2-n-butyl-oxazol-4-yl, 2-isobutyl-oxazol-4yl, 2-n-pentyl-oxazol-4-yl, 2-isoamyl-oxazol-4-yl, 2-nhexyl-oxazol-4-yl, 2-phenyl-oxazol-4-yl, thiazol-4-yl, 2-methyl-thiazol-4-yl, 2-ethyl-thiazol-4-yl, 2 -n-propylthiazol-4-yl, 2-isopropyl-thiazol-4-yl, 2-n-butylthiazol-4-yl, 2-isobutyl-thiazol-4-yl, 2-n-pentylthiazol-4-yl, 2-isoatmyl-thiazol-4-yl, 2-n--hexyl-thiazol- 4-yl, 2-phenyl-thiazol-4-yl, l-methyl-imidazol-4-yl, 1ethyl-imidazol-4-yl, l-n-propyl-imidazol-4-yl,
I-
isopropyl-imidazol-4-yl, l-n-butyl--imidazol-4-yl, 1isobutyl-imidazol-4-yl, l-n-pentyl-imidazol-4-yl-, 1isoamyl-imidazol-4-yl, l-n--hexyl-imidazol-4-yl, 1-nhexyl-2-methyl-imidazol-4-yl, 1- (l-methyl-n-pentyl) imidazol-4-yl, 1- (l-ethyl-n-butyl) -imidazol-4-yl, 1- (1methyl-n-hexyl) -imidazol-4-yl, 1- (l-ethyl-n-pentyl) imidazol-4-yl, 1- (l-n-propyl-n--butyl) -imidazol-4-yl, 1n-heptyl-imidazol-4-yl, l-ethyl-2 -methyl-imidazol-4-yl, l-n-propyl-2-methyl-imidazol-4-yl, 1-isopropyl-2-methylimidazol-4 -yl, l-n-butyl-2 -methyl-imidazol-4-yl, 1isobutyl-2-methyl-imidazol-4-yl, l-n--pentyl-2-methylimidazol-4-yl, l-isoamyl-2-methyl-imidazol-4-yl, 1-nhexyl-2-methyl-imidazol-4-yl, 1-n-heptyl-2-methylimidazol-4-yl, l-cyclopropylmethyl-imidazol-4-yl, 1cyclobutylmethyl-imidazol-4-yl, 1-cyclopentylmethylimidazol-4-yl, 1-cyclohexylmethyl-imidazol-4-yl,
I-
cycloheptylmethyl-imidazol-4-yl, 1- (2-cyclopropylethyl) -imidazol-4-yl, 1- (2-cyclobutylethyl) imidazol-4-yl, 1- (2-cyclopentylethyl) -imidazol-4-yl, 1- (2-cyclohexylethyl) -imidazol-4-yl, 1- (2-cycloheptylethyl) -imidazol-4-y1, 1- (3-cyclopropylpropyl) -imidazol- 4-yl-, l-(3-cyclobutylpropyl)-imidazol-4-yl, l-(3- Scyclopentylpropyl) -imidazol-4-yl, 1- (3-cyclohexyl- -6 propyl) -imidazol-4-yl, 1- (3-cycloheptylpropyl) -imidazol- 4-yl, 1-(2,2,2-trifluoroethyJ4-imidazol-4-yl, 1-(3,3,3trifluoropropy.) -imidazol-4-yl, 1-benzyl-imidazol-4-yl, 1- (2-phenylethyl) -imidazol-4-yl, 1- (3-phenyipropyl) irnidazol-4-yl, 1-(4-fluorobenzyl) -imidazol-4-yl, 1-(4chlorobenzyl) -iinidazol-4-yl, 1- (3-chlorobenzyl) imidazol-4-yl, 1- (4-trifluoromethyl-benzyl) -itnidazol-4yl, 1- (3-methyl-benzyl) -imidazol-4-yl, 1- (4-methylbenzyl) -imidazol-4-yl, 1- (3-methoxy-benzyl) -imidazol-4yl, 1- (4-methoxy-benzyl)-imidazol-4-yl, 1- (3,4dimethoxy-benzyl) -imidazol-4-yl, 1- benzyl) -imidazol-4-yI, 1-cyclopropylmethyl-2--.ethylimidazol-4-yl, 1-cyclobutylmethyl-2-methyl-imidazol-4yl, 1-cyclopentylmethyl-2-methyl-inidazol-4-yl, 1cyclohexylmethyl-2-methyl-imidazol-4-yl, 1-cycloheptylmethyl-2-methyl-imidazol-4-yl, 1- (2cyclopropylethyl) -2-methyl-imidazol-4-yl, 1- (2cyclobutylethyl) -2-methyl-imidazol-4-yl, 1- (2cyclopentylethyl) -2-methyl-imidazol-4-yl, 1- (2cyclohexylethyl) -2-methyl-imidazol-4-yl, 1- (2cycloheptylethyl) -2-tethyl-imidazol-4-yl, 1- (3cyclopropylpropyl) -2-methyl-imidazol-4-yl, 1- (3cyclobutyipropyl) -2-methyl-imidazol-4-yl, 1- (3cyclopentylpropyl) -2-methyl--iridazol-4-yl, 1- (3cycilohexyipropyl) -2-methyl-imidazol-4-yl, 1- (3cycloheptylpropyl) -2-methyl-imidazol-4-yl, 1- (2,2,2trifluoroethyl) -2-methyl-imidazojl-4-yl-, 1- (3,3,3trifluoropropyl) -2-rnethyl-imidazol-4-yl-, 1-benzyl-2methyl-imidazol-4-yl, 1- (2-phenylethyl) -2-methylimidazol-4-yl, 1- (3-phenyipropyl) -2-methyl-imidazol-4yl, 1- (4-fluorobenzyl)-2--methyl-imidazol-4-yl, 1- (4chlorobenzyl) -2-tnethyl-imidazol-4-yl, 1- (3-chiorobenzyl) -2-methyl-imidazol-4-yl, 1- (4-trifluoromethylbenzyl) -2-methyl-inidazol-4-yl, 1- (3-methyl-benzyl) -2methyl-imidazol-4-yl, 1- (4-methyl-benzyl) -2-methylimidazol-4-yl, 1- (3-methoxy-benzyl) -2--methyl--imidazol-4yl, 1- (4-methoxy-benzyl) -2-methyl-imidazol-4-yl, 1- a a a.
a a a a a a a o a 4e a a a a a.
A
I,-
-7 dimethoxy-benzyl) -2-methyl-imidazol-4-yl, 1- dimethoxy-benzyl) -2-methyl-imidazol-4-yl, Icarboxymethyl-imidazol-4-yl, 1- (2-carboxyethyl) imidazol-4-yl, 1-(3-carboxypropyl)-.imidazol-4-yl, 1- (4carboxybutyl) -imidazol-4-yl, 1- (5-carboxypentyl) imidazoil-4-yl, 1- (6-carboxyhexyl)-imidazol-4-yl, 1- (7carboxyheptyl) -imidazol-4-yl, 1-methoxycarbonytnethylimidazol-4-yl, 1- (2-methoxycarbonylethyl) -imidazol-4-yl, 1- (3-metIloxycarbonylpropyl) -imidazo1-4-yl, 1- (4methoxycaZbonylbutyl) -imidazol-4-yl, 1- methoxycarbonylpentyl) -imidazol-4-yl, 1- (6methoxycarbonyihexyl) -itnidazol-4-yl, 1- (7-tnethoxycarbonyiheptyl) -imidazol-4-y., 1-ethoxycarbonylmethylimidazol-4-yl, 1- (2-ethoxycarbonylethyl) -irnidazol-4-yl, 1- (3-ethoxycarbonylpropyl) -imidazol-4-yl, 1- (4ethoxycarbonylbutyl) -imidazol-4-yl, 1- pentyl) -imidazol-4-yl 1- C6-ethoxycarbonylhexyl) imidazol-4-yl, 1- (7-ethoxycarbonyiheptyl) -imidazol--4-yl, l-n-propoxycarbonylnethyl-imidazol-4-yl, 1- (2-npropoxycarbonylethyl) &nidazol-4-yl, 1- (3-npropoxycarbonylpropyl) -imidazol-4-yl, 1- (4-n--propoxycarbonylbutyl) -imidazol-4-yl, 1- penyl-imidazol-4-yl, 1- (6-n-propoxycarbonylhexyl) imidzol4-yl 1-7-npropxycrbonlhetyl-imidazol-4yl 1-spooyaboymty*mdao--l -2 y,1isopropoxycarbonylmethyl-imidazol-4-yl, 1- (2isopropoxycarbonylethyl) -imidazol-4-y, 1- (3isopropoxycarbonyipropyl) -iridazol-4-yl, 1- isopropoxycarbonylbutyl) -imidazol-4-yl, isopropioycarbonylpentyl) -imidazol-4-yl, 1- (6aiorpcarbonyihexyl) -tidazl-4-4-.yl, -mn(7- on etyl) -imidazol-4-yl, 1-me(3-aminocarbonylmpyl)- -8 imidazo.-4-yl, 1- (2-methy2.aminocarbonylethy.) -imidazol- 4-yl, 3-methy.amninocarbony.propy.) -imidazol-4-yl, 1- (4-methy2.aminocarbonylbutyl) -imidazol-4-y., 1- methylaminocarbonyl-enty.) -imidazol-4-y., 1- (6methylaminocarbonyihexyl) -imidazol-4-yl, 1- (7methylaminocarbonyiheptyl) -irnidazol-4-yl, 1ethy2.aminocarbonyJlmethyl-itnidazol-4-yl, 1- (2-ethylaininocarbonylethyl) -inidazo.-4-y., 1- (3-ethylaminocarbonylpropyl) -imidazo2.-4-yl, 1- (4-ethylaminocarbonylbutyl) imidazol-4-y., 1- (S-ethy2.aminocarbonylpenty.) -imidazol- 4-yl, 1- (6-ethylaminocarbonyihexyl) -imidazo2.-4-yl, 1- (7ethylaminocarbony.heptyl) -imidazol-4-yl, 1-npropylaminocarbony.methyl-imidazol-4-yl, 1- (2-npropy2.aminocarbonylethyl) -iinidazol-4-yl, 1- (3-npropylaminocarbonyl-ropyl) -imidazol-4-yl, 1- (4-npropylaminocarbonylbuty.) -imidazol-4-yl, 1- propy2.aminocarbonylenty.) -imidazol-4-yl, 1- (6-npropylaminocarbonylhexy.) -imidazol-4-yl, 1- (7-npropylaminocarbonylheptyl) -imidazo2.-4-yl, 1isopropylaminocarbonylnethy.-imidazol-4-y., 1- (2isopropylaminocarbon2.ethyl) -imidazo2.-4-yl, 1- (3isopropy2.aminocarbonylpropyl) -imidazo2.-4-yl, 1- (4isopropylaminocarbonylbuty.) -imidazol-4-y., isopropylarninocarbonvlpentyl) -imidazol-4-yl, isopropylaminocarbonylhexyl) -imidazo2.-4-yl, 1- (7isopropylaminocarbony.hepty.) -imidazol-4-y., Idimethy2.aminocarbonvmethy-inidazo.-4-y. 1- (2dimethy2.aminocarbonyletlhy.) -imidazo2.-4-yl, 2.-(3-dimethylaminocarbonyipropyl) -imidazol-4-yL, 1- (4dimethylaminocarbonylbutyl) -itnidazol-4-y., 1- dimethylaminocarbonylpentyl) -imidazo.-4-y., 1- (6dimethy.aminocarbony.hexy.) -imidazo2.-4-yl, ~dimethf 1 .aminocarbonv.hepty.) -imidazo.-4-y., 1ditS..oaroymty-iiao--l 1S2 diethylaminocarbony.tethyl)-imidazol-4-yl, 1- (2diethylaninocarbonylpeohy.) -imidazol-4-y., 1- (3diethylaminocarbony.proyl)-imidazo2.-4-yl, 9diethylaminocarbonylpentyl) -imidazol-4-y., diethyl-aminocarbonylhexyl) -imidazol-4-yi, 7diethylaminocarbonylheptyl) -iridazol-4-yl, 1-di-npropylarninocarbonylmethyl-imidazol-4-yl, 1- (2-di-npropylatninocarbonylethyl) -imidazol-4-yl, 1- (3-di-npropylarninocarbonylpropyl) -imidazol-4-yl, 1- (4-di-npropyJlarinocarbonylbutyl) -imidazol-4-yl, 1- propylatninocarbonylpentyl) -imidazo.-4-yl, 1- (G-di-npropylatninocarbonylhexyl) -imidazol-4-yl, 1- (7-di-npropylaminocarbonylheptyl) -imidazol-4-yl, 1-diisopropylatninocarbonylmethyl-imidazol-4-y., 1- (2-diisopropylaminocarbonylethyl) -imidazol-4-yl, 1- (3-diisopropylaminocarbonylpropyl) -imidazol-4-yl, 1- (4-diisopropylarninocarbonylbutyl) -imidazol-4-yl, 1- propylarninocarbonylpentyl) -imidazol-4-y1, 1- (6diisopropylaminocarbonylhexyl) -imidazol-4-yl, 1- (7diisopropylaminocarbonylheptyl) -imidazol-4-yl, 1morpholinocarbonylmethyl-imidazol-4-yl, 1- (2morpholinocarbonylethyl) -imidlazol-4-yl, 1- (3morpholinocarbonyipropyl) -imidazol-4-yl, 1- (4morpholinocarbonylbutyl) -imidazol-4-yl, 1- morpholinocarbonylpentyl) -imidazol-4-yl, 1- (6morpholinocarbonylhexyl) -imidazol-4-yl, 1- (7morpholinocarbonyiheptyl) -irnidazol-4-y., 1thiomor-oholinocarbonylmethyl-imidazol-4-yl, 1- (2thiomorpoholinocarbonylethyl) -imidazol-4-yl, 1- (3thiotnorpoholinocarbonylpropyl) -itnidazol-4-yl, 1- (4thiomor-oholinocarbonylbutyl) -imidazol-4-yl, 1- thiomorpoholinocarbonylpentyl) -imidazol-4-yl, 1- (6thiomorohoJlinocarbonylhexyl) -imidazol-4-yl, 1- (7thiomornoholinocarbonylheptyl) -irnidazol-4-yl, 1oxidothiomorpholinocarbonylmethyl-imidazol-4-yl, 1- (2oxidothiomorpholinocarbonylethyl) -imidazol-4-yl, 1- (3oxidothiomorpholinocarbonylpropyl) -imidazol-4-yl, 1- (4oxidothiomorpholinocarbonylbutyl) -imidazol-4-yl, 1- oxidothiomorpholinocarbonylpentyl) -imidazol-4-yl, 1- (6oxidothiomorpholiinocarbonylhexyl) -imidazol-4-yl, 1- (7f. 0 0 t0 f...0 ft..0.
