CA2073841A1 - Phenylalkyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them - Google Patents

Phenylalkyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them

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Publication number
CA2073841A1
CA2073841A1 CA 2073841 CA2073841A CA2073841A1 CA 2073841 A1 CA2073841 A1 CA 2073841A1 CA 2073841 CA2073841 CA 2073841 CA 2073841 A CA2073841 A CA 2073841A CA 2073841 A1 CA2073841 A1 CA 2073841A1
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Prior art keywords
group
alkyl
atom
groups
methyl
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CA 2073841
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French (fr)
Inventor
Uwe Ries
Manfred Reiffen
Wolfgang Grell
Norbert Hauel
Berthold Narr
Armin Heckel
Andreas Bomhard
Jacques Van Meel
Wolfgang Wienen
Michael Entzeroth
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Boehringer Ingelheim Pharma GmbH and Co KG
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Individual
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Priority claimed from DE4123341A external-priority patent/DE4123341A1/en
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Publication of CA2073841A1 publication Critical patent/CA2073841A1/en
Abandoned legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/68—Halogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • 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
    • C07D403/02—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
    • 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
    • C07D403/02—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
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Abstract Phenylalkyl Derivatives The invention relates to phenylalkyl derivatives of formula I

Description

So12-~58/000.5~9 2 ~ 73 ~ ~ ~

Phenyla.lykyyl clerivatives The present invention re].ates to phenylalkyl derivatives, processes for their preparation and pharmaceutical compositions containing them.
We have now found that certain new phenylalkyl dexivatives have valuable and interesting pharmacological properties in particular as angiotensin-antagonists.
Viewed from one aspect of the invention thus provides compounds of formula I

R - A ~ B - C - ( CH2 ) - Rd Rf (wherein n represents the number O or l;

A represents a straight-chained or branched alkylene group; -:

B represents an oxy~en atom, a carbonyl, hydroxy-methylene, suIphenyl,~sulphinyl or sulphonyl group, a straight-chained or branched~alkylene group, a C24-alkylidene group, a l,l-cycloalkylene:group or an imino group optionally substituted by an alkyl group or by a C14-alkanoyl group;

Ra represents~a chlorine or bromine atom, a hydroxy, :
a~lkylsulphonyloxy,~phenylsulphonyloxy or phenylalkyl- . :
sulphonyloxy`~group~:or~a~group of the formula ;~

:

,~
- 2 - 2~73~1 ~---É~
N

1~ N ~,, E~-R

,. , ~ _ N E-R~
R 2~
~ N~ :
3 X

N - N
3 ~ ~E-R

`
` 3 \ ~ :

X--<~ ~ E-R~
N

R3 : :

; : : : :
~: ~

-- 3 - 2~73~1 R ;~
f~3 t~

~j/ \
o R ~3~ N E- R ~

D6~D or D -~: N

':
~wherein on~ of the groups D1, D2 and D3 represents a methylene or imino:group and the remaining groups of D1, D2 and:D3 are methine groups, whilst additionally a methine group:may be~replaced by a nitrogen atom and one of the methine groups may be~substituted by a group~:Rs and, optionally, another of the:methine groups may be substltuted by a~group R4;

:

2~73~3 none, one or two of the groups D," D5, D6 an~ D7 represent a nitrogen atom and the remaining groups of D4, Ds~ D6 and D7 each represent methine groups, whilst additionally a methine group may be substit~lted by a group R~ and another methine group may be substituted by a group Rs;

E represents a carbon-carbon bond, an oxygen or sulphur atom, a hydroxymethylene or carbonyl group or an imino group optionally substituted by a C16-alkyl group, by a cycloalkyl group, by a C~5-alkanoyl group or by an allyl, phenyl or benzyl group;

X represents an oxygen or sulphur atom or an imino group optionally substituted by an alkyl, phenyl or phenylallcyl group;

R1 represents a straight-chained or branched C19-alkyl, C26-alkenyl or C26-alkynyl group optionally substituted by a cycloalkyl group, by a fluorine, chlorine or bromine atom, or by a hydroxy, amino, alkylamino, dialkylamino or ~,~-difluoroethane group, or R1 may represent a C14-perfluoroalkyl group or a cycloalkyl group, optionally mono- or disubstituted by a trifluoromethyl group or by an alkyl group;

R2 represents a hydrogen, fluorine, chlorine or bromine atom, a C15-alkyl or -perfluoroalkyl group or a cyano or nitro group;

R3 represents a hydrogen atom, a cyano group, a C16-alkyl group optionally substituted by a hydroxy or alkoxy group, a Cl6-per~luoroalkyl group, a C36-alkenyl group optionally substituted by fluorine atoms, a phenylalkyl or phenyl(C24)alkenyl group, or a C1s-alkyl group which is terminally substituted by an imidazol-l-yl, tetrazolyl, phthalimido, R6COO-, R7S-, R7SO-, R7CO-, R NHCOO-, R7NHCO-, R7NHCONR7-, R8CONR7- or R8S02NR7 group ,: : ' :

::

2~73~

by a triazolyl group itself optionaly mono- or disubs~itu-ted by an acetoxy or alkyl group;

R6 represen-ts a Cl~-alkyl or -perfluoroalkyl g~oup, or a cycloalkyl, phenyl, benzyl, phenylethyl, adamantyl, naphthyl, naphthylmethyl or naphthylethyl group;

R7 represents a hydrogen atom or a group R6;

R8 represents a group R7 or a pi.perazino group optionally substituted by an alkyl or phenyl group in the 4-position, or R~ represents a py:rrolidino, piperidino, hexamethyleneimino, morpholino, R70- or (R7)2N-group;

R4 represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, a cycloalkyl group, or a C16-a].kyl group optionally substituted by a cycloalkyl, hydroxy, alkoxy, alkylamino, dialkylamino, alkoxycarbonyl, alkylaminocarbonyl or dialkylamino-carbonyl. group; and R5 represents a hydrogen, ~luorine, chlorine or bromine atom, a straight-chained or branched C16-alkyl or C16 -per~luoroalkyl group, a C26-alkenyl or C26-alkynyl -~. group, in which the above-mentioned alkyl and alkenyl moieties may each be mono- or disubstituted by a heteroaryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, N-alkyl-alkylcarbonylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, piperidinocarbonyl, morpholinocarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazol-5-yl, tetrazol-5-yl-aminocarbonyl, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylamirlosulphonyl, alkylsulphonylaminocarbonyl, heteroarylaminosulphonyl or alkylcarbonylaminosulphonyl group, or . ' ~` ' . :
, ' '~: ' . ' ' : ' ' . .

2~73g~

Rs represents a C17-alkoxy yroup substi-tuted in the 2-, 3-, ~-, 5-, 6- or 7-position by an imidazolyl, tetrazolyl, benzimldazolyl or -tetrahydrobenzimidazolyl group, or a phenylalkoxy group optionally substituted in the alkoxy moiety by a l~l-tetrazol-5-yl or 1-triphenylmethyl-tetrazol-5-yl yroup, or a carboxy group or a group which is metabolically converted into a carboxy group ln vivo, or a C14-alkylsulphony].oxy group, a benzenesulphonyloxy or phenylalkanesulphonyloxy group, or \

an acylam.ino group optionally substituted at the nitrogen atom by a Cl6-alkyl group or by a phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenyl group, wherein the acyl moiety is a C17-alkanoyl group, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, a C16-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenylalkanesulphonyl, naphthylenesulphonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl group, in which the above-mentioned phenyl nuclei may each be mono- or disubstituted by a fluorine, chlorine or bromine atom or -- by a methyl or methoxy group and the substituents may be identical or di~ferent, or a phthalimino, homophthalimino, 2-carboxyphenylcarbonyl-amino or ~-carboxyphenylmethylamino group, in which a carbonyl group in a phthalimino group may be replaced by a methylene, alkyl-methylene or dialkyl-methylene group and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups, wherein the phenyl nuclei in any of said groups may be additionally mono- or disubstituted by alkyl or alkoxy groups optionally wholly or partially hydrogenated, in which the substituents may be the same or different, or ;, : .: ' ,' ' . : , . . .

`~ ! , ' . . ., : . : ., .,; ~. . . . . .

2~3~

a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two alkyl groups or by a tetramethylene pentamethylene group, wherein a methylene yroup may be replaced by a carbonyl or sulphonyl group, or a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene moieties each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, or a glutaric acid imino group in which the n-propylene group may be per~luorinated, may be substituted by one or two alkyl groups or by a tetramethylene or pent~methylene group, or a maleic acid imino or succinimido group optionally mono- or disubstituted by an alkyl or phenyl group, wherein the substituents may be identical or difEerent, or a 5-membered heteroaromatic ring bound via a carbon atom --- or via an imino group, which contains an imino group, an oxygen or sulphur atom, or which contains an imino group and an oxygen, sulphur or nitrogen atom, or R5 represents a 6-membered heteroaromatic ring bound via a carbon atom which contains 1 or 2 nitrogen atoms, which 5- or 6-membered heteroaromatic ring is attached via two adjacent carbon atoms to an n-propylene, n-butylene or 1,3-butadienyl group or via an imino group and an adjacent carbon atom an n--propylene, n-butylene or 1,3-butadienyl gxoup and, in an anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene group in the 3-, 4-position relative to the nitrogen atom of the pyridine ring formed may be ,., ~ , . . .

.
, . ~ . . . . .

. ~
.
, .~ , , ~33~

replaced by a su:Lphur atom or, in an anellated phenyl riny thus formed, one or two methine yroups may be replaced by nitrogen a~oms, whils-t addl.tionally the above-mentioned fused aromatic or heteroaromatic rinys may be monosubstikuted in the carbon s-tructure by a ~luorine, chlorine or bromine atom, or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylamino sulphonyl or dialkylaminosulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy yroups, and any -NH- yroup present in an imidazole ring may be substituted by a C16-alkyl group or by a cycloalkyl group, or a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, wherein a phenyl group may be fused onto the pyridine ring via two adjacent carbon atoms and a methylene gr~up adjacent to the nitrogen atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or an imidazolidinedione group optionally substituted by an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, or a pyridazin-3-one or dihydro-pyridazin-3-one group optionally substituted in the 2-position by an optionally phenyl-substituted alkyl group, and ~ith the carbon structure additionally optionally substituted by 1 or 2 alkyl groups, or an R~1-NR~o-CO-NR9 group (wherein .

2~P~3~
_ 9 _ R9 represents a hydro~en atom, a Cl~-alkyl group or a phenylalkyl group, R~o represents a hydrogen a~om, a C18-alkyl group, a C3 5-alkenyl group, a phenylalkyl group or a C57-cycloalkyl yroup, and R11 represents a hy~rogen atom or a C16-alkyl group, an~

one of the yroups R9, R10 and R1l may also represent a bicyclohexyl or hiphenylyl group, and R~o and Rl1 together with the nitro~en atom between them may represent a straight-chained C46-alkyleneimino group or a morpholino group, and R9 and R11 together may represent a C24-alkylene group));

Rb represents a cyano, trifluoromethylcarbonylamino, trifluoromethylcarbonylaminomethyl, trifluoromethyl-sulphonylamino, trifluoromethylsulphonylaminomethyl, alkylsulphonylamino, alkylsulphonylaminomethyl, arylsulphonylamino, arylsulphonylaminomethyl, aralkylsulphonylamino, aralkylsulphonylaminomethyl, arylsulphonylaminocarbonyl, benzylsulphonylamino-carbonyl, sulpho, aminosulphonyl, alkylaminosulphonyl, aralkylaminosulphonyl, arylaminosulphonyl, alkylcarbonylaminosulphonyl, aralkylcarbonylamino-sulphonyl, arylcarbonylaminosulphonyl, sulphomethyl, aminosulphonylmethyl, alkylaminosulphonylmethyl, aralkylaminosulphonylaminomethyl, arylaminosulphonyl-methyl, alkylcarbonylaminosulphonylmethyl, aralkyl-carbonylaminosulphonylmethyl, arylcarbonylamino-sulphonylmethyl, phosphino, O-alkyl-phosphino, O-aralkyl-phosphino, O-aryl-phosphino, phosphono, O-alkyl-phosphono, O-aralkyl-phosphono, O-aryl-phosphono, 0,0 dialkylphosphono, phosphono-methyl, O-alkyl-phosphono-.~., . . ~ ~ . , - . . . . . .
- : - ~ : .
, , , ,:

1. : ~ : , . . . .

2~3~

me-thyl, O-aralkyl--phosphono-methy:l, O-aryl-phosphono-methyl, O,O-dialkylphosphono-methyl, phosphato, O-alkyl-phosphato, O-aralkyl-phosphato, O-aryl-phosphato or O,o-dialkoxy-phosphoryl group, a lH-tetrazolyl, lH-tetrazolylalkyl, lH-tetrazolylaminocarbonyl or triazolyl group optionally substituted by an alkyl, trifluoromethyl, phenylallcyl or triphenylmethyl group, or an alkylsulphonylaminocarbonyl or perfluoro-(C16alkyl-sulphonylaminocarbonyl group, a carboxy group, a group which is metabolically converted into a carboxy group ln vivo, or an aralkoxycarbonyl group;

Rc represents a hydrogen atom, an alkyl, aralkyl, aryl, carboxy or alkoxycarbonyl ~roup;

Rd represents a strai~ht-chained or branched C110-alkyl chain, a straight-chained or branched C210-alkenyl or C210-alkynyl group, a cycloalkyl or cycloalkylalkyl group, a phenyl group optionally mono- or disubstituted by ~luorine, chlorine or bromine atoms or by methyl or methoxy groups, or a biphenyl, naphthyl or heteroaryl group;

Re and Rf represent hydrogen atoms and if Rs represents a --- phthalimino, homophthalimino, 2-carboxyphenylcarbonyl-amino or 2-carboxyphenylmethylamino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene, alkyl-methylene or dialkyl-methylene group and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups, wherein the phenyl nuclei in any of said groups may be additionally mono- or disubstituted by alkyl or alkoxy groups optionally wholly or partially hydro~enated, in which the substituents may be the same or different, or a carboxy group or a group which is metabolically converted into a carboxy group in vivo, or : . ~ ': .' ', . ..
- ~ , :
, : , : ~ '" " ' " ` ."' ~' ~: :

2~73~

a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group op-tionally substituted by one or two alkyl ~roups or by a tetramethylene or pentamethylene group, wherein a methylene group of the alkyleneimino or alkenyleneimino group may be replaced by a carbonyl or sulphonyl group, or a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene moieties may each contain 9 or 10 carbon atoms and may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, or a glutaric acid imino group wherein the n-propylene group may be perfluorinated or substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a maleic acid imido or succinimido group optionally mono- or disubst.ituted by an alkyl or phenyl group, in which the substituents may be identical or different, or a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group and containing an imino group, an oxygen or sulphur atom or containing an imino group and an oxygen, sulphur or nitrogen atom, or a 6-membered heteroaromatic ring bound via a carbon atom and containing 1 or 2 nitrogen atoms, wherein the 5-or 6-membered heteroaromatic ring is attached via two adjacent carbon atoms to an n-propylene, n-butylene or 1,3-butadienyl group or via an imino group and an adjacent carbon atom to an n-propylene, n-butylene or 1,3-butadienyl group, and in the anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene ring in the 3~ position relative to th~e nitrogen atom of the pyridine ring - , 2~3~.

~ormed may be replaced by a sulphur atc)m or, in ~n anellated phenyl ring -thus formed, one or two methine groups may be replace~ by nitroyen atoms, whils-t ad~itionally the above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carbo~y, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifl.uoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylamino-sulphonyl group or may be disubstituted by fluor.ine or chlorine atoms or by methyl, methoxy or hydroxy groups and any -NH- group present in an imidazole ring may be substituted by a C16-alkyl group or by a cycloalkyl group, or a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, in which a phenyl group may be condensed onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the nitrogen atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or an imidazolidinedione group optionally substituted by an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, or a pyridazin-3-one or dihydro-pyridazin-3-one group optionally substituted in the 2-position by an optionally phenyl-substituted alkyl group and additionally optionally substituted in the carbon skeleton by 1 or 2 alkyl groups, or an R11-NR10-CO-NR9 group (wherein R9, R10 and R11 are defined as hereinbefore), : ~

.

2 ~
- 13 ~
then Re may also represent a hydrogen~ fluorine, chlorine or bromine atom or an alkyl or alkoxy group, and Rf may also represent a f]uorine, chlorine or bromine atom or an alkoxy group;

wherein, unless otherwise stated, any alkyl, alkylene or alkoxy moiety contains 1 to 4 carbon atoms and any cycloalkyl moiety contains 3 to 7 carbon atoms' any aryl group, un].ess otherwise specified is a phenyl group optionally mono- or di-substituted by a fluorine, chlorine or bromine atom or by a hydroxy, alkyl, alkoxy, phenylalkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylamino-sulphonyl group, wherein each alkyl moiety may contain 1 to 4 carbon atoms, or a naphthyl group, any heteroaryl group, unless otherwise specified is a 5-membered heteroaromatic ring which contains an imino group, an oxygen or sulphur atom, or contains an imino group and an oxygen, sulphur or nitrogen atom, or contains an imino group and 2 or 3 nitrogen atoms, and a 6-membered heteroaromatic ring which contains 1, 2 or 3 nitrogen atoms, whilst tha above-mentioned rings may additionally be mono- or di-substituted by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, triflu~romethy:l, alkanoyl, aminosulphonyl, alkylaminos~lphonyl or dialkylamino-sulphonyl group) and the isomer mixtures, tautomers, enantiomers and .

, , ' ! . , ' ~ ' 2~3~1 salts thereof, more part:icularly for pharmaceutical use the physiologically acceptable salts thereof with inorganic or organ.ic acids or bases.

The new compounds of formula I above wherein Ra represents a chlori.ne or bromine atom, a hydroxy, alkylsulphonyloxy, phenylsulphonyloxy or phenylalkylsulphonyloxy group, are valuable intermediate products and the other compounds of formula I above and the physiologically acceptable salts thereof have va.luable pharmacological properties, being angiotensin-antagonists, especially angiotensin-II-antagonists.
The present invention thus relates to the new above-mentioned phenylalkyl derivatives, whilst the corresponding O-substituted phosphono or phosphato compounds and the corresponding cyano, alkoxycarbonyl or triphenylmethyl compounds are also valuable intermediate products.
The present invention thus also relates to new pharmaceutical compositions containiny the above-mentioned pharmacologically active compounds of formula I or corresponding physiologically acceptable salts thereof which are particularly suitable for treating h~pertension and cardiac insufficiency, also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for preventing the progression of cardiac insuf~iciency after myocardial infarction, for treating diabetic nepthropath~, glaucoma, gastrointestinal disorders and diseases of the bladder.
Particularly important compounds according to the invention include those of formula I wherein Ra~ Rbj Rc, Rd, R~, Rf, A, B and n are as hereinbefore defined with the proviso that D4, Ds~ D6 and D7 represent methine groups with the additional provisos (a) to (j), or . ~

- : - ,: , .

, - 15 - 2~73~
D7 represents a nitrogen atom ancl the yroups D~" D5 and D6 represent methine groups wi-th the ad~itional provisos (a) to (g) and (k) to (m) or (a) to (g) and (n) to (p), or one of the groups D4, D5 and D6 represents a nitrogen atom and the remaining groups of groups D4, Ds~ D6 and D7 represent methine groups, or two of the groups D4, Ds~ D6 and D7 represent nitroyen atoms and the remaining groups of groups D4, Ds~ D~ and D7 represent methine groups, with the additional provisos that either (a) n represents the number 1, or (b) Æ has the meanings given for E he.reinbefore with the exception of the carbon-carbon bond, or (c) A has the meanings given for A hereinbefore with the exception of the methylene group, or ~d) B has the meanings for B given hereinbefore with the exception of the oxygen atom, or (e) Rb has the meanings given for Rb hereinbefore with the exception of the carboxyl group, or (f) Rc has the meanings given for Rc hereinbefore with the exception of the hydrogen atom, or (g) Rd has the meani.ngs given for Rd hereinbefore with the exception of the phenyl group, or (h) Rl has the meanings given for R1 hereinbefore with the exception of the n-butyl group, or ' ~ ~ :
.; . ' : : .