0 t C2.
7' ft 10 oxidothiomorpholinocarbonylheptyl) -imidazol-4-yl, 1carboxymethyl-2-methyl-imidazol-4-yl, 1- (2carboxyethyl) -2-methyl--imidazol-4-yl, 1- (3carboxypropyl) -2-methyl-imidazol-4-yl, 1- (4carboxybutyl) -2-methyl-imidazol-4-y1, 1- carboxypentyl) -2-methyl-imidazol-4-yl, 1- (6carboxyhexyl) -2-tnethyl-imidazo.-4-yl, 1- (7carboxyheptyl) -2-methyl-imidazol-4-yl, 1methoxycarbonylmethy.-2-methyl-imidazol-4-yl, 1- (2methoxycarbonylethyl) -2-methyl-imidazol-4-yl, 1- (3methoxycarbonyipropyl) -2-methyl-imidazol-4-yl, 1- (4methoxycarbonylbutyl) -2-methyl-imidazol-4-yl, 1- methoxycarbonylpentyl) -2-methyl-imidazol-4-yl, 1- (6methoxycarbonyihexyl) -2-methyl--imidazol-4-yl, 1- (7methoxycarbonyiheptyl) -2-methyl-imidazol-4-yl, Iethoxycarbonylmethyl-2-tnethyl-imidazo27-4-yl, 1- (2ethoxycarbonylethyl) -2-methyl-imidazol-4-yl, 1- (3ethoxycarbonyipropyl) -2-methyl-itnidazol-4-yl, 1- (4ethoxycarbonylbutyl) -2-methyl-imidazol-4-y1, 1- ethoxycarbonylpentyl) -2-methyl-imidazol-4-yl, 1- (6ethoxycarbonyihexyl) -2-methyl-imidazol-4-yl, 1- (7- .04.:ethoxycarbonyiheptyl) -2-methyl-imidazol-4-yl, 1-npropoxycarbonylmethyl)-2-methyl-imidazol-4-yl, 1- (2-npropoxycarbonyletyl) -2-methyl-itnidazol-4-yl, 1- (3-nprpoycrbnyheyl--mehyl-imidazol-4-y-± 1- propoxycarbonylbutyl) -2-methyl-imidazol-4-yl, ispropoxycarbonyletyl-2-methyl-imidazol-4-yl, 1- prooxycarbonyl) -2-methyl-imidazol-4-yl, 1- ipooxycarbonhpyl -2-methyl-imidazol-4-yl, 1-(4
-S
isopropoxycarbonylpetyl)-2-methyl-imidazol-4-yl, 1- .5pooyabnley)2mehliiao--l -7 isopropoxycarbonyletyl) -2-methyl-imidazol-4-yl, 1-(3 aiorpcarbonylpropy)-2-methyl-imidazol-4-yl, 1- (4- 11 aminocarbonylethyl) -2-methyl-imiclazol-4-yl, 1- (3atninocarbonyipropyl) -2-methyl-imidazol-4-yl, 1- (4aminocarbonylbutyl) -2-tnetlyl-imidazol-4-yl, 1- aminocarbonylpentyl) -2-methyl-imidazol-4-yi, 1- (6aminocarbonyihexyl) -2-methyl-imidazol-4-yl, 1- (7aminocarbonyiheptyl) -2-methyl-imidazol-4-yl, 1methylamtinocarbonylmethyl-2-methyl-imidazol-4-yl, 1- (2methylaminocarbonylethyl) -2-methyl-imidazol-4-yl, 1- (3methylaminocarbonylpropyl) -2-tethyl-imidazol-4-yl, 1- (4methylaminocarbonylbutyl) -2-methyl-imidazol-4-yl, 1- methylaminocarbonylpentyl) -2-methyl-imidazol-4-yl, 1- (6tnethylaminocarbonylhexyl) -2-methyl-imidazol-4-yl, 1- (7methylaminocarbonylheptyl) -2-rethyl-imidazol-4-yl, 1ethylaminocarbonylmethyl-2-methyl-imidazol-4-y-, 1- (2ethylaminocarbonylethyl) -2-methyl-imidazol-4-yl, 1- (3ethylaminocarbonyipropyl) -2-methyl-imidazol-4-yl, 1- (4ethylaminocarbonylbutyl) -2-methyl-imidazol-4-yl, 1- ethylaminocarbo.LfI,-.pentyl) -2-methyl-imidazol-4-yl, 1- (6ethyl amino carbonylhexyl) -2-methyl-imidazol-4-yl, 1- (7ethylaminocarbonyiheptyl) -2-methyl-imidazol-4-yl, 1-npropylaminocarbonyltnethyl-2-methyl-imidazol-4-yl, 1- (2n-rplmncronlty)2mtyliiao.l 1- (3n-propyl amino carbonylh pyl) -2-methyl-imidazol-4-yl, 4.1 (-n-propylaminocarbonylropyl) -2-nethyl-imidazol-4-yl, (5-n-propylaminocarbonylbutyl) -2-methyl-imidazol-4-l y1- (-n-propylaminocarbonylntyl) -2-methyl-imidazol- 4- 1(7npropyainocarbonyhepy)2ethy-ndz1 imidazo.-4-y., 1-isopropylaminocarbonylmethyl-2-methyl- 4mdzl--l .42iorplmnoabnlty)2 mtlimidazol-4-yl, 1- (2 -isopropylaminocarbonyl)tn l2-ethyl-imidazol-4-yl, 1- 3 -isopropylaminoy proyl l-2-methyl-i miid azol-4-yl, -soyaio iorplmncarbonylbuntyl) -2-methyl-imidazol-4-yl, isopoyl aino carbonpnyly) -2-methyl-imidazol-4-yl, 1 1-(-isopropylaminocarbonylheyl) -2-methyl-imidazol-4-l (7-ioprylaminocarbonylheptyl)-2-methyl-imidazol-4yl, 1-(2dimethyainoarbonyethyl-2-methy-imidazo- 12 4-yl, 1- (3-dimethylaniinocarbonylprooyl) -2-methylirnidazol-4-yl, 1- (4-ditethylamirocarbonylbutyl) -2methyl-imidazol-4-yl, 1- (5-dimetiaylarinocarbonylpentyl) 2-methyl-imidazol-4-yl, 1- (6-dimethylaminocarbonylhexyl) -2-methyl-imidazol-4-yl, 1- (7-dimethylaminocarbonyiheptyl) -2-methyl-imidazol-4-yl, 1diethylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1- (2diethylaminocarbonylethyl) -2-methyl-imidazol-4-yl, 1- (3diethylaminocarbonylpropyl) -2-methyl-imidazol-4-yl, I- (4-diethylaminocarbonylbutyl) -2-methyl-imidazol-4-yl, I- -2-methyl-imidazol-4-yl, 1- (6-diethylatninocarbonylhexyl) -2-rethyl-imidazol-4-yl, 1- (7-diethylatninocarbonylheptyl) -2-rethyl-imidazol-4-yl, 1-di-n-propylaminocarbonylmethyl-2-tnethyl-imidazol 4-yl, 1- (2-di-n-propylaminocarbonylethyl) -2-methyl-imidazol-4yl, 1- (3-di-n-propylaminocarbonylpropyl) -2-methylimidazol-4-yl, 1- (4-di-n-propylaminocarbonylbutyl) -2methyl-imidazol-4-yl, 1- pentyl) -2-methyl-imidazol-4-yl, 1- (6-di-n-propylaminocarbonyihexyl) -2-methyl-imidazol-4-yl, 1- (7-di-npropylaminocarbonyiheptyl) -2-methyl-imidazol-4-yl, 1diisproylainocrboylmthy-2 -methyl -imidazol -4y, yl, 1- (3-diisopropylaminocarbonylpropyl) -2-methylimi4dazol-4-yl, 1- (4-diisopropylatninccarbonylbutyl) -2methyl-imidazol-4-yl, 1- pentyl) -2-methyl-imidazol-4-yl, 1- (6-diisopropylaminocarbonyihexyl) -2-methyl-imidazol-4-yl, 1- (7-diisopropylaminocarbonylhepty.) -2-methyl-imidazol-4-yl, 1rrmorphoinocarbonymethyl-2-methyl-i-midazol-4-y1, 1- (2morpholinocarbonylethyl) -2-methyl-imidazol-4-yl, 1- (3tnorpholinocarbonylpropyl) -2-methyl-imidazol-4-yl, 1- (4mopoioabnluy)2mty*-iao--l morpholinocarbonylbutyl) -2-methyl-imidazol-4-yl, 1- moposncroyteoo)d-:hy-mdao--l,1 6 morpholinocarbonyihexyl) -2-methyl-imidazol-4-yl, 1- (7morpholinocarbonyiheptyl) -2-methyl-imidazol-4-yl, 1thiomorpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1- 13 (2-thiomorpholiriocarbonylethyl) -2-methyl-imidazol-4-yl, 1- (3-thiororpholinocarbonylpropyl) -2-methyl-imidazol-4yl, 1- (4-thiomorpholinocarbonyl-butyl) -2-methylimidazol-4-yl, 1- (S-thiomorpholinocarbonylpentyl) -2methyl-imidazol-4-yl, 1- (6-thiomorpholinocarbonylhexyl) -2-tethyl-imidazol-4-yl, 1- (7-thiomorpholinocarbonyiheptyl) -2-methyl-imidazol-4-yl, 1-oxidothiomorpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1- (2oxidothiomorpholinocarbonylethyl) -2 -methyl-imidazol-4yl, 1- (3-oxidothiomorpholinocarbonylpropyl) -2-methylimidazol-4-yl, 1- (4-oxidothiomorpholinocarbonylbutyl) -2methyl-imidazol-4-yl, 1- pentyl) -2-methyl-imidazol-4-yl, 1- (6-oxidothiamorpholinocarbonylhexyl) -2-methyl-imidazol-4-yl, 1- (7oxidothiomorpholinocarbonylheptyl) -2 -methyl-imidazol-4yl, 1- (2-hydroxyethyl) -imidazol-4-yl, 1- (3hydroxypropyl) -imidazol-4-yl, 1- (4-hydroxybutyl) imidazol-4-yl, 1- (2-tethoxyethyl) -imidazol-4-yl, 1- (3methoxypropyl) -imidazol-4-yl, 1- (4-methoxybutyl) imidazol-4-yl, 1- (2-ethoxyethyl) -imidazo1l-4-y1, 1- (3ethoxypropyl) -imidazol-4-yl, 1- (4-ethoxybutyl) -imidazol- .go.:4-yl, 1- (2-n-propoxyethyl) -imidazol-4-yl, 1- (3-no:propoxypropyl) -imidazol-4-yl, 1- (4-n-propoxybutyl) imidazol-4-yl, 1- (2-isopropoxyethyl) -imidazol-4-y., 1- (3-isopropoxypropyl) -imidazol-4-yl, 1- (4-isopropoxybutyl) -imidazol-4-yl, 1- (2-imidazol-1-yl-ethyl)- 0 imidazol-4-yl, 1- (3-Imidazol-l-yl-propyl) -imidazol-4-yl, 1- (4-imidazol-1-yl-butyl) -imidazol-4-yl, 1- (2,2diphenyl-ethyl) -imidazol-4-yl, 1- (3,3-dipheriyl-propyl) ,06:0*imidazol-4-yl, 1-(4,4-diphenyl-butyrl) -imidazol-4-yl, 1-
SO
"Se a(2-hydroxyethyl) -2-methyl-imidazol-4-yl, 1- (3-hydroxy- 0 propyl) -2-rethyl-imidazol-4-yl, 1- (4-hydroxybutyl) -2methyl-imidazol-4-yl, 1- (2-methoxyethyl) -2-methylimidazol-4-yl, 1- (3-methoxypropyl) -2-methyl-imidazol-4yIl, 1- (4-methoxybutyl) -2-methyl-imidazol-4-yl, 1- (2ethoxyethyl) -2-methyl-imidazol-4-yl, 1- (3-ethoxypropyl) 2-methyl-imidazol-4-yl, 1- (4-ethoxybutyl) -2-methyl- 14 imidazol-4-yl, 1- (2-n-propoxyethyl) -2-methyl-imidazol-4yl, 1- (3-n-propoxypropyl) -2-tethyl-imidazol-4-yl, 1- (4ui-propoxybutyl) -2-methyl-imidazol-4-yl, 1- (2isopropoxyethyl) -2-methyl-imidazol-4-yl, 1- (3isopropoxypropyl) -2-tethyl-imidazol-4-yl, 1- (4isopro)-,oxybutyl) -2-methyl-imidazol-4-yl, 1- (2-imidazol- 1-yl -ethyl) -2-methyl-imidazol-4-yl, 1- (3-imidazol-l-ylpropyl) -2-methyl-imidazol-4-yl, 1- (4-iridazol-l-ylbutyl) -2-methyl-imidazol-4-yl, 1- (2,2-diphenyl-ethyl) -2methyl-imidazol-4-yl, 1- 3-diphenyl-propyl) -2-methylimidazol-4-yl, 1- 4-diphenyl-butyl) -2-methyl-imidazol- 4-yl, 1- (2-methoxyethoxy) -ethyl] -imidazol-4-yl, 1- [3- (2-methoxyethoxy) -propyl] -iraidazol-4-yl, 1-114- (2rnethoxyethoxy) -butyl] -imidazol-4-yl, 1-f 2- (2ethoxyethoxy) -ethyl] -imidazol-4-yl, 1- (2ethoxyethoxy) -propyl] -imidazol-4-yl, 1- (2ethoxyethoxy) -butyl] -imidazol-4-yl, 1- (2-npropoxyethoxy) -ethyl] -imidazol-4-yl, 1-13- (2-npropoxyethoxy) -propyl] -imidazol-4-yl, 1- (2-npropoxyethoxy) -butyl] -imidazol-4-yl, 1- (2isopropoxyethoxy) -ethyl] -imidazol-4-yl, 1-113- (2isopropoxyethoxy) -propyl] -imidazol-4-yl, 1-114- (2isopropoxyethoxy) -butyl] -iridazol-4-yl, 1- (2dimethylaminoethyl) -imidazol-4-yl, 1- (2-diethylaminoethyl) -imidazol-4-yl, 1- (2-di-n-propylamino-ethyl) imidazol-4-yi, 1- (2-diisopropylaminoethyl) -irnidazol-4yl, 1- (3-dimethylaminopropyl) -imidazol-4-yl, 1- (3diethylaminopropyl) -imidazol-4-yl, 1- (3-di-npropylamino-propyl)-irnidazol-4-yl,1- (3-didimethylamino-butyl) -imidazol-4-yl, 1- (4-diethylaminobutyl) -imidazol-4-yl, 1- (4-di-n-propylamino-butyl) itnidazol-4-yl, 1- (4-diisopropylamino-butyl) -imidazol-4yl, 1- (2-morpholino-ethyl) -imidazol-4-yl, 1- (3morpholino-propyl) -imidazol-4-yl, 1- (4-morpholinobutyl) -imidazol-4-yl, 1- (2-pyrrolidino-ethyl) -imidazol- 4-yl, 1- (3-pyrrolidino-propy l) -imidazol-4-yl, 1- (4- 4' pyrrolidino-butyl) -imidazol-4-yl, 1- (2-piperidino- 15 ethyl) -imidazol-4-yl, 1- (3-piperidino-propyl) -imidazol- 4-yl, 1- (4-piperidino-butyl) -imidazol-4-yl, 1- (2hexamethyleneimino-ethyl) -imidazol-4-yl, 1- (3hexamethyleneimino-propyl) -iiidazol-4-yl, 1- (4hexamethyleneimino-butyl) -imidazol-4-yl, 1- (2thiomorpholino-ethyl) -imidazol-4-yl, 1- (3-thiamorpholino-propyl) -imidazol--4-yl, 1- (4-thiomorpholinobutyl) -imidazol-4-yl, 1- (l-oxido-thiomorpholino) ethyl] -imidazol-4-yl, 1- (l-oxido--thiomorpholino) propyl] -imidazol-4-yl or 1- (l-oxido-thiomorpholino) butyl] -imidazol-4-yl group;
R
3 may represent an ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, cyclopropyl, cyclobutyl, ethoxy, n-propoxy, isopropoxy, ethylthio, n-propylio or isopropylthio group; and
R