2~3g~1 (i) R, has -the meanings given for R4 hereinbefore with the except.ion of the methy~ group in position 7, or (j) R5 has the meanings given for Rs hereinbefore wi.th the exception of the hydroyen atom, or (k) R1 has the meanings given for R1 hereinbefore with the exception of the ethyl group, or (1) R4 has the meanings given for R4 hereinbefore with the exception of the methyl group in position 7, or (m) Rs has the meanings given for Rs hereinbefore with the exception of the methyl group in position 5, or (n) R1 has the meanings g.iven for R1 hereinbefore with the exception of the n-propyl group, or (o) R4 has the meanings given for R4 hereinbefore with the exception of the hydrogen atom, or (p) R5 has the meanings given for R5 hereinbefore with the exception of the hydrogen atom, and the remaining groups have the meanings given hereinbefore, whilst additionally a methine group mentioned in the above definitions of groups D4, D5, D6 and D7 may be substituted by a group R4 and a further methine group ment~oned in the above definitions of groups D4, D5, D6 and D7 may be substituted by a group Rs;

and the isomers and salt thereof.

Examples of the heteroaromatic groups mentioned hereinbefore in the definitions of groups D4, Ds/ D6 and - , . . .
:~ .: . . . .. :, -.. , , ~ - . : , , , , , .:
:
.

2 ~

D7 include the pyri~o, pyrlmido, pyrazino or pyridazino groups which may be suhstituted in the carbon skeleton by the groups R4 and R5.
Examples of groups which are metabolically converted into a carboxy group ln vivo, in the compounds of the invention include, for example, the esters of formulae -CO-OR', -CO-O-(HCR'')-O-CO-R''I and -CO-O-(HCR")-O-CO-OR"' (wherein R' represents a straight-chained or branched C16-alkyl group, a Cs7-cycloalky]. group, a benzyl, 1 phenylethyl, 2-phenylethyl, 3-phenylpropyl, pivaloyloxymethyl, phthalidylme~hyl, (1,3-dioxa-2-oxo-4-methyl-cyclopenten-5-yl)-methyl, methoxymethyl or cinnamyl group, R" represents a hydrogen atom or a methyl group and R"' represents a straight-chained or branched C16-alkyl group, a Cs7-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group).

-- Preferred compounds according to the in~ention include those of formula I wherein n represents the number 0 or 1;

A represents a straight-chained or branched alkylene group;

B represents an oxygen atom, a straight-chained or branched C13-alkylene group or an imino group optionally substituted by an alkyl group or by a C14-alkanoyl group;

Ra represents a group of the formula .

2~7~

?

2 ~ ~
.~ _ E - R

~"
o\ or
4 ~r :
. ,.... . ~ . . : ~

. ~ .

2~3~

(whereirl none, one or two o~ the groups D,,, Ds~ D6 ~nd D7 represents a nitro~en atom and the remaining groups of D" Ds~ D6 ~nd D7 each represent methine groups, whilst additionally a methine group may be substituted by the group R4 and a fur-ther methine group may be substituted by the group Rs;

E represents a carbon-carbon bond, an oxygen or sulphur atom or an imino group optionally substituted by a C1~,~
alkyl group;
.
X represents an oxygen or sulphur atom:

Rl represents a straight-chained or branched C16-alkyl group, a straight-chained or branched C26-alkenyl or C26-alkynyl group, whilst the above-mentioned saturated and unsaturated alkyl moieties may each be substituted by a fluorine, chlorine or bromine atom or by a hydroxy or amino group, or a C36-cycloalkyl group;

R2 represents a hydrogen, fluorine, chlorine or bromine ato~, a C1s-alkyl or C15-perfluoroalkyl group or a cyano or nitro group;
.
R3 represents a hydrogen atom, a cyano group, a C13-alkyl group optionally substituted by a hydro~y or alkoxy group, a C13-perfluoroalk~l group, a C36-alkenyl group optionally substituted by fluorine atoms, a Cl3-alkyl group which is substituted in the terminal position by an R6COO-, R7S-, R7SO-, R7S02-, R7CO-, R7NHCOO-, R7NHCO-, R7NHCONR7-, R8CONR7- or R8SO2NR7-group (wherein R6 represents a C14-alkyl or C14-perfluoroalkyl group or a cycloalkyl, phenyl, benzyl or phenylethyl group;

-,, : ., - .-' ' : ` .. ~' ' ' ' :~:'" : ~ '. ' : ,.
: ' . :

2~3~ 1 R7 represents a hydroyen atonl or a group R6; and R8 represents a group R7);

R4 represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, a cycloalkyl ~roup, a C16-alkyl group optionally substituted by a hydroxy, alkoxy or alkoxycarbonyl group; and represents a hydrogen, ~luorine, chlorine or bromine atom, or a straight-chained or branched C16-alkyl or C16-perfluoroalkyl group, a C~6-alkenyl or C26-alkynyl group, whilst the above-mentioned alkyl and alkenyl moieties may each be mono- or di-substituted by a het~roaryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, N-alkyl-alkylcarbonylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or tetrazol-5-yl group, or a C1s-alkoxy group or an ~-(lH-tetrazol-5-yl)-benzyloxy group, or ,- .
a carboxy group or a group which is metabolically converted into a carboxy group in vivo, or a C14-alkylsulphonyloxy group or a benzenesulphonyloxy or phenylalkylsulphonyloxy group, or an acylamino group optionally substituted at the nitrogen atom by a C16-alkyl group or by a phenyl, cycloalkyl, phenylalkyl or cycloalkylalkyl group, in ~: which the acyl group is a C1s-alkanoyl group, an alkoxyca:rbonyl group with a total of 2 to 4 carbon atoms, a C16-alkylsulphonyl group, a benzoyl, :: ~

.

.
:
:

2~73$~1 benzenesulphony], cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl group, wh.ilst the above-mentioned phenyl nuclei may each be ~ono- or di-substituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group and the substituents may be identical or different, or a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene, alkyl-methylene or dialkyl-methylene group, and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups wherein the phenyl nucle.i in any Oe said groups may be additionally mono or disubstituted by alkyl or alkoxy groups optionally wholly or partially hydrogenated, in which the substituents may be the same or different, or a 5-, 6- or 7-membered alkyleneimino group optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, wherein a methylene group o~ the alkyleneimino group may be replaced by a carbonyl or sulphonyl group, or a maleic acid imido or succinimido group optionally mono- or disubstituted by an alkyl or phenyl group, wherein the substituents may be identical or dif~erent, or a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group, which contains an imino group, an oxygen or sulphur atom or which contains an imino group and an oxygen, sulphur or nitrogen atom, or a 6-membered heteroaromatic ring bound via a carbon atom which contains 1 or 2 nitrogen atoms, which 5- or 6-memb~red he~eroaromatic ring is connected via two adjacent carbon atoms to an n--propylene, n~butylene or 1,3-butadienyl group or via an imino group and an adjacent carbon atom -- - , :

.

2~3~1 to an n-propylene, n-hutylene or 1,3-butadienyl group and, in an anellate~ pyridine ring thus formed, a methine group may be replaced by a nitroyen atom and a vinylene group in the 3-, 4-po6ition relative to the nitrogen atom of -the pyridine ring ~`ormed may be replaced by a sulphur atom or, in an anellated phenyl ring thus formed, one or two methine groups may be replaced by nitrogen atoms, whilst additionally the above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted in ~he carbon structure by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylami.nocarhonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylamino-sulphonyl or dialkylaminosulphonyl group or may be disubstituted by ~luorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and any NH- group present in an imidazole ring may be substituted by a C16-alkyl group, or an R11-NRlo-CO-NR~ group (wherein R9 represents a hydrogen atom, a C16-alkyl group or a phenylalkyl group, R1o represents a hydrogen atom, a C16-alkyl group, a phenylalkyl group or a C57-cycloalkyl group, R-1 represents a hydrogen atom or a C16-alkyl group, or R10 and R11 together with the nitrogen atom between them represent a straight-chained C46-alkyleneimino group or a morpholino group, or ~ and R11 together represent a C24-alkylene group));

.

,:.. .

.

2~ ~3~ ~

Rb represents a cyano, carboxy, arylsulphonylamino-carbonyl, benzylsulphonylaminocarbonyl, sulpho, alkylcarbonylaminosu]phonyl, a:ralkylcarbonylamino-sulphonyl, arylcarbonylaminosulphonyl, alkylcarbonyl-aminosulphonylmethyl, aralkylcarbonylaminosulphonyl-methyl, arylcarbonylaminosulphonylmethyl, phosphino, o-alkyl-phosphino, phosphono, O-alkyl-phosphono, 0,0-dialkylphosphono, phosphono-methyl, O-alkyl phosphono-methyl, O,O-dialkylphosphono-methyl, phosphato or 0-alkyl-phosphato group, a lH-tetrazolyl or lH-tetrazolyl-alkyl group optionally subst.ituted by a phenylalkyl or triphenylmethyl group, an (C16alkyl)sulphonylamino-carbonyl or perfluoro(C16alkyl)sulphonylaminocarbonyl, a group which is metabolically converted into a carboxy group ln vivo, or an aralkoxycarbonyl group;

Rc represents a hydrogen atom, a methyl, phenyl, benzyl, carboxy or alkoxycarbonyl group;

R~ represents a straight-chained or branched C16-alkyl group, a straight-chained or branched C26-alkenyl or C26alkynyl group, a cycloalkyl or cycloalkylalkyl group, a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl or -- methoxy groups, or a biphenyl, naphthyl or heteroaryl group;

Re and Rf represent hydrogen atoms or, if R5 represents a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene, alkylmethylene or dialkylmethyl~ne group and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups, wherein the phenyl nuclei in any of said groups may be additionally mono- or disubstituted by alkyl or alkoxy groups optionally wholly or partially ' ' ' " ' '' ' ~ ' '' '" ' `;

.. : : ' .