4 may represent a hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, tert butyloxycarbonyl, npentyloxycarbonyl, isoamyloxycarbonyl, n-hexyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, 1 -phenylethyloxycarbonyl, 2phenylethyloxycarbonyl, 3 -phenyipropyloxycarbonyl, .methoxymethoxycarbonyl, cinnamyloxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, nbutyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, n-pentanoyloxymethoxycarbonyl, isopentanoyloxymethoxycarbonyl, pivaloyloxytnethoxycarbonyl, nhexanoyloxymethoxycarbonyl, cyclopentanoyloxymethoxycarbonyl, cyclohexanoyloxymethoxycarbonyl, phenylacetoxymethoxycarbonyl, 2 -phenyipropionyloxymethoxycarbonyl, 3 -phenyl-propionyloxymethoxycarbonyl, 4-phenylbutyryloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, 1-acetoxyethoxycarbonyl, 1- *.propionyloxyethoxycarbonyl, 1--uyyoy .i ethoxycarbonyl, 1-isobutyryloxyethoxycarbonyl, 1-n- 16 pentanoyloxyethoxycarbonyl, 1-isopentanoyloxyethoxycarbonyl, 1-pivaloyloxyet-hoxycarbonyl, 1-nhexanoyloxyethoxycarbonyl, 1-cyclopentanoyloxyethoxycarbonyl, 1-cyclohexanoyloxyethoxycarbonyl, 1phenylacetoxyethoxycarbonyl, 1- (l-phenyipropionyloxy) ethoxycarbonyl, 1- (2 -phenyipropionyloxy) -ethoxycarbonyl, 1- (3-phenylbutyryloxy) -ethoxycarbonyl, 1benzoyloxyethoxycarbonyl, methoxycarbonyloxymethoxycarbonyl, ethoxycarbonyloxynethoxycarbonyl, npropyloxycarbonyloxynethoxycarbonyl, isopropyloxycarbonyloxyrnethoxycarbonyl, n-butyloxycarbonyloxymethox~ycarbonyl, isobutyloxycarbonyloxymethoxycarbonyl, tert butyloxycarbonyloxymethoxycarbonyl, npentyloxycarbonyloxymethoxycarbonyl, isoamyloxycarbonyloxymethoxycarbonyl, n-hexyloxycarbonyloxymethoxycarbonyl, cyclopentyloxycarbonyloxymethoxycarbonyl, cyclohexyloxycarbonyloxymethoxycarbonyl, benzyloxycarbonyloxytnethoxycarbonyl, 1 -phenylethoxycarbonyloxymethoxycarbonyl, 2 -phenylethoxycarbonyloxymethoxycarbonyl, 3 -phenyipropyloxycarbonyloxymethoxycarbonyl, cinnamyloxycarbonyloxynethoxycarbonyl, 1- (methoxycarbonyloxy) -ethoxycarbonyl, 1- (ethoxycarbonyloxy) -ethoxycarbonyl, 1- (npropyloxycarbonyloxy) -ethoxycarbonyl, 1- (isopropyloxycarbonyloxy) -ethoxycarbonyl, 1- (nbutyloxycarbonyloxy) -ethoxycarbonyl, 1- (isobutwloxycarbonyloxy) -ethoxycarbonyl, 1- (tert .butyloxycarbonyloxy) -ethoxycarbonyl, 1- (n-pentyloxycarbonyloxy) ethoxycarbonyl, 1- (isoamyloxycarbonyloxy) ethoxycarbonyl, 1- (n-hexyloxycarbonyloxy) ethoxycarbonyl, 1- (cyclopentyloxycarbonyloxy) -er -hoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) -ethoxycarbonyl, cyclopentylcarbonyloxymetboxycarbonyl, 1- (benzyloxycarbonyloxy) -ethoxycarbonyl, 1- (1phenylethoxycarbonyloxy) -ethoxycarbonyl, 1- (2phenylethoxycarbonyloxy) -ethoxycarbonyl, 1- (3phenylpropyioxycarbonyloxy) -ethoxycarbonyl, 1- 9 9 9 9t .9 *9**99 9 99 9 9 9 .9 9 *99 9*99 9 9 9* *9 *9 *9 9 .9 ~s.
99.j
/A
17 (cinnamyloxycarbonyloxy)-ethoxycarbonyl, cyano, 1Htetrazolyl, 1-triphenylmethyl-tetrazolyl or 2triphenylmethyl-tetrazolyl group.
Preferred compounds according to the invention include those of formula I wherein R, represents a C 1 .3-alkyl group, a hydrogen, fluorine, chlorine or bromine atom;
R
2 in the 6-position of the benzimidazole ring represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a C 1 6 -alkyl group or by a phenyl group and substituted in the 1-position by a C, 1 7 -alkyl group substituted in the 4-, 6- or 7- position by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxidothiomorpholinocarbonyl group, gj by a C2-4-alkyl group substituted in the 3- or 4- .position by a hydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxidothiomorpholino or imidazol-l-yl group, by a C,-alkyl group substituted by a trifluoromethyl group, by a C3-7-cycloalkyl group or by a phenyl group itself optionally mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, *,c~ik\ 18 or by a Ci.3-alkyl group substituted by two phenyl groups, where unless otherwise specified the above-mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms;
R
3 represents a C 2 _4-alkyl, C 2 _3-alkoxy, Cz.
3 -alkylthio, cyclopropyl or cyclobutyl group; and
R
4 represents a carboxy, cyano, IH-tetrazolyl, 1triphenylmethyl-tetrazolyl or 2-triphenylmethyltetrazolyl group or a group convertable in vivo into a carboxy group and the salts thereof.
Particularly preferred compounds according to the invention include those of formula I wherein RI represents a hydrogen or chlorina atom or a methyl group;
R
2 in the 6-position of the benzimidazole ring represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-Fosition by a phenyl group *fl.
or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the 1-position by a Ci 1 7 -alkyl group substituted in the 4-, 6- or 7-position by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido- 19 thiomorpholino-carbonyl group, by a C 2 4 -alkyl group substituted in the 3- or 4-position by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-1-yl group, or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, 2-phenylethyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-methylbenzyl, 4-trifluoromethylbenzyl, or 2,2-diphenylethyl group;
R
3 represents a C 2 _4-alkyl, C 2 -3-alkoxy, C 2 _.-alkylthio cyclopropyl or cyclobutyl group; and
R
4 represents a carboxy or IH-tetrazolyl group or a group convertable in vivo into a carboxy group; and the salts thereof.
More particularly preferred compounds of formula I include those wherein R, represents a hydrogen atom or a methyl group;
R
2 in the 6-position of the benzimidazole ring represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the 1position 0 by a C 1 7 -alkyl group substituted in the 4-, 6- or 7-position by a carboxy, methoxycarbonyl, dimethylaminocarbonyl or morpholinocarbonyl group, 20 by a C 2 4 -alkyl group substituted in the 3- or 4position by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-1-yl group, or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl or 4-f luoro-benzyl group;
R
3 represents a C 2 4 -alkyl, ethoxy, ethylthio, cyclopropyl or cyclobutyl group; and
R
4 represents a carboxy or 1H-tetrazolyl group; and the salts thereof.
The present invention particularly relates to the following compounds of formula I: II(2-n-propyl-4-methyl-6- (1-(2-N-morpholinoethylimidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid; [(2-n-Propyl-4-methyl-6-(l-(2-methoxyethoxy-2ethyl) -imidazol-4-yl) -benzimidazol-l-yl) -methyll biphenyl carboxylic acid; (2-Ethyl-4-tnethyl-6- (1-(2-diethylaminoethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (lHterzo Sl)bphnl [(2-Ethyl-4-methyl-6- (1-(3-N-piperidinopropyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (lH- -biphenyl; J dimethylaminopropyl) -imidazol-4-yl) -benzimidazol-l-yl) 21 methyl] -biphenyl-2-carboxylic acid; 4' -[(2-Ethyl-4-methyl-6- (1-(2-N-morpholinoeth-ryl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid; 1(2-Ethyl-4-methyl-6-(l-(2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (l- -bipheny.; 4'-[I(2-Ethyl-4-methyl-6-(l- (2-N-pyrrolidinoethyl) imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2carboxylic acid; 41- [(2-Ethyl-4-methyl-6- (1-(2-N-pyrrolidinoet-hyl) imidazol-4-yl) -benzimidazol-l- i) -methyl] (lH- -biphenyl; [(2-Ethyl-4-methyl-6- (l-(2-diethylaminoethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenvl1-2carboxylic acid; 4 [(2-Ethyl-4-methyl-6- (1-(3-::.q-piperidinopropyl) imidaz ;L-4-yl) -benzimidazol-l-yl) -methyl] -biphen*/l-2carboxylic acid an th atCteef Acorin to an thehe saltst thhereofonls provides a process for the preparation of compounds of C:the invention, said process comprising at least one of the following steps: a) cyclising a compound of formula II 22
X
1
(II)
(wherein one of the groups X, and Yi represents a group of formula
R
-NRs-CH 2O
O
and the other group X 1 or Yj represents a group of formula Z, Z2 NH C R3 R represents a hydrogen atom or an R 3 CO group, R1, R 2
R
3 and R 4 are as hereinbefore defined, ZI and Z 2 which may be identical or different, represent S S optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by C 1 .e-alkyl groups which may be identical or different or Z and Z 2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a CI.--alkyl group, or an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms) or an N-oxide thereof and optionally subsequently reducing a cyclized N-oxide thus obtained; 23 b) reacting a benzimidazole of formula III
R
1
N
R
R
N
H
(where in
R
1
R
2 and R 3 are as hereinbef ore defined) with a biphenyl compound of formula IV
R
Z
3
-CH
2 DC
(IV)
(wherein R4 is as hereinbefore defined and Z3 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a *too*methanesulphonyloxy, phenylsulphonyloxy or p- 00R9* Oer* toluenesulphonyloxy group); to 0:0 c) (to prepare a compound of formula I wherein R 4 represents a carboxy group) converting a compound of formula V t oo 6 24
RI
(V)
(wherein RI, R 2 and R3 are as hereinbefore defined, and
R
4 represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis; d) (to prepare a compound of formula I wherein R 4 represents a IH-tetrazolyl group) cleaving a protecting group from a compound of formula VI R1
N
R2R R
(VI)
(wherein
R
1 Rz and R 3 are as hereinbefore defined and
R
4 represents a IH-tetrazolyl group protected in the 1or 3-position by a protecting group); e) (to prepare a compound of formula I wherein R 4 represents a 1H-tetrazolyl group) reacting a compound of formula VII 25
R
R 3 CN SN 3 CH2Q 0
(VII)
(wherein R R 2 and R 3 are as hereinbefore defined) with hydrazoic acid or a salt thereof; f) converting a compound of formula I wherein R 4 denotes a carboxy group, by esterification into a corresponding compound of formula I wherein R 4 denotes a group convertable in vivo into a carboxy group; g) converting a compound of formula I wherein R 2 denotes an imidazol-4-yl group substituted in the 1- position by a C2 4 -alkyl group itself substituted in the 3- or 4position by an alkoxy or alkoxyalkoxy group, by ether splitting into a corresponding compound of formula I wherein R 2 denotes an imidazol-4-yl group substituted in the 1-position by a C2-4-alkyl group substituted in the 3- or 4-position by a hydroxy group; S•h) separating the 1-isomer from a 3-isomer mixture Sof a compound of formula I by isomer separation; i) converting a compound of formula I into a salt thereof, more particularly into a physiologically acceptable addition 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 j) performing a process as defined in any one of steps Ah't to above on a corresponding protected compound 26 and subsequently removing the protecting groups used.