~73~ L
- 2~ -hydrogenated, in which the sub~ti-tuents may be the same or di~ferent, or a carboxy group or a group which is metabolically converted into a carboxy group ln VlVo, or a 5-, 6- or 7-membered alkyleneimino group optionally substituted by one or two alky:L groups or by a tetramethylene or pentamethylene group, wherein a methylene group of the alkyleneimino group may be replaced by a carbonyl or sulphonyl group, or , ~ .
a maleic acid imido or succinimido group optionally mono- or di-substituted by an alkyl or phenyl group, the substituents being identical or different, or a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group, which contains an imino group, an oxygen or sulphur atom or which contains an imino group and an oxygen, sulphur or nitrogen atom, or a 6-membered heteroaromatic ring bound via a car~on atom which contains 1 or 2 nitrogen atoms, which 5- or 6-m~mbered heteroaromatic ring is attached via two adjacent carbon atoms to an n-propylene, n-butylene or 1,3-butadienyl group or via an imino group and an adjacent carbon atom to an n-propylene, n-butylene or 1,3-butadienyl group and, in an anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene group in the 3-, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or, in an anellated phenyl ring thus formed, one or two methine groups may be replaced by nitrogen atoms, whilst additionally ~he above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted in the carbon structure by a fluorine, chlorine or bromine atom or by an alkyl, alko~y, hydroxy, phenyl, nitro, amino, alkylamino, ~ , : , : , , . . :

; ' . ~
,: ' ~ ' . ' , , -~ ' ' , : ,.
. .
.
.

2~3~1 diallcylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, am:inocarbonyl, alkylami.nocarbonyl, dialkylaminocarbonyl, tri~luoromethyl, alkanoyl, aminosulphonyl, alkylamino-sulphonyl or dialkylaminosulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and any -NH- group present in an imidazole ring may be substituted by a C16~alkyl group, or an R11-NR10-CO-NR~ group wherein R9 to R11 are defined as hereinbefore, then Re may also represent a hydrogen, ~luorine, chlor:ine or bromine atom or an alkyl or alkoxy group and Rf may also represent a fluorine, chlorine or bromine atom or an alkoxy group;

whilst unless otherwise specified groups which are converted metabolically into a carboxy group in vivo are as defined hereinbefore, any alkyl, alkylene or alkoxy moiety contains 1 to 4 carbon atoms and any cycloalkyl moiety contains 3 to 7 carbon atoms, any aryl group, unless otherwise specified is a phenyl group optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a hydroxy, alkyl, alkoxy, phenylalkoxy, phenyl or nitro group, wherein each alkyl moiety may contain ~rom 1 to 4 carbon atoms, or a naphthyl group, and any heteroaryl group, unless otherwise specified is a 5-membered heteroaromatic ring which contains an imino group, an o~ygen or sulphur atom or which contains an - . , .

!. ~ ~ ` ' ! . .

.~: `. ' ' ` ': , ` . ' ' . .
' .: ' ' :. ' , 2~3~

imino group and an oxygen, sulphur or nitrogen atom or which contains an imino group and 2 or 3 nitrogen atoms, and a 6-membered heteroaromatic ring which contains 1, 2 or 3 nitrogen atoms, whilst the above-mentioned rings may additionally be mono- or d:isubstituted by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl or nitro group]

the isomer mixtures, the tautorners, enantiomers and salts thereof, with the exclusion of the following compounds:

(i) 2-n-butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-benzimidazole, (ii) 2-n-propyl-7-methyl-3-[4-[(~-carboxy)benzyloxy]-benzyl]imidazo[4,5-b]pyridine and (iii) 5,7-dimethyl-2-ethyl-3-[4-~(~-carboxy)benzyloxy]-benzyl]imidazo[4,5-b]pyridine and their salts.

Particularly preferred compounds according to the invention include those of formula I wherein ` n represents the number O;

A denotes a methylene, ethylene or ethylidene group;

B denotes an oxygen atom, a methylene, imino, methylimino or acetylimino group;

Ra denotes a group of the formula 3 ~,"~ E - R
N

,: . - ,:, . . :
. .

:: , , ~ : . - , `, '' ' ~

~73~

N ~ E- 1 N~
o or 15 ~ \~E-R

(wherein none, one or two of the groups D4, D5, D6 and D7 represents a nitrogen atom and the remaining groups of D4, Ds~ D6 and D7 each represent methine groups, whilst additionally a methine group may be substituted by a group R4 and another methine group may be substituted by a group R5;

E represents an oxygen atom or a carbon-carbon bond;

R1 represents a straight-chained or branched C16-alkyl group; :

-R2 represents a hydrogen, fluorine, chlorine or bromine atom;

~ ' : ~: ' ;' ' ' '.' ' . ' . ~ ~ ' ' . ' 2~73~

R3 represents a hydroxyalkyl group h~vi.ng l or 2 carbon atoms;

R4 represents a hydroyen atom or a C13-alkyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom, or a straight-chained or branched C13-alkyl group or an ~-(lH-tetrazol-5-yl)-benzyloxy group, or an amino or nitro group, or a carboxy group or a (C13-alkoxy)carbonyl group, or an acylamino group optionally substituted at the nitrogen atom by a C15-alkyl group, wherein the acyl yroup is a Cl5-alkanoyl group or a benzenesulphonyl group, the above-mentioned phenyl nucleus optionally being mono- or di-substi-tuted by a methyl or mekhoxy group and the substituents b~ing identical or different, or a 5-, 6- or 7-membered alkyleneimino group optionally substituted by one or two methyl groups, wherein a methylene group of the alkyleneimino group may be replaced by a carbonyl or sulphonyl group, or a 2,3-dimethylsuccinimido, phthalimino, homophthalimino or isoindolin-1-on-yl group, or a benzimidazol-2-yl group optionally substituted in the 1-position by a C13-alkyl group, or an R~1-NR10-CO-NR9 group (wherein R9 represents a hydrogen atom, a C1s-alkyl group or a phenylalkyl group having 1 to 3 carhon atoms in the alkyl moiety, 2~7~

R10 represents a hydrogen a-tom, a C1s-alkyl group or a cyclohexyl group, R11 represen-ts a hydrogen atom, a benzyl group or a C1s-alkyl yroup or R9 and R1.l together represent a C23-alkylene group));

Rb represents a carboxy, lH-tetrazolyl or O-alkyl-phosphono or alkylsulphonylaminocarbonyl group haviny 1 to 3 carbon atoms in the alkyl moiety;

Rc represents a hydrogen atom or a phenyl group;

Rd represents a straight-chained or branched C14-alkyl group, a cyclohexyl, cyclohexylmethyl, phenyl, biphenyl, methoxyphenyl, chlorophenyl, pyridyl or naphthyl group;

Re and Rf represent hydrogen atoms or, if R5 represents a benzimidazol-Z-yl group optionally substituted in the 1-position by a C13-alkyl group, or a 2,3-dimethylsuccinimino group, or , ~ .
a 5 , 6- or 7-membered alkyleneimino group optionally substituted by one or two methyl groups, wherein a methylene group may be replaced by a carbonyl or sulphonyl group, or an R11-NR10-CO-NR~ group, wherein R9 to R11 are defined as hereinbefore, then Re may also represent a hydrogen, chlorine or bromine atom or a methoxy group and Rf:may also represent a chlorine or bromine atom or a - , ~ :

:
,, : ~ :

~7~3-~ 1 methoxy group, the isomer mixtures, the tautomers, en~ntiomers ~nd sal~s thereof, with -the exclusi.on of -the following compound~:

(i) 2-n-butyl-1-[4-[(~~carboxy)benzyloxy]benzyl]-benzimidazole, (ii) 2-n-propyl-7-methyl-3-[~-[(~-carboxy)benzyloxy]-benzyl]imidazo[4,5-b]pyridine and (iii) 5,7-dimethyl-2~ethyl-3-[4-[(~-carboxy)benzyloxy]-benzyl]imidazo[4,5-b]pyridine, and thelr salts.
The present invention particularly relates to the following compounds of formula I:

(a) 2-n-propyl-4-methyl-1-[4-[(~-carboxy)benzyloxy]-benzyl]benzimidazole;

(b) 2-n-butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-6-dimethylaminocarbonylamino-benzimidazole;

(c) 2-n-propyl-6-(1-methyl-benzimidazol-2-yl)-4-methyl-[4-~(~-carboxy)benzyloxy]benzyl]benzimidazole;

(d) 2-methyl-4-[4'-[(~-carboxy)benzyloxy]benzyloxy]-quinoline;

(e) 2-n-butyl-8-methyl-3-[4-[(~-carboxy)benzyloxy]-benzyl]quinazolin-4-one semihydrate;

(f) 2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-[4-[~-(lH-tetrazol-5-yl)benzyloxy]benzyl]-benzimidazole;

(~) 2-n-butyl-6-(N-propionyl-methylamino)-1-[4-[(1-.
.

; ~
, . :

.~ .

., ~ .

2~73~

3l carboxy-3-methyl)butyloxylbenzyl]benzimidazole;

(h) 2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1~l)-pyrimidinon-1-yl)-3-[~-[~-(lH-tetrazol-5~yl)-benzyloxy]benzyl]imidazol[4,5-b]pyridine; and (i) 2-n-butyl-1-[4-[~ -ethyl--phosphono)benzylamino]-benzyl]benzimidazole;

and the isomers, isomer mixtures, the tautomers, enantiomers and salts thereof.

Viewed from a further aspect the invention also provides a process for the preparation of compounds of the invention, said process comprising at ]east one of the following steps:

a) reacting a compound of formula II

Ra H (II) (wherein Ra is as hereinbefore defined) with a compound of formula III

Z1 ~ A ~ C-(C12) -Rd (III) Rf :::
(wherein A, B, n, Rb, Rc, Rd, Re and Rf are as hereinbefore defined and Z1 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, . ~. . . .

-:~' ': ~ ` , :

~3~

or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluene-sulphonyloxy group) optionally followed by hydrolysis;

b) reacting a compound of formula IV

~ ~ / (IV) `., Rf (wherein R~, Re~ Rf and A are as hereinbefore defined, B' represents a skraight-chained or branched Cl4-alkylene group and Z2 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group) with a compound of formula V

Rb I

CH -- ( CH2 ) n ~ Rd ( V ) Rc (wherein Rb, Rd and n are as hereinbefore defined and Rc' represents an alkoxycarbonyl group) if necessary with subsequent hydrolysis and/or decarboxylation;

c) (to prepare compounds of formula I wherein B
represents an oxygen or sulphur atom or an optionally alkyl-substituted imino group) reacting a compound of formula VI

:

-~ .