The cyclisation of step is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, e.g. at temperatures between 0 and 250°C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphuryl-chloride, sulphuric acid, ptoluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid or acetic anhydride, or optionally in the presence of a base such as potassium ethoxide or potassium tert.butoxide. However, the cyclisation may also be carried out without a solvent and/or condensing agent.
It is particularly advantageous to carry out the :reaction of step by preparing a compound of formula II in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of formula R 3 CCOH, or by acylation of a corresponding o-diamino compound. When the reduction of the nitro group is broken off at the hydroxylamine stage, the N-oxide of a compound of formula I is obtained in the subsequent cyclisation. The resulting N-oxide is then converted by reduction into a corresponding compound of formula I.
The subsequent reduction of the N-oxide of formula I obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney 27 nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic acid, hydrochloric acid or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium ditihionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50"C, but preferably at ambient temperature.
The reaction of step is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethyl-sulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, sodium hydride, 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.
In the reaction of step a nixture of the 1and 3- isomers is preferably obtained from which subsequently the 1-isomer is isolated by crystallisation or chromatography using a substrate 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 and •anhydrides, and nitrile and tetrazolyl groups may be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. tert.butylesters, may be converted by thermolysis into a carboxy group and esters with aralkanols, e.g. benzylesters, may be converted by hydrogenolysis into a carboxy group.
The hydrolysis of step is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid or in the S presence of a base such as sodium hydroxide or potassium 28 hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol, water/dioxane, methylene chloride or chloroform at temperatures between -10 0 C and 120"C, e.g.
at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups present may simultaneously be converted into a corresponding acyloxy group such as a trifluoroacetoxy group.
If R 4 in a compound of formula V represents a cyano or aminocarbonyl group, such a group may also be converted into a carboxy group with a nitrite, e.g.
sodium nitrite, in the presence of an acid such as sulphuric acid, which may simultaneously also be used as solvent, at temperatures between 0 and 50 0
C.
If R 4 in a compound of formula V represents for example a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, conveniently at temperatures between 40"C and 100 0 C, preferably at the boiling temperature of the solvent used.
If R 4 in a compound of formula V represents, for example, a benzyloxycarbonyl group, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal in a S: suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 0 C, e.g. at an-'ient temperature, under a 999**9 'u hydrogen pressure of 1 to 5 bar. During hydrogenolysis, other groups may be reduced at the same time, e.g. a j ,6.
29 nitro group may be reduced to the amino group, a benzyloxy group to the hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.
Suitable protecting groups for use in step (d) include, for example, triphenylmethyl, tributyl tin and triphenyl tin groups.
The cleaving of a protecting group used is preferably carried out in the presence of a hydrohalic acid, more preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia, in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, at temperatures between 0 and 100 0 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 0
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°C. Advantageously, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g. from sodium azide, in the presence of a weak acid such as ammonium chloride, or the tetrazolide salt obtained in the reaction mixture by reacting with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which are also conveniently prepared 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 Sacid such as 2N hydrochloric acid or 2N sulphuric acid.
The conversion in step of a carboxyl group into 30 a group which is metabolically convertable in vivo into a carboxy group is expediently carried out by esterification with a corresponding alcohol or with a corresponding reactive acyl derivative, conveniently in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide or in an excess of an acylating agent as solvent, optionally in the presence of an acid activating or dehydrating agent such as thionyl chloride, with the anhydrides, esters or halides thereof, optionally in the presence of an inorganic or tertiary organic base, such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, whilst the latter two may simultaneously be used as solvent, at temperatures between -25 and 100 0 C, but preferably at temperatures between -10 and The subsequent ether splitting is conveniently carried out hydrolytically in an aqueous solvent, e.g.
in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydriodic acid or hydrobromic acid, but preferably under the effect of a Lewis acid such as boron trifluoride, boron tribromide, boron trichloride, dimethyl borobromide or aluminium trichloride in a suitable solvent such as dichloromethane or chloroform, or with 0 a the aid of bromotrimethylsilane, iodotrimethylsilane or chlorotrimethylsilane/sodium iodide in a suitable solvent such as acetonitrile, dichloromethane or chloroform, at temperatures between 0 and 100°C, preferably at 20"C, with subsequent aqueous working up.
In the reactions described above, any reactive groups present such as hydroxy, amino or alkylamino groups may be protected during the reaction by means of 0 conventional protecting groups which are split off again after the reaction.
0 Examples of suitable protecting groups for a ALi\ hydroxy group include trimethylsilyl, acetyl, benzoyl, 31 methyl, ethyl, tert.butyl, benzyl and tetrahydropyranyl groups and suitable protecting groups for an amino, alkylamino or imino group may include acetyl, benzoyl, ethoxycarbonyl and benzyl groups.
The optional subsequent cleaving of a protecting group is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100"C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is preferably cleaved 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 but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar.
An isomer mixture of a compound of formula I thus .obtained may if desired be resolved by chromatography 0*0. using a substrate such as silica gel or aluminium oxide.
The compounds of formula I obtained may, if 0*0: desired, 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 hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic S"acid, lactic acid, citric acid, tartaric acid and maleic acid.
Furthermore, the new compounds of formula I thus Sobtained, if they contain a carboxy or 1H-tetrazolyl group, may if desired subsequently be converted into the 32 addition 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.
Some of the compounds of formulae II to VII used as starting materials are known from the literature.
Otherwise those compounds may be obtained by methods known from the literature.
Thus, for example, a compound of formula II may be obtained by alkylation of a corresponding o-aminoacylamino compound with a compound of formula IV. The o-amino-acylamino compound required for this may be obtained by reduction of a corresponding o-nitroacylamino compound which in turn may be obtained by nitration of a corresponding acylamino-acetophenone, subsequent conversion of the resulting corresponding onitro-acylamino-acetophenone into the corresponding ebromo-acetophenone, subsequent cyclisation of the wbromo-acetophenone with a corresponding acid amide and subsequent reduction of the nitro group. Before the reduction of the nitro group an oxazol-4-yl compound thus obtained may be converted into the corresponding imidazol-4-yl compound by means of a corresponding amine, preferably with ammonia, under pressure, or an a imidazol-4-yl compound unsubstituted in the l-position obtained in this way may be converted by alkylation into a corresponding imidazol-4-yl compound alkylated in the l-position.
A starting compound of formula III may be obtained by reduction and cyclisation of an o-nitro-acylamino ccmpound as described hereinbefore.
Starting compounds of formulae V, VI and VII may be obtained by reacting a compound of formula III with a corresponding compound of formula IV.
4 The new compounds of formula I and the 33 physiologically acceptable salts thereof have valuable pharmacological properties. They are angiotensinantagonists, in particular, angiotensin-II-antagonists.
The compounds of formula I wherein P. represents a group convertable in vivo into a carbc group, a carboxy or lE-tetrazolyl group have, in particular, useful pharmacological properties since they are angiotensin-antagonists, particularly angiotensin-IIantagonists. The other compounds of formula I are valuable as intermediate products for preparing the compounds mentioned above.
By way of example, the following compounds: A [(2-n-propyl-4-methyl-6- (l-methyl-imidazol-4-yl) benzimidazol-l-yl) -metuhyl] -biphenyl-2-carboxylic acid; B L(2-n-propyl-4-methyl-6- (l-isopropyl-imidazol-4yl) -benzimidazol-l-yl) -methyl] (lH--tetrazol-5-yl) biphenyl; C [(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid; EO 4S[2npoy--ehl6(-ylhpy-mdzl D 4'-(4-oyl-ben(lioprol-imidaz-metyl-ihnl 2-aboyi acid;an 34 G 4'-[(2-n-propyl-4 lethyl-6-(1-(3-dimethylaminopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid-dihydrochloridepentahydrate were investigated for their biological activities as follows: Description of method: angiotensin-II-receptor bonding The tissue (rat's lung) is homogenised in tris buffer (50 mMol Tris, 150 mMol NaCI, 5 dmol EDTA, pH 7.40) and centrifuged twice for 20 minutes each time at 20,000 x g. The finished pellet is resuspended in incubation buffer (50 mMol Tris, 5 mMol MgCl 2 0.2% BSA, pH 7.40) 1:75, based on the moist weight of the tissue.
Each 0.1 ml of homogenate is incubated for 60 minutes at 37 0 C with 50 pM [125s] -angiotensin-II (NEN, Dreieich, FRG) and increasing concentrations of the test substance in a total volume of 0.25 ml. The incubation is ended by rapid filtration through glass fibre filter mats.
The filters are each washed with 4 ml of ice cold buffer mMol Tris, 2.5 mMol MgC1 2 0.1% BSA, pH 7.40). The bound radioactivity is measured in a gamma-counter. The corresponding ICso value is determined from the dosageactivity curve.
Substances A to G show the following ICs 5 values in the test described: *the test described: 6 *oo 6 *6 "6 *6 Substance ICs 5 [nM] A 1.2 B C D E F 3.4 G 1.3 35 In view of their pharmacological properties, namely a hypotensive effect with a diuretic/saluretic component, the new compounds and the physiologically acceptable addition salts thereof are suitable for the treatment of hypertension and cardiac insufficiency and also for treating chronic renal insufficiency, ischaemic peripheral circulatory disorders Raynaud's syndrome) and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and retinopathy, glaucoma, gastrointestinal diseases and bladder diseases.
Furthermore, the new compounds and the physiologically acceptable salts thereof are suitable for treating pulmonary diseases, e.g. lung cedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout.
Because of the effect of angiotensin on the release of acetylcholine and dopamine in the brain, the new angiotensin antagonists are also suitable for alleviating central nervous system disorders, e.g.
depression, Alzheimer's disease, Parkinson's syndrome, as well as diso- iers of cognitive functions.
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 present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension and cardiac insufficiency and also for *0 0 0 0000 0000 00 0 0 00 0 00 0 0 'A4 .3 36 treating chronic renal insufficiency, ischaemic peripheral circulatory disorders Raynaud's syndrome) and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy axid rstinopathy, glance~ gastrointestinal diseases and bladder diseaser.
In particular, ihe present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of pulmonary diseases, for preventing arterial re-sterosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout.
More particularly, the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for alleviating central nervous system disorders.
Viewed from a yet still further aspect the present S.invention provides a method of treatment of the human or non-human animal body to combat hypertension and cardiac insufficiency and also for treating chronic renal insufficiency, ischaemic peripheral circulatory disorders and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the Iprogression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and retinopathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I or a \physiologically acceptable salt thereof.
In particular, the present invention provides a method of treatment of the human or non-human animal j t 37 body to combat pulmonary diseases, for preventing arterial re-sterosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
More particulary, the present invention provides a method of treatment of the human or non-human animal body to combat central nervous system disorders, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
The dosage required to achieve these effects in adults is appropriately, when administered intravenously, 0.5 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, for example, hypotensive agents, 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, micro-crystalline cellulose, magnesium stearate, polyvinyl-pyrrolidone, 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.
Examples of additional active substances which may 'be used in the combinations mentioned above include bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzothiazide, .0?~v~l i s tS 38 cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosin, atenolol, propranolol, (di)hydralazinehydrochloride, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, nitrendipine, captopril, enalapril, lisinopril, cilazapril, quinapril, fosinopril and ramipril. The dosage of these active substances is conveniently 1/5 of the lowest dose normally recommended up to 1/1 or the normally recommended dosage, that is for example 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorothiazide, 15 to 200 mg of ethacrinic acid, 5 to 80 mg of furosemide, 20 to 480 mg of propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipine or 5 to 60 mg of nitrendipine.
The following non-limiting Examples are provided to illustrate the invention. All percentages and ratios given are by weight, other than eluant or solvent ratios which are by volume.
O0 0*
S.