2 ~

~ (VI) Rf (whereinRa~ Re~ R~ and A are as hereinbefore defined and B" represents an oxygen or sulphur atom or an optionally alkyl-substituted, eg. C16 alkyl substituted, imino group) with a compound of formula VII

El~b Z3 - C - (CH2) n ~ Rd (VII) Rc (wherein Rb, Rc, Rd and n are as hereinbefore defined and Z3 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluene-sulphonyloxy group) if necessary with subsequent hydrolysis;

d) (to prepare a compound of formula I wherein Rb represents a carboxy group) converting a compound of formula VIII

R - A ~ s - c (cH~ - Rd (VIII) :: :
~ :

2 ~1 ~ 3 ~

- 3~ -(wherein ~, Rc, Rd, Re, Rf, A, ~ and n are as hereinbefore defined and Rb' represents ~ group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a compound of formula I by hydrolysis, thermolysis or hydrogenolysis;

e) (to prepare a compound of formula I wherein Rb represents a lH-tetrazolyl group) cleaving a protective group -from a compound of formula IX

e K - A ~ ~ B - C ( C H 2 ) ~ ( I X ) R
Rf c (wherein Ral Rc~ Rd, Rel Rf, A, B and n are as hereinbefore defined and Rb" represents a lH-tetrazolyl group protected in the 1-or 2-position by a protecting group);

f) (to prepare a compound of formula I wherein Rb represents a lH-tetrazolyl group) reacting a compound of formula X
Re ~ CN
2a ~ A ~ `~ B - C (CH ) 2 (X) R~

(wherein Ra~ Rc~ Rd, Rel Rf, A, B and n are as hereinbefore defined) with hydrazoic acid or a salt thereof;

.. . . . .
. :': . '~ ' ' . ' ' ' ' :
, 2~3~ ~

g) (to prepare compoun~s of formula I wherein Ra represents a group of -the forrnula ~D9 N

D ~ ~ ~ E~

cyclisi.ng a compound of formula XI

~D X1 D5 ~ (XI) i) (wherein D1, D2, D3, D4, Ds/ D6 and D7 are as hereinbefore defined, one of the groups X1 or Y1 represents a group of formula e - 11r/ - A -~3 B - C ~CHz ~ - Rd R
Rf and the other group X1 or Y1 represents a group of formula Z4~ ~Zs - NH - C - E - R

(wherein R1, A, B, E, n, Rb, Rc, Rd, Re and Rf are as hereinbefore defined, Z4 and Zs~ which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl (eg. C1~6aIkyl) group_ or ... ..
, . . .
., 2 ~ 7 ~3 ~

Z4 and Zs toge-ther represent an oxygen or sulph~r atom, an imino group optionally substituted by a C1~-alkyl group, or an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms));

h) (to prepare compounds of formula I wherein Rs represents an R11-NR10-CO-NR9 group) reacting a compound of formula XII

a A ~ 1 2 n Rd (XII) r Rc R~

(wherein Rb, Rc, Rd, Re~ Rf, A, B and n are as hereinbefore defined and Ral represents a group Ra as defined hereinbefore wherein Rs is an amino group, a C1~-alkylamino group or a phenyl(C14alkyl)amino group) with a compound of formula XIII

N - CO ~ Z6 (XIII) (wherein R~o represents a hydrogen atom, a C18-alkyl group, a C3 5-alkenyl group, a phenylalkyl group or a Cs7-cycloalkyl group, R11 represents a hydrogen atom or a C16-alkyl group, or one of the groups R10 or R11 may also represent a bicyclohexyl or biphenylyl group, or R10 and R11 together with the nitrogen atom between them , . ' :', : ~

2~73~

represent a s-traight-chained C46-alkyleneimino group or a morpholino group, an~
Z6 represents a nucleophilic leaving group such as a chlorine or bromine atom or, if one of the groups R1o or R11 represents a hydrogen atom, Z6 together with ~10 or R11 represents a nitrogen-carbon bond);

i) (to prepare compounds of formula I wherein Rs represents an acylamino group optionally substitu~ed at the nitrogen atom by a C16-alkyl group or by a phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenyl group, wherein the acyl group is a C~ 7-alkanoyl group, a C24-~alkoxycarbonyl) group, a C1-6-alkylsulphonyl group, a benzoyl, benzenesulphonyl., phenylalkanesulphonyl, naphthalenesulphonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl group, whilst the above-mentioned phenyl nuclei may each be mono- or di-substituted by a fluorine, chlorine or bromine atom, by a methyl or methoxy group and the substituents may be identical or different, a phthalimino ~r homophthalimino group wherein the phenyl nucleus in each case may be mono- or di-substituted by C13-alkyl or C13-alkoxy groups, or a maleic acid imido or succinimido group optionally mono- or di-substituted by an alkyl or phenyl group, wherein the substituents may be identical or different) acylating a compound of formula XIV

Ra" - A ~ B - c - (CH2~n d (XIV) Rf (wherein ,.. :

~ ` "'' '" '"
.

2 0 r~ 3 ~ ~ l -- 3~ --Rb, RC~ RCl, Rc~ Rf, A, B and n ar.e as he:reinbefore defined and R~" represents a group R~ as he:re:inbefore defined wherein Rs represents an amino group optionally substituted by a C16-alkyl group or by a phenyl, cycloalkyl, phenylalkyl, cycloalkyalkyl, bicyclohexyl or biphenyl yroup) with a compound of formula XV

HO - U - R12 (XV) (wherein U represents a carbonyl or sulphonyl group and R12 represents a C16-alkyl group, a C13-alkoxy group, a phenyl, phenylalkyl, naphthyl or cycloalkyl group, wherein the above-mentioned phenyl nuclei may each be mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group and the substituents may be idPntical or different, or, if U
represents a carbonyl group, R12 may also represent a hydrogen atom, a phenyl group which is substituted in the o-position by a carboxy or carboxymethyl group and wherein the phenyl nucleus may be mono- or di-substituted by C~3-alkyl or C13-alkoxy groups and may additionally be wholly or partially hydrogenated, a 2-carboxy-ethyl or 2-carboxy-ethenyl group in which the ethyl and ethenyl moiety may each be mono- or di-substituted by an alkyl or phenyl group) or with a reactive derivative thereof such as an acid halide, acid ester or acid anhydride thereof;

j) to prepare compounds of formula I wherein Rb represents a phosphono or O-alkyl-phosphono group) hydrolysing a compound of formula XVI
Re ~ (XVI) :: ' , : ~ :;
.

' . ~

2~ ~3~

(wherein A, B, Ra~ Rc, Rd, R~, Rf and n are as hereinbefore define~
and Rb"' represents an O-alkyl- or O,O-dia:l.kyl-phosphono group in whlch each alkyl moiety may ~ontain 1 to 5 carbon atoms);

k) resolving a compound of formula I by isomer separation into the isomers or enantiomers thereof;

1) converting a compound of formula I into a sal.t thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound; and m) performing a process as defined in any one of steps (a) to (1) above on a corresponding protected compound and subsequently removing the protecting group used.

The reaction of step (a) is conveniently carried out in a solvent or mixture of solvenks such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, preferably at temperatures between O and 100C, e.g. at temperatures between ambient temperature and 50C.
The subsequent hydrolysis is appropriately 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 presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, , . , ~ . .

, : : ~ : : . .

:
: ~ :

2~3~
-- ~o --water/meth~nol, ethanol, wa-ter/ethanol, water/isopropanol or water/dioxane a~ ternperatures between -10C and 120C, e.g. at -temperatures between ambient temperature and the boiliny te~perature of the reaction mixture.
In the reaction, a mixture of possible isomers is preferably obtained which may subsequelltly, if desired, be resolved into the corresponcling isomers, preferably by chromatography, using a carrier such as silica gel or aluminium oxide.
The reaction o~ step (b) is conveniently carried out in a solvent or mixture o~ solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, preferably at temperatures between 0 and 100C, e.g. at temperatures between ambient t0mperature and 50C.
The optional subsequent hydrolysis is appropriately 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 presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10C and 120C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
The optional subsequent decarboxylation is conveniently carried out in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, t:richloroacetic acid or trifluoroacetic acid in a suitable solvent such as water, , : ' . ' i . . .

2~73~1 water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane ~t te~peratures between 50~C and 120C, e.g. at temperatures between 60~c and the boiling tempe~ature of the reaction mixture.
The reaction o~ step (c) is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or benzene, optionally in the pres~ence of an acid binding agent such as sodium acetate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, preferably at temperatures between 0 and lOO~C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
The optional subsequent hydrolysis is appropriately 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 presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10C and 120C, e.g. at temperatures bPtween ambient temperature and the boiling temperature o~ the reaction mixture.
In step (d) functional derivatives of the carboxy group such as the optionally substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides, the nitrile group or the tetrazolyl group may be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. the tert.butylester group, may be converted by thermolysis into a carboxy group and esters with aralkanols, e.g. the benzylester, may be converted by hydrogenol.ysis into a carboxy group.

- : .

~ ' : ': ' 2~73~ 1 - ~2 -The hy~rolysis of step (d) is appropriately carried out either :in the presence of an acid such as hydrochloric aci~, sulphuric aci~, phosphoric acid, trichloroacetic acid or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/
methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10C and 120C, preferably at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
When hy~rolysis is carried out in the presence of an organic aci~ such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy yroups present may simultaneously be converted into a corresponding acyloxy group such as the trifluoroacetoxy group.
If Rb' in a compound of formula VIII represents a cyano or aminocarbonyl group, these groups may also be converted into the 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 50C.
If Rb' in a compound of formula VIII represents for example a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as trifluoroacetic acid, p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40C and 100 C .
If Rb' in a compound of formula VIII represents a benzyloxycarbonyl group, for example, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal , , - ' ~

.:

2~73~

- ~3 -in a suitable solvent such as methanol, eth~nol, ethanol/water, glacial ace-tic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50C, e.g. at ambient temperature, under a hydrogen pressure of 1 to 5 bar. During hydrogenolysis, other ~roups may be reduced at the same time, e.g. a nitro group may be reduced to the amino group, a benzyloxy group to the hydroxy group, a vinylidena group to the correspondiny alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen may be replaced by a hydrogen atom.
Suitable protecting groups for use in step (e) include, for example, the triphenylmethyl, tributyl tin or triphenyl tin groups.
The cleaving o-f a protecting group used in step (e) is preferably carried out in the presence of a hydrohalic acid, preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol at temperatures between 0 and 100C, 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 150C, preferably at temperatures between 120 and 140C.
The reaction of step (f) is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150C, preferably at 125C. Appropriately, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g. sodium azide, in the presence o~ a weak acid such as ammonium chloride or the tetrazolide salt obtained in the reaction mixture during the reaction with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which is :

2 ~ L

also preferably produced in the reaction mixture by reactiny aluminium chlori~e or tributyl tin chlori~e with an alkali metal azide such as sodium azide, is subsequently libera-ted by acidification with a dilute acid such as 2N hydrochloric or 2N sulphuric acid.
The cyclisation of step (g) is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol-monomethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamic~e, tetraline or in an excess of the acylating agent used to prepare the compound of formula XI, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, e.g. at temperatures between 0 and 250C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide.
However, cyclisation may also be earried out without a - solvent and/or condensing agent.
However, it is partieularly advantageous to carry out the reaction by preparing a eompound of formula XI
in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of formula Ra-E-COOH, 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 ' - ': '. '............... ; - .

- . . ~

2 ~ 7 ~

- ~5 --L 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 nic]cel, platinum or palla~ium/c:harcoal, 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 dithionite, or with hydrazine in the presence of ~aney nickel at temperatures between 0 and 50C, but preferab y at ambient temperature.
The reaction of step (h) is preferably carried out in a solvent such as tetrahydrofuran, dioxane, ethylene chloride or benzene, optionally in the presence of an acid-~inding agent such as triethylamine or pyridine, expediently at temperatures between 0 and 100C, preferably at temperatures between 20 and ~0C.
Examples of reactive derivatives of a compound of formula XV usd in step (i) include the esters thereof such as the methyl, ethyl or benzylester, the thioesters thereof such as the methylthio or ethylthioester, the halides thereof such as the acid chloride and the anhydrides or imidazolides thereof.
The reaction of step (i) is conveniently carried out in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide with a corresponding carboxylic acid in the presence o* an acid activating or dehydrating agent such as thionylchloride, with the anhydrides thereof such as acetic acid anhydride, with the esters thereof such as ethyl acetate, with the halides thereof such as acetylchloride or methanesulphonyl chloride, 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 also be used as solvent, at temperatures between -25 and ~ ' ' , .
- .: . : .
.

: : :

2~73~

- ~6 -lOO'C, but preferably at temperatures between 10 ~nd 800C.
The reaction of step (j) is pre~erably carried out in a solvent such as methanol, methanol/water, ethanol or isopropanol in order to prepare a corresponding 0-alkylphosphono compound of formula I in the presence of a base such as potassium hydroxide or potassium methoxide or in order to prepare a corresponding phosphono compound of ~ormula I in the presence of an acid such as hydrobromic acid at the boiling temperature of the reaction mixture.
It is particularly advantageous to prepare a phosphono compound of formu].a I by reacting a corresponding O-alkyl or O,O-dialkyl compound of formula XVI with bromine/t.rimethylchlorosilane in acetonitrile with subsequent hydrolysis using water at ambient temperature.
If according to the invention a compownd of formula I is obtained wherein R2 or ~5 represents a nitro group, this may be converted by reduction into a corresponding compound of formula I wherein R2 or Rs represents an amlno group, or if according to the invention a compound o~ formula I is obtained wherein B represents an imino group, this may be c~nverted by alkanoylation into a corresponding compound of formula I wherein B represents an imino group substituted by a C14-alkanoyl group, or if according to the invention a compound of formula I is obtained wherein B represents an imino group, this may be converted by alkylation into a corresponding compound of formula I wherein B represents an imino group substituted by a Cl3-alkyl group, or i~ according to the invention a compound of formula I is obtained wherein Rb or Rb and Rs each represent a carboxy - ~ . , , , , :

2~17~

- ~7 -group, this may be conver-ted by esterifica-tion into a corresponding compound of formula I wherein Rb or Rb and Rs represent a group which is me-tabolically converted 1n v o into a carboxy yroup, or if according to the invention a compound of formula I is obtained wherein Rb represents a carboxy group, thi~ may, after conversion into a corresponding acid halide, be converted by reaction with a corresponding sulphonamide into a compound of formul.a I wherein Rb represents an alkanesulphonylaminocarbonyl, perfluoroalkanesulphonyl-aminocarbonyl, arylsulphonylami.nocarbonyl or benzyl-sulphonylaminocarbonyl group.

The subsequent reduction of the nitro group is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, suitably with hydrogen in the presence of a hydrogenation catalyst such as Raney nic~el, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid, with salts such as iron(II)sulphate, tin(II)chloride, sodium sulphide, sodium hydrogen sulphite or sodium dithionite, or with hydra~ine in the presence of Raney nickel at temperatures between 0 and 80C, but preferably at temperatures between 20 and 40C.
The s~bsequent alkanoylation is suitably carried out in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide with a corresponding carboxyli.c acid in the presence of an acid-activating or dehydrating agent such as thionylchloride, with the anhydrides thereof such as acetic anhydride, with the esters thereof such as ethyl acetate, with the halides thereof such as acetylchloride, optionally in the presence of an inorganic or tertiary organic base, such as sodium hydroxide, potassium carbonate, triethylamine ' '' ~ ". ' ' ' .: ' - ~8 -or pyrid:ine, wh.ilst -the latter two may simultaneously also be used as solvent, a-t temperatures bet~leen -25 and 100C, but preferably at temperatures between -lo and 80~C.
The subsequent alkylation is suitably carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.butoxide, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, with an alkylatin~ agent such as methyliodide, ethyliodide, isopropylbromide, dimethyl-sulphate, diethylsulphate or methyl p-toluenesulphonate, pre~erably at temperatures between 0 and 100C, e.g. at temperatures between ambient temperature and 50~C.
The conversion of a carboxyl group into a group which is metabolically converted ln vivo into a carboxy group, is conveniently carried out by esterification with a corresponding alcohol or with a corresponding reactive acyl derivative, suitably in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide or in an excess of the acylating agent as solvent, optionally in the presence of an acid-activating or dehydrating agent such as thionylchloride, 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 also be used as solvent, at temperatures between -25 and 100C, but preferably at temperatures between -10 and 80C. :~
The subsequent reaction of an acid halide with a corresponding sulphonamide is suitably carried out in a solvent such clS acetone, tetrahydrofuran or dioxane in .: ., . . ,... :
~, . . . . . .

_ ~9 ~ 3~1 -the presence of a base such as triethylamine at temperatures between 0 and 50C, preferably at temperatures between 10 and 30~c.
In the reaction steps (a) to (j) described hereinbefore, any reactive ~roups present such as hydroxy, amino or alkylamino groups ~ay optionally be protected during the reaction by conventional protecting groups which are split off again after the reaction.
Examples of protecting (~rol1ps for a hydroxy yroup inclwde trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.-butyl, benzyl and tetrahydropyranyl groups and prot~cting yroups for an amino, alkylamino or imino group include acetyl, benzoyl, ethoxycarbonyl and benzyl groups.
The optional subsequent cleaving of a protecting group is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric 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 100C, preferably at the boiling temperature of the reaction mixtureO 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 50C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably of 3 to 5 bar~
An isomer mixture of a compound of formula I thus obtained may if desired be resolved by chromatography using a substrate such as silica gel or aluminium oxide.
Moreover, the compounds of formula I obtained may be converted into the acid addition salts thereof, more particularly for pharmaceutical use the physiologically .
- . , ' ~, .
-`
,~
: :

2~73~41 accept~ble sal-ts thereof wit~ lnoryanic or oryanic acids. Sultable acids for -this purpose include hydrochloric acid, hydrobromic acid, sulph-lric ~cid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, -tartaric acid or maleic acid.
Furthermore, the new compounds of formula I thus obtained, if they contain a carboxy or lH-tetrazolyl group, may if desired subsequently be converted into the addition salts thereof with inorganic or organic bases, more particularly for pharmaceutical use into the physioloyically acceptable addition salts thereof Suitable bases include for example sod:ium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of formulae II to XVI used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature.
Thus, for example, substituted pyrimidines of formula II are described in EP-A-424317, substituted pyrimidinones are described in EP-A-407342 and EP-~-419048, substituted triazoles are described in EP-A-409332, substituted triazolinones, triazolthiones and triazolimines are described in EP-A-412594, substituted pyrazoles in EP-A-411507, substituted quinazolinones in EP-A-411766, substituted quinolines in EP-A-412848, 5-membered condensed imidazo derivatives in EP-A-407102, benzimidazoles in EP-A-392317, imidazopyridines and purines in EP-A-400974 and EP-A-399731 and substituted imidazoles in EP-A-253310.
The compounds of formulae III and IV used as starting materials may be obtained by reacting a eorresponding alcohol with hydrohalic acid, with tetrabromomethane/triphenylphosphine or wi-th a eorresponding sulphonic acid halide.
The eompounds o~ ~ormulae VIII, IX, X, XII, XIV and XVI used as starting materials may be obtained by - : .
, .
' :
: : .

2~73~

alkylating a corresponding compound w:ith a compound analogous to a compound o~ formula II:[.
The new compounds of formula I and the physiologically acceptable adclition salt~ thereof have valuable pharmacological properties. They are angiotensin antagonists, particularly angiotensin-II-anta~onists.