0* 0
S
gO Vii O 39 Example A 4'-[(2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid a) 3-Methyl-4-butvrylamino-5-nitro-acetophenone 32.6 g (148 mMol) of 3-methyl-4-butyrylaminoacetophenone are added in batches to 300 ml of fuming nitric acid, with stirring, at -15C and stirred for a further 30 minutes at -15°C. The reaction mixture is then poured onto 3 litres of ice with stirring, the crude product precipitated is suction filtered, washed with 400 ml of water, dried and purified by recrystallisation from ethanol/diethylether Yield: 23.8 g (61.0% of theory), Rf value: 0.32 (silica gel; methylene chloride) Rf value: 0.48 (silica gel; methylene chloride/methanol 50:1) b) 3-Methyl-4-butvrylamino-5-nitro-c-bromoacetophenone At ambient temperature, with stirring, a solution of 16.0 g (200 mMol) of bromine in 140 ml of dioxane is slowly added dropwise to a solution of 23.8 g (90 mMol) of 3-methyl-4-butyrylamino-5-nitro-acetophenone in 900 ml of dichloromethane so that the reaction mixture is constantly completely decolorised. It is then stirred for a further two hours, then the reaction mixture is evaporated to dryness in vacuo, the residue thus obtained is triturated with about 20 ml of dichloromethane/diethylether suction filtered and then dried. 23 g (74% of theory) of 3-methyl-4butyrylamino-5-nitro-a-bromoacetophenone are thus obtained, containing about 10% of starting material.
0 The product is further reacted without any more purification.
IA Rf value: 0.69 (silica gel; methylene chloride/methanol 40 50:1) Rf value: 0.84 (silica gel; methylene chloride/methanol 9:1) c) 2-Butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene A solution of 6.8 g (20 mMol) of 3-methyl-4in 20 ml of formamide is heated to 140°C for 2 hours. The cooled solution is then poured into about 50 ml of 1 N ammonia and stirred for about 15 minutes. The crude product precipitated is suction filtered, washed with about ml of water and dried. In this way, 4.4 g (75% of theory) of the product are obtained, which is further reacted without any more purification.
Rf value: 0.29 (silica gel; methylene chloride/methanol 9:1) d) 2-Butyrylamino-3-nitro-5-(l-methyl-imidazol-4-yl)toluene 1.3 g (9.5 mMol) of methyl iodide are added dropwise at ambient temperature to a solution of 2.5 g (8.7 mMol) of 2-butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene and 5.2 g (30 mMol) of potassium carbonate dihydrate in ml of dimethylsulphoxide at ambient temperature and then stirred for 2 hours. The reaction mixture is then stirred into about 150 ml of water and then extracted four times with 25 ml of ethyl acetate. The organic •extracts are washed with about 30 ml of water, dried and concentrated by evaporation. The crude product thus obtained is purified by column chromatography (300 g silica gel, eluant: methylene chloride/methanol 30:1).
Yield: 640 mg (24% of theory), Rf value: 0.54 (silica gel; methylene chloride/methanol 9:1) e) 2-Butyrylamino-3-amino-5-(l-methyl-imidazol-4-yl)toluene Cri A/h 41 640 mg (2.1 mMol) of 2-butyrylamino-3-nitro-5-(l-methylimidazol-4-yl)-toluene are hydrogenated at ambient temperature under a hydrogen pressure of 5 bar in 30 ml of methanol after the addition of about 200 mg of palladium/charcoal. After all the water has been absorbed the catalyst is filtered off and the filtrate is evaporated down. The crude product thus obtained is further reacted without any more purification.
Yield: 600 mg (100% of theory), Rf value: 0.23 (silica gel; methylene chloride/methanol 9:1) f) 2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)benzimidazole 600 mg (2.1 mMol) of 2-butyrylamino-3-amino-5-(1-methylimidazol-4-yl)-toluene are refluxed in 10 ml of glacial acetic acid for one hour. Then the mixture is evaporated to dryness in vacuo, the residue is mixed with about 15 ml of water, made alkaline with ammonia and extracted four times with about 10 ml of ethyl acetate. The organic extracts are washed with about ml of water, dried and finally evaporated down. The crude product thus obtained is further reacted without any more purification.
Yield: 420 mg (79% of theory), Rf value: 0.37 (silica gel; methylene chloride/methanol 9:1) g) Tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-methylimidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylate 280 mg (0.8 mMol) of tert.butyl 4'-bromomethyl-biphenyli 2-carboxylate are added to a solution of 200 mg (0.79 mMol) of 2-n-propyl-4-methyl-6-(l-methyl-imidazol- 4-yl)-benzimidazole and 90 mg (0.8 mMol) of potassium tert.butoxide in 5 ml of dimethylsulphoxide and the mixture is stirred for 90 minutes at ambient 42 temperature, then stirred into about 40 ml of water, extracted four times with about 10 ml of ethyl acetate, then the organic extracts are washed with 10 ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel; eluant; dichloromethane/methanol 30:1) Yield: 230 mg (56% of theory), R, value: 0.61 (silica gel; methylene chloride/methanol 9:1) h) 4'-((2-n-Propyl-4-methyl-6-(-methyl-imidazol-4-yl)benzimidazol-l-yl)-methyll -biphenyl-2-carboxylic acid A solution of 230 mg (0.44 mMol) of tert.butyl propyl-4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazoll-yl)-methyl-biphenyl-2-carboxylate and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane is stirred overnight at ambient temperature and then evaporated to dryness. The residue is dissolved in about 5 ml of dilute sodium hydroxide solution, the solution is neutralised with acetic acid, the precipitate formed is suction filtered, washed with water and dried.
:09: Yield: 120 mg (59% of theory), 0 Melting point: 293-295 0
C
Rf value: 0.39 (silica gel; methylene chloride/methanol a 9:1) *0*06: Example B 4'-[(2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)benzimidazol-1-yl)-methyll -2-(1H-tetrazol-5-yl)biphenyl-hydrate a) 4'-[(2-n-Propyl-4-methyl-6-(l-methylimidazol-4-yl benzimidazol-l-vl)-methyll-2-cyano-biphenyl 43 218 mg (0.8 mol) of 4'-bromomethyl-2-cyano-biphenyl are added to a solution of 200 mg (0.79 mMol) of 2-n-propyl- 4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole and mg (0.8 mMol) of potassium tert.butoxide in 6 ml of dimethylsulphoxide and the mixture is stirred for 14 hours at ambient temperature. Then it is stirred into about 40 ml of water, extracted four times with about ml of ethyl acetate, the organic extracts are washed with about 10 ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel; eluant: dichloromethane/ethanol 50:1).
Yield: 240 mg (67% of theory), Rf value: 0.38 (silica gel; methylene chloride/ethanol 19:1) b) 4'-[(2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)benzimidazol-1-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl-hydrate A solution of 222 mg (0.5 mMol) of 4'-[(2-n-propyl-4methyl-6-(l-methyl-imidazol-4-yl)-benzimidazol-1-yl)methyl]-2-cyano-biphenyl, 660 mg (10 mMol) of sodium azide and 540 mg (10 mMol) of ammonium chloride in 12 ml of pure dimethylformamide is heated to 140 0 C for 18 hours. The solution is then evaporated substantially to dryness and the product is isolated by column chromatography (60 g of silica gel, eluant: dichloromethane with 10% ethanol). The product thus obtained is taken up in about 10 ml of dilute ammonia solution and the solution is then adjusted to pH 6 with acetic acid. A greasy residue is formed which becomes crystalline af:er the addition of a little ethyl acetate and several hours' stirring. The crystalline product is suction filtered, washed with about 5 ml of water and dried.
Yield: 61.0 mg (24.0% of theory), 44 Melting point: 255-257 0
C
C
29
H
28
N
8 x H20 (506.62) Calculated: C 68.75 H 5.97 N 22.12 Found: 68.90 5.97 22.03 Rf value: 0.24 (silica gel; mnethylene chloride/methanol- 9 :1) e
S
S
S S
S
S S S S 5* S S
S.
S S
I
.41 45 ExampleQ I [(2-n-Propyl-4-methyl-6- (1-cyclopentylmethylimidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example A from tert.butyl 4'- [I(2-n-propyl-4-methyl-6- (l-cyclopentylmethyl-imidazol-4yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Exampale 2 4'-[1(2-n-Propyl-4-methyl-6- (l-cyclohexylmethyl-imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'- [(2-n-propyl-4-methyl-G- (l-cyclohexylmethyl-imidazol-4yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 3 [(2-n-Propyl-4-methyl-6- (1-(4-fluorobenzyl) -imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid *~.Prepared analogously to Example A from tert.butyl 4'- I (2-n-propyl-4-methyl-6- (1-(4-fluorobenzyl) -imidazol-4yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
The following compounds may be obtained analogously to Example 3: 46 [(2-n-propyl-4-methyl (1-(3-chlorobenzyl) -imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid [(2-n-propyl-4-methyl-6- 5-dimethoxybenzyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid 4!.-[(2-n-propyl-4-methyl-6- (1-(4-methylbenzyl) -imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid 4' (2-n-propyl-4-methyl-6- (1-(4-trifluoromethylbenzyl) -imidazol-4-yl) -benzimidazol---yl) -methyl] biphenyl-2 -carboxylic acid Example 4 4' -[(2-n-Propyl-4-methyl-6- (1-(2-phenylethyl) -imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'- [(2-n-propyl-4-methyl-6- (1-(2-phenylethyl) -imidazol-4yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
I IExample [(2-n-Propyl-4-methyl-6- 2-trifluoroethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example A from tert.butyl 4'- I (2-n-propyl-4-methyl-6- 2-trifluoroethyl) 1 imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2- 47 carboxylate and trifluoroacetic acid in methylene chloride.
Example 6 41- (2-n-Propyl-4-methyl-6- (3,3,3-trifluoropropyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example A from tert.butyl 4'- I (2-n-propyl-4-methyl-6- 3-trifluoropropyl) imidazol-4-yl) -benzimidazol-1-yl) -methyll -biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Examiple 7 [(2-n-Propyl-4-methyl-6- (1-arinocarbonylmethylimidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2carboxylic acid :Prepared analogously to Example A from tert.butyl 4'- C (2-n-propyl-4-methyl-6-(l-aminocarbonylmethyl-imidazol- 606:604-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 8 4- [(2-n-Propyl-4-methyl-6- (1-cyclobutylmethyl-imidazol- 4 -yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid Prepared ana-logously to Example A from tert.butyl 4'- [(2-n-propyl-4-methyl-6- (1-cyclobutylmethyl-imidazol-4- 48 yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 9 4- II(2-n-Propyl-4-methyl-6- (1-cyclopropylmethylimidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example A from tert.butyl 4'- I(2-n-propyl-4-methyl-6- (l-cyclopropylmethyl-imidazol-4yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 59.0%0 of theory, Melting point: 2790-280 0
C
C
32 H3 2
N
4 0 2 (504.64) Calculated: C 76.16 H 6.39 N 11.10 Found: 76.41 6.37 11.20 Rf value: 0.44 (silica geli methylene chloride/methanol- 9:1) Mass spectrum: tn/c 504 Example 4 [(2-n-Propyl-4-.-ethyl-6- (l-cyclopropylmethylimidazol-4-yl) -benzimidazol-l-yl) -methyl] (lHtetrazol-5-yl) -biplhenyl a) II(2-n-Propyl-4-methyl-6- (l-cyclopropylrnethylimidazol-4-yl) -benzimidazol-l-yl) -methyl] (2- -biiphenvI *To a solution of 300 mg (1.0 mMol) of 2-n-propyl-4methyl-6- (l-cyclopropylmethyl-imidazol-4-yl) benzimidazole and 110 mg (1.0 mMol) potassium tert.butoxide in 20 ml of dimethylsulphoxide are added @*see: a 0 560 mg (1.0 mMol) of 41-bromomethyl-2- (2- 49 and the mixture is stirred for 16 hours at ambient temperature, then stirred into about 120 ml of water and extracted four times with 15 ml of ethyl acetate. The organic extracts are washed with about 30 ml of water, dried and then evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel, eluant: methylene chloride/methanol 30:1) Yield: 460 mg (60 of theory), Rf value: 0.78 (silica gel; methylene chloride/methanol 9:1) b) 4'-[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethylimidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H- A mixture of 460 mg (0.6 mMol) of 4'-[(2-n-propyl-4methyl-6-(l-cyclopropylmethyl-imidazol-4-yl)benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyland 10 ml of saturated ~.:thanolic hydrochloric acid is stirred for one hour at _.nbient temperature. The mixture is then evaporated to dryness, the residue is dissolved in dilute ammonia solution and washed with ether. The aqueous phase is adjusted to pH 5 to 6 with acetic acid and subsequently 'i the solid precipitate is suction filtered. The crude product thus obtained is purified by column chromatography (100 g silica gel, eluant: methylene chloride/methanol 15:1) S* Yield: 130 mg (41% of theory), Melting point: amorphous
C
32
H
32
N
8 (528.67) R value: 0.32 (silica gel; methylene chloride/methanol 9:1) Mass spectrum: m/e 528 *s a o eo 50 Example 11 4'-L (2-n-Propyl-4-methyl-6- (1-cyclobutylmethyl-imidazol- 4-yl) -benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl- 4-methyl-6- (l-cyclobutylmethyl-imidazol-4-yl) benzimidazol-l-yl) -methyl] (2-triphenylmethyland sodium azide in dimethy2 ormamide.
4' -[(2-n-Propyl-4-methyl-6- (2-methyl-oxazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl>2-carboxyli c acid Prepared analogously to Example A from tert.butyl 4'- [(2-n-propyl-4-metbhyl-6-(2-methyl-oxazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 67.0-0 of theory, Melting point: 241-243 0
C
0 *soC 29
H
27 N30 3 (465.56) Calculated: C 74.82 H 5.85 N 9.03 r ound: 74.65 5.98 8.85 Rf value: 0.27 (silica gel; methylene chloride/ethanol 19:1) Exml 13 4* C Srpl4-ehl6-2mthloaol4y) 555 9zo--l-mtyl2-l-erao--l)bpey Irprdaaogul oEapl 0fo 51 4-methyl- 6- (2-methyl-oxazol-4-yl) -benzimidazol-1-yl) methyl] (2-triphenylmethyl-tetrazol-5-yl) -biphenyl and sodium dizide in dimethylformamide.
Example 14 4' -[E(2-n-Propyl-4-methyl-6- (2-phenyl-oxazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'- [(2-n-propyl-4-methyl-6- (2-phenyl-oxazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate arnd trifluoroacetic acid in methylene chloride.
Yield: 87.0%0 of theory, Melting point: 281-283 0
C
C
34
H
29
N
3 0 3 (527.63) Calculated: C 77.40 H 5.54 N 7.96 Found: 77.09 5.71 7.76 Rf value: 0.18 (silica gel; methylene chloride/ethanol 19 :1) :Exam-Ole (2-n-Propyl-4-methyl-6- (2-phenyl-oxazol-4-yl) benzimidazol-1-yl) -methyl] (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl- 4-methyl- 6- (2-phenyl-oxazol-4-yl) -benzimidazol-l-yl) methyl] (2-triphenylmethyl-tetrazol-5-yl) -biphenyl and sodium azide in dimethylformamide.
52 Example 16 4 ((2-Ethoxy-G- (l-isopropyl-itnidazol-4'-yl) benzimidazol-l-yl) -methyl] (lH-tetraz-ol-5-yl) -biphenyl Prepared analogously to Example 10 frc-i 41-1(2-ethoxy-6- (l-isopropyl-imidazol-4-yl) -benzimidazol- l-yl) -methyl] 2- (2-triphenylmethyl-tetrazol-5-yl) -bizhenyl.
Yield: 69.0§ of theory, Melting point: 175-178 0
C
C
29 11 28
N
8 0 (504.61) Calculated: C 69.03 H 5.59 N 22.21 Found: 68.85 5.58 21.97 Rf value: 0.27 (silica gel; methylene chloride/ethanol 9:1) Mass spectrum: m/e =504 Exam'ple 17 4 t- ((2-Ethoxy-6- (l-isopropyl-imidazol-4L-yl) benzimidazol-l-yl) -methyl] -bipheriyl-2- :arboxylic acid .0o.:Prepared analogously to Example A from tert.butyl 4'- 0,0: (2 -ethoxy-6- (l-isopropyl-imidazol-4 -benzimidazol-lyl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic 606:6 acid in methylene chloride.
0 Yield: 38.0§ of theory, *S P*Melting point: 220-223 0
C
C
29
H
28
N
4 0 3 (480.58) Calculated: C 72.48 H 5.87 N !1.6S Found: 72.36 6.05 ll *Rf value: 0.26 (silica gel; methylene chloride/methanol 0 0 9:1) 0 90Mass spectrum: m/e 480 53 Examle 18 4 (2-Ethoxy-5- (l-isopropyl-imidazol-4-yl) benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 10 from 4J-L(2-ethoxy-5- (l-isopropyl-imidazol-4-yl) -benzimidazol-l-yl) -methyl] 2- (2-triphenylmethyl-tetrazol-5-yl) -biphenyl.
Yield: 44.001 of theory, Melting point: amorphous
C
29
H
28 NB0 (504.61) Rf value: 0.24 (silica gel; methylene chloride/ ethanol 9:1) Mass spectrum: m/e 504 Exampale 19 4' -n-Propyl-4-methyl-6- (1-cycloheptyl--imidazol-4yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'- -n-propyl-4-methyl- 6- (1-cycloheptyl- imidazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 79.00- of theory, Melting point: from 190 0 C (decomp.)
C
3 sH 38
N
4
O
2 (546.71) Rf value: 0.36 (silica gel; methylene chloride /methanol :0 Mass spectrum: m/e 546 Example C(2-n-Propyl-4-methyl-6- (l-cycloheptyl-imidazol-4- 54 yl) -benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) biphenyl Prepared analogously to Example 10 from 41-[(2-n-propyl- 4-methyl-6- (l-cycloheptyl-imidazol-4-yl) -benzimidazol-lyl) -methyll (2-triphenylmethyl-tetrazol-5-yl) biphenyl.
Yield: 27.0-0 of theory, Melting point: 198-201 0
C
C
3 sH 38
N
8 (570.75) Rf value: 0.48 (silica gel; methylene chloride/methanol- 9 :1) Mass spectrum: m/e =570 E~xample 21 [(2-n-Propyl-4-methyl-6- (1-(l-n-propyl-n-butyl) itnidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example A from tert.butyl 4'- (2-n-propyl-4-methyl-6- (1-(l-r-propyl-n-butyl) imidazol-4-yl) -benzirnidazol-l-yl) -methyl] -biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 28.00% of theory, Melting point: 236-238 0
C
*C
35
H
40
N
4 0 2 (548.73) Rf value: 0.61 (silica gel; methylene chloride/methanol= 9:1) O*V. Mass spectrum: m/e 548 Example 22
S
4' (2-Ethoxy-4-methyl-6- (l-cyclopropylmethyl-imidazol- 55 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.buty. 41- [(2-ethoxy-4-methyl-6- (l-cyclopropylmethyl-imidazol-4yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 52.0-0 of theory, Melting point: 172-173 0
C
C3 1
H
30
N
4 0 2 (506.61) Calculated: C 73.50 H 5.97 N 11.06 Found: 73.36 5.94 11.30 Rf value: 0.52 (silica gel; methylene chloride/methanol 9:1) Mass spectrum: m/e =506 Example 23 41- (2-Ethoxy-4-methyl-6- (l-cyclopropylmethyl-imidazol- 4-yl) -benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) b iphenyl Prepared analogously to Example 10 from 41- [(2-ethoxy-4methyl-6- (l-cyclopropylmethyl-imidazol-4-y1) benzimidazol-l-yl) -methyl] (2-triphenylmethyl- -biphenyl.
*Yield: 42.0-0 of theory, Melting point: amorphous
*C
31 11 30 N60 (530.64) :Rf value: 0.50 (silica gel; methylene chloride/methanol 9:1) Mass spectrum: m/e =530 56 Exam~ple 24 4 [(2-n-Propyl-4-methyl-6- (1-(l-n-propyl-n-butyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (1H- -biphenyl Prepared analogously to Example 10 from 41-[(2-n-propyl- 4-methyl-G- Cl- (l-n-propyl-n--butyl) -imidazol-4 -yl) benzimidazol-l-yl) -methyl] (2-triphenylinethyl- -biphenyl.
Yield: 12.00% of theory, Melting point: from 150 0 C (sintering)
C
35
H
40
N
8 (572,76) Rf value: 0.34 (silica gel; methylene chloride /methanol 9: 1) Mass spectrum: m/e =572 Example 4' I(2-n-Propyl-4-methyl-6-Cl, 2-dimethyl-imidazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid hydrate 00OVa) tert. Butyl (2-n-propyl-4-methyl-6- (2-methyloxazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylate A souto of28g(1mo)o 2npoy--ehl 0 0 ouino 1 *l f2npoy--ehl6 (2-methyl-oxazol-4-yl)-benzimidazole and 1.7 g (15 mMol) of potassium tert.butoxide in 60 ml of dimethylsulphoxide is stirred for 15 minutes at ambient temperature. Then 5.2 g (15 m~vol) of tert.butyl 41bromomethyl-biphenyl-2-carboxylate are added and the mixture is stirred for a further 14 hours at ambient temperature. Then the solution is stirred into about 150 ml of saturated sodium chloride solution, the crude 57 product precipitated is suction filtered and purified by column chromatography (430 g of silica gel; eluant: methylene chloride with 1 to 2% ethanol).
Yield: 3.5 g (61.4% of theory), Melting point: amorphous Rf value: 0.90 (silica gel; methylene chloride/ethanol 4:1) b) 4'-[(2-n-Propyl-4-meth-l-6-(1,2-dimethyl-imidazol-4yl)-benzimidazol-l-yl,-methyl]-biphenyl-2-carboxylic acid hydrate A mixture of 1.5 g (3 mMcl) of tert.butyl propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-lyl)-methyl]-biphenyl-2-carboxylate, 10 ml of 40% Nmethylamine solution and 15 ml of N-methylformamide is heated for 10 hours to 2CO0C in an autoclave. After cooling, the contents of :he autoclave are stirred with about 40 ml of water, this suspension is adjusted to pH with glacial acetic acid, then the crude product precipitated is suction filtered and dissolved in 1N sodium hydroxide solution. This solution is washed successively with 25 ml cf acetic acid and diethylether, then adjusted to pH 6 wi:h 20% citric acid. The product precipitated is suction filtered, washed with about 30 ml of water and dried, then triturated with diethylether and dried in a high vacuum.
Yield: 950 mg (68% of theory), Melting point: 239-240 0
C
C
30 H3oN 4 02 x H 2 0 (496.62) Calculated: C 72.55 H 6.49 N 11.28 Found: 72.62 6.62 11.54 Rf value: 0.70 (silica geL; methylene chloride/ethanol 4:1) Example 26
L
i v. 58 4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)biphenyl-hydrate a) 4'-[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl- A solution of 2.8 g (11 mMol) of 2-n-propyl-4-methyl-6- (2-methyl-oxazol-4-yl)-benzimidazole and 1.7 g (15 mMol) of potassium tert.butoxide in 60 ml of dimethylsulphoxide is stirred for 15 minutes at ambient temperature. Then 6.0 g of (11 mMol) of 4'-bromomethyl- 2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl are added and the mixture is stirred for a further 3 hours at ambient temperature. Then the solution is stirred into about 150 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (500 g of silica gel; eluant: petroleum ether/ethyl acetate 1:1) Yield: 3.6 g (45% of theory) b) 4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4biphenvl-hydrate A mixture of 3.6 g (4,9 mMol) of 4'[(2-n-propyl-4methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl, 20 ml of 40% N-methylamine solution and 30 ml of Nmethylformamide is heated to 200 0 C for 10 hours in an autoclave. After cooling, the contents of the autoclave are stirred with about 50 ml of water, this suspension is adjusted to pH 6.5 with 20% citric acid, then the crude product precipitated is suction filtered and purified by column chromatography (200 g silica gel; eluant: methylene chloride with 5 to 20% ethanol).
*O
4 4 4 0 4 4.
44*f 4 4.
eoe~ .t 4 oo
A
*ftft. ft *f J i.* v 1
V
\i f 59 Yield: 1.0 g (411 of theory), Melting point: from 195 0 C sintering
C
30
OH
30
N
8 x H 2 0 (520.6) Calculated: C 69.21 H 6.19 N 21.52 Found: 68.99 6.26 21.37 Mass spectrum: m/e 502 Example 27 4' f(2-Ethyl-4-methyl-6- (1-(2-methoxyethyl) -imidazol-4yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'- [(2-ethyl-4-methyl-6-(1- (2-methoxyethyl) -imidazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 49%1 of theory, Melting point: 165-167 0
C
C
30
H
30
N
4 03 (494.60) Calculated: C 72.85 H 6.11 N 11.33 Found: 72.G2 6.27 11.35 .4 4.
4 4 4 4 4e 4* 444444 4 4 .4 44 4 4 4 4 4 4 4 4*t* 4* 4* .4 44 4 4* 44 4 Mass spectrum: m/e 494 Example 28 4' -[(2-Cyclopropyl-4-methyl-6- (1-(2-methoxyethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphe-nyl- 2carboxylic acid Prepared analogously to Example A from tert. butyl 4'- [(2-cyclopropyl-4-methyl-6- (1-(2-methoxyethyl) -imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylate and trifluoroacetic acid in methylene 4. 4 4 i,.4 4 4 ~t
N
A'~
1' 60 chloride.
Yield: 780- of theory, Melting point: 179-181 0
C
C3 1
H
30
N
4 0 3 (506.61) Calculated: C 73.50 H 5.97 N 11.06 Found: 73.37 6.02 11.02 Mass spectrum: m/e =506 Example 29 4' I(2-n-Propyl-4-methyl-6- (l-aminocarbonylmethylimidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example A from tert. butyl 4'- II(2-n-propyl-4-methyl-6- (l-aminocarbonylmethyl-imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and tr-'2-luoroacetic acid in methylene chloride.
Yield; 26-0 of theory, Melting point: 190-192 0
C
C
30
H
29
N
5 0 3 (507.60) Rf value: 0.44 (silica gel; methylene chloride/methanol 8:2) Example as" 4'-f (2-n-Propyl-4-methyl-6- (1-ethoxycarbonylmethyl- .5 imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2 carboxylic acid Prepared analogously to Example A from tert.butyl 4'a. a [(2-n-propyl-4-methyl-6- (1-ethoxycarbonylmethylimidazol-4-yl) -benzimidazol-l-yl) -methyll -biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 180% of theory, 61 Melting point: 223-224°C
C
32 H3 2
N
4 04 (536.63) Rf value: 0.69 (silica gel; methylene chloride/methanol 8:2) Mass spectrum: m/e 536 Example 31 4'-[(2-Cyclopropyl-4-methyl-6-(1-(2-hydroxyethyl)imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylic acid A solution of 500 mg (1.0 mMol) of 4'-[(2-cyclopropyl-4methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and 1.5 g (6.0 mMol) of boron tribromide in 50 ml of methylene chloride is stirred for 16 hours at ambient temperature, then mixed with about 30 ml of water and stirred vigorously for another 10 minutes. This mixture is evaporated to dryness and the residue is refluxed in about 40 ml of ethanol for 10 minutes. The mixture is evaporated to dryness once more, the residue is dissolved in about 30 ml of 2N ammonia solution and this solution is adjusted to pH 5-6 with 2N acetic acid. The crude product precipitated is suction filtered and purified by column chromatography (80 g silica gel; eluant: methylene chloride/methanol 4:1).