By way of example, the ~ollowing compounds of formula I

A = 2-n-propyl-4-methyl-1-[4-[(~-carboxy)benzyloxy]-benzyl]benzimidazole;

B -- 2-n-butyl-1-[4-[(~-carboxy)benzyloxy~benzyl]-6-dimethylaminocarbonylamino-benzimidazole;

C = 2-n-propyl-6-(1-methyl-benzimidazol 2-yl)~4-methyl-1-[4-[(~-carboxy)benzyloxy]benzyl]benzimidazole;

D = 2-methyl-4-[4'-[(~-carboxy)benzyloxy]benzyloxy]-quinoline;

E = 2-n-butyl-8-methyl-3~[4-[(~-carboxy)benzyloxy]-- benzyl]quinazolin-4-one-semihydrate;

F = 2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-[4-[~-(lH-tetrazol-5-yl)benzyloxy]benzyl]-benzimidazole;

G = 2-n-butyl-6-(N-propionyl-methylamino)-1-[4-[(1-carboxy-3-methyl)butyloxy]benzyl]benzimidazole;

H = 2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-3-[4-[~-(lH-tetrazol-5-yl)-benzyloxy]benzyl]imidazol[4,5-b]pyridine; and '' : ' ' : , 2~73~1 I = 2-n-butyl-1-[4-[[~-[~-ethyl-phosphono~benzylamino]-benzyl]benzimidazole were investigated for their biological effects as follows:

Description of method: Angiotensin II-receptor bondin~
The tissue (rats lung) is homogenised in Tris-buffer (50 mMol Tris, 150 mMol NaC]., 5 mMol EDTA, pH
7.40) and centrifuged twice fo:r 20 minutes at 20,000 x g. The finished pellets are resuspended in incubating buffer (50 mMo]. Tris, 5 mMol MgCl2, 0.2% BSA, pH 7.40) 1:75, based on the mo:ist weight of the tissue.
Each 0.1 ml of homogenate is incubated for 60 minutes at 37C with 50 pM [12sI]-angiotensin II (NEN, Dreieich, FRG) with increasing concentrations of the test substance in a total volume of 0.25 ml. Incubation is ended by rapid filtration through glass fibre filter mats. The filters are each washed with 4 ml of ice cold buffer (25 mMol Tris, 2.5 mMol MgCl2, 0.1% BSA, pH 7.40).
The bound radioactivity is measured using a gamma-counter. The corresponding ICso value is obtained from the dose-activity curve.
In the test described, substances A to I show the following ICso values:
. ~
Substance ICso [nM]

C

,, ., ~ . , ,: . , , :

:: :

2~3~

Moreover, when the above-mentioned compoun~s were administered in a dose of 30 mg/kg i.v. no toxic si~e effects, e.g. negative inotropic effects or disorders in heart rhythm, were observed. 'rhe compounds are therefore well tolerated.
In view of their pharmacological properties, the new compounds and the physiologically acceptable addition salts thereof are suit:able for the treatment of hypertension and cardiac insufiiciency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
The new compounds and the physiologically acceptable addition salts thereof are also suitab]e for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventiny arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetylcholine and dopamine in the brain, the new angiotensin antagonists are also suitable for alleviating central nervous system disorders, e.g.
depression, Alzheimer's disease, Parkinson syndrome, bulimia and disorders of cognitive function.
Thus viewed from a further aspect the invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acc~ptable salt thereof together with at least one physiologically acceptable carrier or excipient.
V:iewed 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 with an angiotensin ~73~
- 5~ -antagon:istic activi-ty.
In particular, the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the n\anufacture of a therapeutic agent to treat hyper-tension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for -the prevention of the progression of cardiac insufficiency after myocardial inearction and for treating diabetie nephropathy, glaueoma, gastrointestinal diseases and bladder diseases.
Additiona]ly, the present invention provides the use of a eompound of formula I or a physiologieally aeceptable salt thereof for the manufacture of a therapeutic agent to treat lung oedema and chronic bronchitis, for preventing arterial re~stenosis after angioplasty, for preventing thickening of blood vessel walls after vaseular operations, and for preventing arterioselerosis and diabetic angiopathy as well as other pulmonary diseases.
Yet further, the present invention provides the use of a eompound of formula I or a physiologieally aeeeptable salt thereof for the manufacture of a therapeutie agent to treat depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of eognitive funetion and other nervous system disorders.
Viewed from a yet still further aspeet the present invention provides a method of treatment of the human or non-human animal body to eombat hypertension and eardiac insuffieiency and also for treating ischaemie peripheral eireulatory disorders, myoeardial isehaemia (angina), for the prevention of the progression of eardiae insuffieiency after myoeardial infaretion and for treating diabetie nephropathy, glaueoma, gastrointestinal diseases and bladder diseases, said method eomprising administering to said body a eompound of formula I or a physiologieally aeeeptable salt , - . . .
,~ , - : ' - : : , 2 ~ ~ 3 ~

thereof.
In particular, the present invention provides a method of treatment of the human or non-human animal body to combat lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy as wel:L as other pulmonary diseases, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
Additionally, the present invention provides a method of treatment of the human or non-human animal body to combat depression, ~lzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function and other nervous system disorders, said method eomprising 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, 20 to 100 mg, preferably 30 to 70 mg, and, when administered orally, 50 to 200 mg, preferably 75 to 150 mg, 1 to 3 times a day. For this purpose, the eompounds of general formula I prepared according to the -^~ invention, optionally in conjunction with other active substances, such as hypotensives, diuretics and/or ealcium antagonisks, may be incorporated together with one or more inert eonventional carriers and/or diluents, e.g. with corn stareh, lactose, glueose, mierocrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene-glycol, propylene-glycol, eetylstearyl 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 .

,, : , 2~73~

or suppositories.
Additional active substances which may be included in the combinations mentioned above might be, for example, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzothiazide, cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosine, atenolol, propranolol, (di)hydralazine hydrochloride, diltiazem, felodipin, nicardipin, nifedipin, nisoldipin and nitrendipin. The dosage for these active substances is appropriately one fifth of the lowest recommended dose Up to 1/1 of the normally recommended dose, i.e., for example, 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorothiazide, 15 to 200 mg of ethacrinic acid, 5 to 80 mg of furosemide, 20 to 480 mg of propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipin or 5 to 60 mg of nitrendipin.
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.

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Example A

4-(~-Ethoxycarbonyl-benzyloxy)benzylbromide a) EthYl 2-bromo-phenylacetate 43.0 g (0.2 mol) of DL-2-bromo-phenylacetic acid are dissolved in 400 ml of ethanol at ambient temperature with stirring. At 5-10C 11.8 g (0.2 mol) of thionylchloride are slowly added dropwise whilst cooling with ice. A_ter 12 hours at ambient temperature the solvent is distilled off and the residue is taken up in ethyl acetate. After extraction with saturated sodium bicarbonate solution and saturated saline solution the product is dried over sodium sulphate and evaporated down.
Yield: 41,85 g (86% of theory), Rf value: 0.60 (silica gel; eluant: ethyl acetate/petroleum ether = 1:19) b) ~ Ethoxycarbonyl-benzyloxy)benzyl alcohol 41.8 g (0.172 mol) of ethyl 2-bromo-phenylacetate and 21.3 g (0.172 mol) of 4-hydroxybenzyl alcohol are dissolved in 850 ml of acetone and 24.8 g (0.18 mol) of potassium carbonate and 5.0 g ~0.03 mol) of potassium iodide are added thereto. The reaction mixture is refluxed for 60 hours with stirring. Then the inorganic salts are filtered off and the residue is washed with hot acetone. The filtrate is evaporated down and the residue is purified ovsr a silica gel column (particle si~e: 0.063-0.02 mm), initially using pstroleum ether as eluant and then using mixtures of petroleum ether and ethyl acetate of incrsasing polarity ~9:1, 8:2 and 7:3), The unified fractions are evaporated down ln _cuo.
Yield: 30.65 g (62.5% of theory), Rf vaIue: 0.40 (silica gel; eluant: ethyl acetate/pstroleum ether = 3:7) ,: . . . . . . .
.. .

, ~ ' ' , .

2~ 13~ ~

c) 4~ h'thox~r o~l-henzyloxy)benzylbro_ide 28.6 g (0.l mol) of 4-(~-ethoxycarbonyl-benzyloxy)benzyl alcohol are dissolved in 300 ml of dichloromethane and mixed with 31.6 g (0.12 mol) of triphenylphosphine.
Whilst cooling with ice, a solution of 40.0 g (0.12 mol) of carbon tetrabromide in 100 ml of dichloromethane is added dropwise. The mixture is stirred for 30 minutes at ambient temperature and then concentrated by evaporation. The residue is purified over a silica yel column ~particle size: 0.063-0.02 mm), using as eluant first petroleum ether and then mixtures of petroleum ether and ethyl acetate of increasing polarity (9:1 and 8:2). The unified fractions are evaporated down 1n vacuo.
Yield: 20.45 g (59% of theory), Oil, Rf value: 0.70 (silica gel; eluant: ethyl acetate/
petroleum ether = 1:4) C17H16BrO3 (349.24) Calculated:C 58.20 H 4.95 Br 22.80 Found:58.23 4.84 23.12 .,_ .

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2~3~

Example 1 2-n-Propyl-4-methyl-1-[~-[(Q-carboxy)benzyloxy]benzyl]-benzimidazole a) 2-n-Propyl-4-methyl-1-[4-[(~-ethoxycarbonyl)-benzyloxy]benzylLbenzimidazc)le _ __ _ 350 mg (2.0 mMol) of 2-n-propyl-4-methyl-benzimidazole (prepared analogously to Chemistry of ~Ieterocyclic Compounds, Vol. 40, Part 1, ~-12) are adde~ to a solution of 220 mg o~ potassium tert.butoxide in 30 ml of dimethylsulphoxide. After 30 minutes at ambienk temperature a solution of 700 mg (2.0 m~ol) of 4-(Q-ethoxycarbonyl-benzyloxy)benzy:Lbromide in 5 ml oP
dimethylsulphoxide is added dropwise. Af-ter 12 hours at ambient temperature the reaction solution is stirred into ice water and extracted 3 times with 100 ml of ethyl acetate. The combined organic phases are washed with 100 ml of saline solution and dried over sodium sulphate. After the solvent has been eliminated, the residue is purified over a silica gel column (particle size 0.063-0.02 mm), using as eluant methylene chloride to start with, then mixtures of methylene chloride and ethanol of increasing polarity (50:1 and 25:1). The uniform fractions are concentrated by evaporatio~ in vacuo.
Yield: 500 m~ (55% of theory), Oil, Rf value: 0.55 (silica gel; eluant: methylene chloride/methanol = 13:1) b) 2-n-Propyl-4-methyl-1-[4-[(Q-carboxy)benzyloxy]-benz~l]benzimidazole 500 mg (1.1 mMol) of 2-n-propyl-4-methyl-1-[4-[(Q-ethoxycarbonyl)benzyloxy]benzyl]benzimidazole are dissolved in 10 ml of ethanol and mixed with 10 ml of 1 N sodium hydroxide solution. The mixture is stirred at ambient temperature for 30 minutes. Then the mixture is concentrated by evaporation and taken up in water.