S* Yield: 150 mg (30% of theory), Melting point: 220-222°C
C~
0
H
28
N
4 0 3 (492.58) Rf value: 0.20 (silica gel; methylene chloride/mechanol 9:1) *s Mass spectrum: m/e 492 9 62 Example 32 4' -[(2-n-Propyl-4-methyl-6- (1-(2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example A from tert. butyl 41- [(2-n-propyl-4-methyl-6- (1-(2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol---yl) -methyl] -biphenyl-2carboxylate and trifluoroacetic acid in methyllene chloride.
Yield: 54-* of theory, Melting point: 259-261 0
C
C
34
H
37
N
5 0 3 (563 Calculated: C 72.44 H- 6.62 N 12.42 Found: 72.G8 6.65 12.53 Mass spectrum: m/e =563 Example 33 4' I(2-n-Propyl-4-tnethyl-6- (1-(2-methoxyethoxy-2-ethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2- :carboxylic acid 0 Prepared analogously to Example A from tert.butyl 4'- [(2-n-propyl-4-methyl-6- (1-(2-methoxyethoxy-2-ethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2- :carboxylate and trifluoroacetic acid in methylene chloride.
*Yield: 490- of theory, Melting point: 192-194 0
C
:C
33 H3 6
N
4 0 4 (552.67) Calculated: C 71.72 H 6.57 N 10.14 Found: 71.52 6.36 10.25 63 Rf value: 0.36 (silica gel; dichloromethane/methanol 9:1) Mass spectrum: m/e 552 Example 34 4 [(2-n-Propyl-4-miethyl-6- (1-(3-dime-thylaminopropyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid dihydrochioride-pentahydrate Prepared analogously to Example A from tert.butyl 4'- Ii(2-n-propyl-4-methyl-6- (1-(3-dimethylaminopropyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylate and trifluoroacet-ic acid in methylene chloride.
Yield: 12%i of theory, Melting point: from 128 0 C (decomp.)
C,
3
H
3 7 N.0 2 x 2 HUl x S H~2O (535.70) Rf value: 0.20 (silica gel; dichloromethane/methanol 9:1) Mass spectrum: m/e 535 ,:..Examiple 4'I(2-n-propyl-4-methyl-6-(2-methyl-thiazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylice aid Yild 329o hoy Me..n pon:24-50 G4
C
29
H
27 N30 2 S (481.62) Calculated: C 72.32 H 5.65 N 8.72 Found: 72,21 5.83 8.67 Rf value: 0.26 (silica gel; dichioromethane/methanol 9:1) Mass spectrum: tn/e 481.
t(2-n-Propyl-4-methyl-6- (2-methyl-thiazol-4-yl) benzimidazol-1-yl) -methyl] (1H-tetrazol-5-yl) biphenyl -dihydrochioride Prepared analogously to Example 10 from 41-[(2-n-propyl- 4-methyl-6- (2-methyl-thiazol-4-yl) -benzimidazol-1-yl) methyl] (2-triphenylmethyl-tetrazol-5-yl) -biphenyl.
Yield: 910- of theory, Melting point: from 219 0 C (decomp.)
C
29
H
29 Cl 2
N
7 S (578.58) Calculated: C 60,20 H 5.05 N 16.95 Cl 12.25 Found: 59.96 5.19 16.63 12.42 Rf value: 0.32 (silica gel; dichloromethane/methanol 9:1) mass spectrum: m/e =505 Exapl~e37 [(2-Ethyl-4-methyl-6- Cl- (2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example A from tert.butyl 4'- (2-ethyl-4-methyl-6- (1-(2-N-morpholinoethyl) -imidazol- 4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylate
S
S S
S
.55..
S
55 S S
S
S
S
S
S
95*5 S S S C 55 0S
S
55
S
S
555
S
65 and trifluoroacetic acid in methylene chloride.
Yield: 27 0- oif theory, Melting point: 201-202*C
C
33
H
3 5NSO 3 (549.65) Calculated: C 72.11 H 6.42 N 12.74 Found: 72.00 6.48 12.62 Rf value: 0.36 (silica gel; methylene chloride/methanol- 9:1) mass spectrum: m/e =549 Example38 41 E(2-Ethyl-4-methyl-G- (2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (1H- -biphenyl-hydrate Prepared analogously to Example 10 from 41-[(2-ethyl-4methyl-6- (1-(2-N-morpholinoethyl) -imidazol-4-yl) benzimidazol-l-yl) -methyl] (2-triphenylmethyl- -biphenyl.
Yield: 14 -0 oaf theory, Melting point: above 180 0 C (decomp.)
C
3 3 H3 5 N.O x H 2 0 (573.68) Calculated: C 66,98 H 6.30 N 21.31 Found: 66.87 6.36 21.22 Rf value, 0.32. (silica gel; methylene chloride/methanol 9:1) mass spectrum: m/e 573 a. 9* .9 S. .9 a 9 9 S *9@9 9* 9a 9.
0 9904.9 9 S. 95 9 9 9 9 99 99 a fr** 0 a 99 99 5S 9* 9 09 99
S
9.
9 9 9 0 99.9.9 9 ((2-Ethyl-4!-methyl-6- (1-(2-aminocarbonylethyl) imidazol-4-yl' -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example A from tert~butyl 41- 66 t(2-ethyl-4-methyl-G- (1-(2-aminocarbonylethyl) -imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2--carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 66 -0 of theory, Melting point: above 185*C (decomp.)
C
30
H
29
N
5 0 3 (507.59) Calculated: C 70.99 H 5.76 N 13.80 Found: 70.73 5.72 13.66 mass spectrum: nile 507 Exam-ale Q 4' -[(2-Ethyl-4-rnethyl-6- (1-(2-aminocarbonylethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (lH- -biphenyl Prepared analogously to Example 10 from 41-[(2-ethyl-4methyl-6- (-aminocarbonylethyl) -imidazol-4-yl) benzimidazol-l-yl) -methyl] (2-triphenylmethyl- -biphenyl.
Yield: 42 of theory, Melting point: above 191 0 C (decomp.) 0: C0H2N90 53163) Calculated: C 67.78 H 5.50 N 23 .71 *Found: 67.79 5.40 23.66 *.Rf value: 0.20 (silica gel; methylene chloride/methanol 8:2) mass spectrum: rule 531.
Example 41 4 (2-Ethyl-4-methyl-6- (1-(2-N-pyrrolidinoethyl) imidazol-4-yl) -benzirnidazol-l-yl) -methyl] -biLphenyl-2carboxylic acid 6 7 Prepared analogously to Example A from tert.butyl 4'- [(2-ethyl-4-methyl-6- (1-(2-N-pyrrolidinoethyl) -imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 60 0- of theory, Melting point: 215-217 0
C
C
33
H
3 sN 5 0 2 (533 .67) Calculated: C 74.27 H 6.61 N 13.12 Found: 74.03 G.85 13.11 Rf value: 0.30 (silica gel; methylene chloride/methanol- 8:2) mass spectrum: m/e =533 Exampole 42 [(2-Ethyl-4-methyl-6- (1-(2-N-pyrrolidinoethyl) imidazol-4-yl) -benzimidazol-1-yl) -methyl] (1H- -biphenyl Prepared analogously to Example 10 from 41-[(2-ethyl-4methyl-6- (1-(2-N-pyrrolidinoethyl) -imidazol-4-.yl) benzimidazol-l-yl) -methyl] (2-triphenylmethyl- -biphenyl.
Yield: 38 *1 of theory, Melting point: above 128 0 C (sintering) 0: so'C 33
H
35
N
9 (551.71) :*Calculated: C 71.84 H- G.39 N 22.85 Found: 71.G3 6.20 22.49 value: 0.23 (silica gel; methylene chloride/methanol :8:2) Example 43 4'-[C2-Ethyl-4-methyl-6-(l-(2-diethylaminoethyl)- ,~imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2- 68 carboxylic acid-dihydrochioride Prepared analogously to Example A from tert.butyl 4'- [(2-ethyl-4-methyl-G- (1-(2-diethylaminoethyl) -imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 32 -0 of theory, Melting point: 255-257 0 C (decomp.)
C
3 3 H3 7
N
5 0 2 x 2 HCl (608.60) Rf value: 0.24 (silica gel; methylene chloride/methanol 9 :1) mass spectrum: m/e =535 Exampole 44 4 ((2-Ethyl-4-methyl-6- (1-(2-diethylaminoethyl) imidazol-4-yl) -benzinmidazol-l-yl) -methyl] (lii- -biphenyl Prepared analogously to Example 10 from 4'-((2-ethyl-4methyl-6- (1-(2-diethylaminoethyl) -imidazol-4-yl) benzimidazol-l.-yl) -methyl] (2-triphenylmethyltetrazol-5-yl) -biphenyl.
Yield: 51 01 of theory, Melting point: 191-193 0
C
C
33
H
3 7N 9 (559.70) :.Calculated: C 70.81 H 6.66 N 22.52 Found: 70.59 6.66 22.58 Rf value: 0.30 (silica gel; methylene chloride/methanol 8:2) Example [(2-Ethyl-4-methyl-G- (1-(3-N-piperidinopropyl) imidazol-4-yl)-benzimidazol-l-yl) -methyl] -biphenyl-2- 69 Prepared analogously to Example A from tert.butyl 4'- [(2-ethyl-4-methyl-6- (1-(3-N-piperidinopropyl) -imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxyl~ate and trifluoroacetic acid in methylene chloride.
Yield: 19 of theory, Melting point: amorphous
C
3 sH 29 NsO 2 (561.73) Calculated: C 74.84 H 7.00 N 12.47 Found. 74.61 6.92 12.31 Rf value: 0.34 (silica gel; methylene chloride/methanol- 8:2) Example 46 4 t-[(2-Ethyl-4-methyl-6- (1-(3-N-piperidinopropyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (lH- -biphenyl Prepared analogously to Example 10 from 4'-[(2-ethyl-4methyl-6- (1-(3-N-piperidinopropyl) -imidazol-4-yl) benzimidazol-l-yl) -methyl] (2-triphenylmethyl-- -biphenyl.
Yield: 71 01 of theory, Melting point: above 140 0 C (decomp.)
C
35
H
39
N
9 (585.76) Calculated: C 71.77 H 6.71 N 21.52 Found: 71.58 6.68 21.44 Rf value: 0.22 (silica gel; methylene chloride/..methanol 8:2) a a.
70 In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I including the physiologically acceptable salts thereof, particularly those wherein R 4 represents a carboxy or 1H-tetrazolyl group, may be used as the active substance: Example I Ampoules containing 50 mg of active substance per 5 ml Active substance
KH
2
PO
4 Na 2
HPO
4 x 2H 2 0 NaCl Water for injections ad 50 mg 2 mg 50 mg 12 mg 5 ml Preparation: The buffer substances and isotonic substance are dissolved in some of the water. The active substance is added and, once it has been completely dissolved, water is added to make up the required volume.
Example II Ampoules containing 100 mg of active substance per 5 ml 0 o *r K A,( Active substance Methyl glucamine Glycofurol Polyethyleneglycol-polypropyleneglycol block polymer Water for injections ad 100 mg 35 mg 1000 mg 250 mg 5 ml 71 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 Polyvinylpyrrolidone Magnesium stearate 50.0 mg 70.0 mg 40.0 mg 35.0 mg 3.5 mg 1.5 mc 200.0 mg Preparation: The active substance, CaHP0 4 lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50°C in a circulating air dryer and screened again.
After the lubricant has been added, the granules are compressed in a tablet making machine.
Example IV Coated tablets containing 50 mg of active substance .r
I
IB Active substance Lysine 50.0 mg 25.0 mg 72 Lactose Corn starch Gelatin Magnesium stearate 60.0 mg 34.0 mg 10.0 mg 1.0 mg 180.0 mg Preparation: The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying, the granules are mixed with magnesium stearate and compressed to form tablet cores.
The cores thus produced are covered with a coating by known methods. A colouring may be added to the coating suspension or solution.
Example V Coated tablets containing 100 mg of active substance 0* 0 t 0 a a.
a a a Active substance Lysine Lactose Corn starch Polyvinylpyrrolidone Microcrystalline cellulose Magnesium stearate 100.0 mg 50.0 mg 86.0 mg 50.0 mg 2.8 mg 60.0 mg 1.2 ma 350.0 mg Preparation: The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm screen and dried at After drying, it is screened again and the magnesium 73 stearate is added. This mixture is compressed into cores.
The cores thus produced are covered with a coating by known methods. Colourings may be added to the coating suspension or solution.
Example VI Capsules containing 250 mg of active substance Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 mg 320.0 mg Preparation: The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The final mixture is packed into size 1 hard gelatin capsules.
o: Example VII Oral suspension containing 50 mg of active substance per ml Active substance 50.0 mg Hydroxyethylcellulose 50.0 mg Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg 74 Water ad 5.0 ml Preparation: Distilled water is heated to 70"C. Hydroxyethylcellulose is dissolved therein with stirring. By the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and active substance are added. The suspension is evacuated with stirring to remove any air. One dose of 50 mg is contained in 5.0 ml.
Example VIII Suppositories containing 100 mg of active substance Active substance 100.0 mg Solid fat 1600.0 me 1700.0 mg Preparation: The hard fat is melted. At 40C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38"C and poured into slightly chilled S"suppository moulds.
*4 S S S S

Claims (10)

1. Compounds of formula i R3 R N CHQ0 S.0 .00. *as: (wherein R, represents a C 1 _3-alkyl group, a hydrogen, fluorine, chlorine or bromine atom; R 2 represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl. group, or an imidazol-4-yl group optionally substituted in the
2-position by a C 1 -6-alkyl group or by a phenyl group and substituted in the I-position by a C 1 7 -alkyl group substituted in the 4-,
6- or 7- position by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, iorpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido- thiomorpholinocarbonyl group, by a C 2 4 -alkyl group substituted in the 3- or 4- position by a hydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxido- thiomorpholino or imidazol-l-yl group, by a C'- 3 -alkyl group substituted by a trifluoromethyl group, by a C3- 7 -cycloalky! group or by a phenyl group 76 itself Tit_%r mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or tnethoxy groups, or by a C 13 -alkyl group substituted by two phenyl groups, where unless otherwise specified the above-mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms; R 3 represents a C 2 4 -alkyl, C 2 -3-alkoxy, C 2 ,3-alkylthio, cyclopropyl or cyclobutyl group; and R 4 represents a carboxy, cyano, lH-tetrazolyl, 1- triphenylmethyl-tetrazolyl or 2 -triphenylmethyl- tetrazolyl group or a group convertable in vivo into a carboxy group) and the compounds 4' I(2-n-Propyl-4-methyl-6- (1-(2-phenylethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2- carboxylic acid, [(2-n-Propyl-4-methyl-6- (2-methyl-oxazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid, 4'-t (2-n-Propyl-4-methyl-6- (2-methyli.oxazol-4-yl) benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) biphenyl, ((2-Ethoxy-6- (l-isopropyl-imidazol-4-yl) benzimidazol-1-yl) -methyl] (lH-tetrazol-5-yl) biphenyl, 77 t(2-Ethoxy-6-(1-isopropyl-imidazol-4-yl) benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid I(2-Ethoxy-6-(l-isopropyl-imidazol-4-yl)- benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) biphenyl, (2-n-Propyl-4-methyl-6- (l-cycloheptyl-imidazol- 4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid, E(2-n-Propyl-4-methyl-6-(l-cycloheptyl-inidazol- 4 -yl) -benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) biphenyl, 4'1 [(2-n-Propyl-4-methyl-6- (l-r-propyl-ri-butyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2- carboxylic acid, 4'1 ((2-n-Propyl-4-methyl-6- (1-(l-n-propyl-n-butyl) imidazol-4-yl) -benzimidazol-1-yl) -methyl] (lH- -biphenyl, [(2-n-Propyl-4-methyl-6-(l,2-dimethyl-imidazol-4- yl) -benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic *acid hydrate, [(2-n-Propyl-4-methyl-6- 2-dimethyl-imidazol-4- ~yl) -benzimidazol-l-yl) -methyl] (lH-tetrazol-5-yl) biphenyl, (in) L(2-n-Propyl-4-methyl-6- (2-methyl-thiazol-4-yl) benzimidazol-1-yl) -methyl] -l-ero--l-biphenyl-2croyi cd Nar1 78 and the salts thereof. 2. Compounds of formula I as claimed in claim 1, wherein RI represents a C 1 alkyl group, a hydrogen, fluorine, chlorine or bromine atom; R 2 in the 6-position of the benzimidazole ring represents an oxazol-4-yl or thiazol-4-yl group optionally substituted in the 2-position by a methyl or phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a C,. 6 -alkyl group or by a phenyl group and substituted in the 1-position by a Ci. 7 -alkyl group substituted in the 4-, 6- or 7- position by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido- thiomorpholinocarbonyl group, by a C2-4-alkyl group substituted in the 3- or 4- position by a hydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxido- S"thiomorpholino or imidazol-l-yl group, by a Cl- 3 -alkyl group substituted by a trifluoromethyl group, by a C 3 .7-cycloalkyl group or by a phenyl group S: itself eptaonaly mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, or S *see*: by a Ci. 3 -alkyl group substituted by two phenyl groups, 4> ^b~ 79 where unless otherwise specified the above-mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms; R3 represents a C 2 .4-alkyl, C.. 3 -alkoxy, C2- 3 -alkylthio, cyclopropyl or cyclobutyl group; and R 4 represents a carboxy, cyano, IH-tetrazolyl, 1- triphenylmethyl-tetrazolyl or 2-triphenylmethyl- tetrazolyl group or a group convertable in vivo into a carboxy group and the salts thereof. 3. Compounds of formula I as claimed in claim 1, wherein R, represents a hydrogen or chlorine atom or a methyl group; R 2 in the 6-position of the benzimidazole ring represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the 1-position I by a C 1 7 -alkyl group substituted in the 4-, 6- or 7-position by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, Sn-propylaminocarbonyl, dimethylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido- thiomorpholino-carbonyl group, f'oi 1 80 by a C 2 4 -alkyl group substituted in the 3- or 4-position by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, tnorpholino or ixidazol-1-yl group, or by a 2,2, 2-trifluoroethyl, 3,3, 3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, r''W.4-f luorobenzyl, 3 -chlorobenzyl, 4-methylbenzyl, 4- trifluoromethylbenzyl, or 2,2-diphenylethyl group; R3 represents a C 2 4 -alkyl, C 2 3 -alkoxy, C 2 3 -alkylthio, cyclopropyl or cyclobutyl group; and R 4 represents a carboxy or 1H-tetrazolyl group or a group convertable in vivo into a carboxy group; and the salts thereof. 4. Compounds of formula I as claimed in any one of claims 1 to 3 wherein RI, R 2 and R3 are as defined in any one of claims 1 to 3; R 4 denotes a carboxy group or a group of formula O~o CO OR', 0 CO -O0- (HCR"I) 0 -CO R"'I or (wrei -CO -O0- (HCR"I) 0 -CO OR"' RI denotes a straight-chain or branched Cl.,.alkyl group or a CS 57 -cycloalkyl, benzyl, 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, RI" denotes a hydrogen ac.om or a methyl group, and MJ- 81 denotes a straight-chain or branched CI-6-alkyl group or a Cs,7-cycloalkyl, phenyl, benzyl, 1-phenylethyl, 2- phenylethyl or 3-phenylpropyl group); and the salts thereof. Compounds of formula I as claimed in claim 1, wherein R, represents a hydrogen atom or a methyl group; R, in the 6-position of the benzimidazole ring represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the position by a CI. 7 -alkyl group substituted in the 4-, 6- or 7-position by a carboxy, methoxycarbonyl, dimethylaminocarbonyl or morpholino-carbonyl group, by a C 2 4 -alkyl group substituted in the 3- or 4- position by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-1-yl group; or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl 'leie4 or 4-fluoro-benzyl group; *R 3 represents a C 2 4 -alkyl group, an ethoxy, ethyithio, cyclopropyl or cyclobutyl group; and R 4 represents a carboxy or 1H-tetrazolyl group; K:;rI 82 and the salts thereof. 6. Compounds of formula I as claimed in claim 1 being: £(2-n-propyl-4-methyl-6- (1-(2-N-morpholirioethyl- imidazol.-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2- carboxylic acid; ((2-n-Propyl-4-methyl-6- (1-(2-methoxyethoxy-2- ethyl) -imidazol-4-yl) -benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid; t(2-Ethyl-4-methyl-6- (1-(2-diethylaminoethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (lH- -biphenyl; [(2-Ethyl-4-methyl-6- (1-(3-N-piperidinopropyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (lH- -biphenyl; [(2-n-Propyl-4-methiyl-6- dimethylaminopropyl) -imidazol-4-yl) -lenzimidazol-l-yl) methyl] -biphenyl-2-carboxylic acid; [(2-Ethyl-4-methyl-6- (1-(2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2- carboxylic acid; 1(2-Ethyl-4-tuethyl-6- (1-(2-N-morpholinoethyl) imidazol-4-yl) -benzimidazol-l-yl) -methyl] (11- -biphenyl; 4'-[(2-Ethyl-4-methyl-6-(l-(2-N-pyrrolidinoethyl) imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2 carboxylic acid; 4'-E(2-Ethyl-4-metbhyl-6-(l-(2-N-pyrrolidinoethyl)- 83 imidazol-4-yl) -benzimidazol-l-yl) -methyl] (1H- -biphenyl; 4'1 t(2-Ethyl-4-methyl-6- (1-(2-diethylaminoethyl)- imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2- carboxylic acid; 4'-[t(2-Ethyl-4-methyl-6- (1-(3-N-piperidinopropyl) imidazol-4-yl) -benzimidazol-1-yl) -methyl] -biphenyl-2- carboxylic acid or a salt thereof.
7. [(2-n-propyl-4-methyl-6- (1-(2-N-morpholinoethyl- imidazol-4-yl) -benzimidazol-l-yl) -methyl] -biphenyl-2- carboxylic acid and the salts thereof.
8. A compound as claimed in any one of claims 1 to 7 being a physiologically acceptable addition salt of a ::compound of formula I as claimed in any one of claims I to 7. A pharmaceutical composition containing a compound of formula I as claimed in any one of claims 1 to 7 or a 5:physiologically acceptable salt thereof together with one or more physiologically acceptablP r--4ers or O*V. excipients. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps: a) cyclising a compound of formula II 84 RR R-, I(I (wherein one of the groups X, and Yj represents a group of formula R -NR s-CH 2 and the other group X, or Yi represents a group of the formula Z, Z S" NH C R3 R s represents a hydrogen atom or an R 3 CO- group, R 1 R 2 R 3 and R 4 are as defined in any one of claims 1 to 6, Z, and Z 2 which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by C-_6-alkyl groups which may be identical or different or Zi and Z 2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C 1 3 -alkyl group, or an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms) or an N-oxide thereof and optionally subsequently reducing a cyclized N-oxide thus obtained; 85 b) reacting a benzimidazole of formula III H (III) (wherein R 1 R 2 and R 3 are as defined in any one of claims 1 to 6) with a biphenyl compound of formula IV R Z3-CH :0-O ;n. (IV) (wherein R 4 is as defined in any one of claims 1 to 6 and Z3 represents a nucleophilic leaving group); c) (to prepare a compound of formula I wherein R 4 represents a carboxy group) converting a compound of formula V R N (V) (wherein RI, R 2 and R3 are as defined in any one of claims 1 to 6 86 and R 4 represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis; d) (to prepare a compound of formula I wherein R 4 represents a IH-tetrazolyl group) cleaving a protecting group from a compound of formula VI RN R N R R4" N AH2 (VI) (wherein RI, R 2 and R 3 are as defined in any one of claims 1 to 6 and R 4 represents a 1H-tetrazolyl group protected in the 1- or 3-position by a protecting group); e) (to prepare a compound of formula I wherein R 4 represents a 1H-tetrazolyl group) reacting a compound of formula VII R* N R "A H 3 CN H (VII) (wherein 87 RI, R 2 and R 3 are as defined in any one of claims 1 to 6) with hydrazoic acid or a salt thereof; f) converting a compound of formula I wherein R 4 denotes a carboxy group by esterification into a corresponding compound of formula I wherein R 4 denotes a group convertable in vivo into a carboxy group; g) converting a compound of formula I wherein R2 denotes an imidazol-4-yl group substituted in the 1- position by a C 2 .4-alkyl group substituted in the 3- or 4- position by an alkoxy or alkoxyalkoxy group, by ether splitting into a corresponding compound of formula I wherein R 2 denotes an imidazol-4-yl group substituted in the 1-position by a C 2 -4-alkyl group substituted in the 3- or 4-position by a hydroxy group; h) separating the 1-isomer from a 3-isomer mixture of a compound of formula I by isomer separation; i) converting a compound of formula I into a 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 o j) performing a process as defined in any one of steps to above on a corresponding protected compound and subsequently removing the protecting groups used.
11. A method of treatment of the human or non-human animal body to combat hypertension and cardiac insufficiency and also for treating chronic renal insufficiency, ischaemic peripheral circulatory disorders and cerebovascular circulatory disorders, mycoardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and 88 retinopathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 7 or a physiologically acceptable salt thereof.
12. A method of treatment as claimed in claim 11 to combat pulmonary diseases, for preventing arterial resterosis after angioplasty, for preventing thickening of the vascular walls after vascular operations and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout.
13. A method of treatment as claimed in claim 11 for alleviating central nervous system disorders.
14. A compound of formula I as claimed or claim 1 or a pharmaceutical composition thereof substantially as herein disclosed in any one of the Examples. DATED this 14th day of February 1995 DR KARL THOMAE GmbH •by their Patent Attorneys CALLINAN LAWRIE i *i C. CoC 89 ABSTRACT Benzimidazoles The invention relates to benzimidazoles of formula S. S S S S. S 0* S S p 5*5* S. SO S. e S. 5 S S S. S. S S S 5
55.5 S. .5 0* S S S. S 6* 5 .0 S S 555 5 0 SeeS S (wherein RI, R 2 R 3 and R 4 are as def ined in the claims) and the addition salts thereof, compounds which have valuable properties, in particular, as angiotensin-II antagonists. io
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DE4201554 1992-01-22
DE4201554A DE4201554A1 (en) 1992-01-22 1992-01-22 New benzimidazol-1-yl-methyl-bi:phenyl derivs.
DE4219782A DE4219782A1 (en) 1992-01-22 1992-06-17 New benzimidazol-1-yl-methyl-bi:phenyl derivs.
DE4219782 1992-06-17
DE4225756A DE4225756A1 (en) 1992-01-22 1992-08-04 Benzimidazoles, medicaments containing these compounds and process for their preparation
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US9636328B2 (en) 2013-06-21 2017-05-02 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
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US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU640505B2 (en) * 1990-07-23 1993-08-26 Dr. Karl Thomae Gmbh Benzimidazoles
AU655794B2 (en) * 1991-02-06 1995-01-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Benzimidazole compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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