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The solu-tion i.s acidified by the addition of glacial acetic acid. The precipitate formed i6 guction filtered, washed with water until neutral and dried.
The crude product is taken up in methylene chloride and purified over a silica gel column (particle size 0.063--0.02 mm), using as eluant a mixture of methylene chloride and methanol (19:1). The uniform fractions are concentrated by evaporation ln vacuo and the residue is triturated with hexane/ether and suction filtered.
Yield: 60 mg (13% of theory), Melting point: amorphous C26Hz6N2O3 (414.51) Mass spectrum: (M + H)t = 415 Example 2 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-6-propionylamino-benzimidazole-hydrochloride a) 2-n-butyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-
6 nitro-benzimidazole and 2-n-butyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-5-nitro-banzimidazole _ _ Prepared analogously to Example la from 2-n-butyl-5-nitro-benzimidazole (prepared analogous].y~o Chemistry of Heterocyclic Compounds, Vol. 40, Part 1, 6-12) and 4-[(~-ethoxycarbonyl)-benzyloxy]benzylbromide.
Yield: 70.5% of theory, Oil, Rf value: 0.25 (silica gel; eluant: methylene chloride/ethanol = 50:1) b) 2-n-Butyl-6-amino-1-[4-[(~-ethoxycarbonyl)benzyloxy]-benzyl]-benzimidazole Prepared by catalytic hydrogenation of 2-n-butyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-5/6-nitro-benzimidazole in the presence of Raney nickel in ethanol at 50~C under 5 bars of hydrogen pressure, followed by chromatographic separation of the 5-amino-2-n-butyl-l-~, . . .

, .

:

2~3~

[4-[(~-ethoxycarbonyl)~benzyloxy]benzyl]herlæimidazole.
Yield: 21.8% of theory, Oil, Rf value: 0.30 (silica gel; eluant: petroleum ether/methylene chloride/ethanol =
7:2:1) c) 2-n-Butyl-6-propionylamino-1-[4-[(~-ethoxycarbonyl)-benzyloxy]benzyllbenzimi~ ole Prepared from 2-n-butyl-6-amino-1-[4-[(~-ethoxy-carbonyl)benzyloxy]benzyl~benzimidazole and propionyl chloride/pyridine.
Yield: 70.2% of theory, Melting point: 207~209C

d) 2 n-Butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-6-propionylamino-benzimidazole-hydrochloride Prepared analogously to Example lb from 2-n-butyl-6-propionylamino-1-[4-[(a-ethoxycarbonyl)benzyloxy]-benzyl]benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 43.5% of theory, Melting point: sinters from 93C
C29H31N34 x HCl (522.67) Calculated: C 66.50 H 6.12 N 8.08 Found: 66.73 6.34 7.81 Example 3 2-n-Butyl-1-[4-[(~-carboxy~benzyloxy~benzyl]-6-dimethylaminocarbonylamino-benzimidazole _ .
Prepared analogously to Example lb from 2-n-butyl-1-[4-[(a-ethoxycarbonyl)benzyloxy]benzyl]-6-dimethylamino-carbonylamino-benzimidazole and 2 N sodium hydroxide solution in ethanol.
Yield: 80% of theory, Melting point: 183-185C
C29H32N4O4 (500.60) :
.: .

~73~3 Calculated:C 69.59 }I 6.~ N 11.19 Eound:69.5~ 6.~3 10.66 Example 4 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]benzyl] 6-cyclohexylaminocarbonylamino-benzimidazole-hydrochloride a) 2-n-Butyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-6-cyclohexylaminocarbonylamino-be-nzimidazole Prepared from 2-n-butyl-1-[4-[(~-ethoxycar~onyl)benzyl-oxy]benzyl]-6-amino-benzimidazole and cyclohexyl-~
~' isocyanate/triethylamine in te-trahydrofuran.
Yield: 65.4% of theory, Oil, Rf value: 0.40 ~silica gel; eluan-t: methylene chloride/ethanol = 19:1) b) 2-n~Butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-6-cyclohexylaminocarbonylamino-benzimidazole-hydrochloride Prepared analogously to Example lb from 2-n-butyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-6-cyclohexylamino-carbonylamino-benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 40.7% of theory, Melting point: sinters from 184C
C33H3sN4~4 x HCl (591.17) Calculated: C 67.00 H 6.60 N 9.45 Found: 67.15 6.71 9.30 Example 5 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-5-cyclohexylaminocarbonylamino-benzimidazole-hydrochloride Prepared analogously to Example lb from 2-n-butyl-1-[4-[(a-ethoxycarbonyl)benzyloxy]benzyl]-5-cyclohexylamino-carbonylamino-benzimidazole and l N sodium hydroxide : ~ -,.: :
. .
, 2~73~
- 6~ -solu-tio~ in ethanol.
Yield: 46.1% of theory, Melting point: sinters from 196C
C33H3sN44 x HCl (591.17) Calculated: C 67.00 H 6.60 N 9.45 Found: 67.22 6.74 9.49 Example_6 2-n-Butyl-1-[4-[(~-carboxy)benz:yloxy]benzyl]-6-(3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l--yl)-benzimidazole . ~
Prepared analogously to Example lb from 2-n-butyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-6-(3,4,5,6 tetrahyclro-2(lH)-pyrimidinon-l-yl)-benzimidazole and 1 N
sodium hydroxide solution in ethanol.
Yield: 8.8% of theory, Melting point: 260-262C
C30H32N4O4 (512-61) Mass spectrum: (M + H)+ = 513 Example 7 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-6-(3-benzyl-3,4,5,6-tetrahydro-2(1~)-pyrlmidinon-1-yl)-benzimidazole Prepared analogously to Example lb from 2-n-butyl~ 4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-l-yl)-benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 80.4% of theory, Melting point: 124-126C
C37H38N404 (602.74) Calculated: C 73.73 H 6.35 N 9.30 Found:73.47 6.50 9.05 : - . . . .

:, , : ., , ': , ,, 2~73,~1 - 6~ -_ample 8 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-6-(N-cyclo-hexylaminocarbonyl-methylamlno~-benzimidazole a) 2-n-Bu-tyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-6-(N-cyclohexylaminocarbonyl-methylamino)-_ nzimidazole Prepared analogously to Example la from 2-n-butyl-6-(N-cyclohexylaminocarbonyl-methylamino)benzimidazole and 4-[(~-ethoxycarbonyl)-benzyloxy]benzylbromide and subsequent chromatographic separation of the 2-n-~utyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-5-(N-cyclohexylaminocarbonyl-methylamino)-benzimidazole.
Yield: 50.0% of theory, Oil, Rf value: 0.50 (silica gel; eluant: methylethyl ketone/xylene = 1:1) b) 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-6-(N-cvclohexylaminocarbonyl-methylamino)benzimidazole Prepared analogously to Example lb from 2-n-butyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-6-(N-cyclohexyl-aminocarbonylmethylamino)benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 93.0% of theory, Melting point: 168-169C
C34H40N4O4 (568.72) Calculated: C 71.81 H 7.09 N 9.85 Found: 71.78 7.02 9.71 Example g 2-n-Propyl-5-(2-methyl-propionylamino)-3-[4-[~-carboxy)benzyloxy]benzyl]imidazo[4,5-b~pyridine a) 2-n-Propyl-5-(2-methyl-propionylamino)-imidazo r 4,5-b]pyridine 2.62 g (15 mMol) of 2-n-propyl-5-amino-..
: , " ' ' , . .

2 ~

imidazo[4,5-b]pyri~ine are suspended in 100 ml of absolute methylene ~h]oride an~ 3.16 g (30 mMol) o~
isobutyric acid chloride are a~ded, with stirring an~
cooling with ice. Then, at -5 DC/ a solution of 3.03 g (30 mMol) of -triethylamine in 5 ml of methylene chlori~e is added dropwise. ~fter one hour at ambient temperature the reaction mixture is combined with loO ml o~ 2 N hydrochloric aci~ and the mixture is stirred for a further hour. ~hen the solut;ion is poured onto ice water and mixed with saturated sodium hydrogen carbonate solution. The aqueous phase is extracted 3 times with 100 ml of ethyl acetate, the combined organic phases are then washed with saline solution, dried over sodium sulphate and concentrated by evaporation. The crude product is taken up in methylene chloride and purified over a silica gel column (particle size 0.063-0.2 mm), using as eluant methylene chloride to begin with, followed by mixtures of methylene chloride and ethanol of increasin~ polarity (25:1 and 19:1). The unified fractions are concentrated by evaporation and the residue is triturated with petroleum ether/ether = 1:1 and suction filtered.
Yield: 2.05 g (56% of theory), Melting point: 206C
Cl3H18N40 (246.30) Calculated: C 63.39 H 7.37 N 22~.75 Found: 63.64 7~57 22.93 b) 2-n-Propyl-5-(2-methyl-propionylamino)-3-[4-[~-ethoxycarbonyl)benæyloxy]benzyl]imidazo[4,5-b]-pyridine Prepared analogously to Example la from 2-n-propyl-5-(2-methyl-propionylamino)imidazo[4,5-b]pyridine and 4-[(~-ethoxycarbonyl)benzyloxy]benzylbromide.
Yield: 33.7% of theory, Meltin~ point: 100-101C

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2 ~ 7 3 ,~

c) 2-n-Propyl-5-(2-methyl-propionylamino) 3-[~-[(~-carboxy)benz~ oxy1benzyll1midazo L4,5-~,~rldine_ Prep~red analogously to Example lb from 2-n-propyl-5-(2-methylpropionylamino)-3-[4-[(~-ethoxycarbonyl)-benzyloxy]benzyl~imidazo[4,5-b]pyridine ~nd l N sodium hydroxide solution in ethanol.
Yield: 52.0% of theory, Melting point: 134C
C28H30N4o4 (486-58) Calculated: C 69.12 H 6.21 N 11.51 Found: 69.03 6.11 11.36 Example 10 2-n-Butyl-5-valeroylamino-3-[4-[(~-carboxy)benzyloxy]-benzyl~imidazo[4,5-b]pyridine-semihydrate Prepared analogously to Example lb from 2-n-butyl-5-valeroylamino-3-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-imidazo[4,5-b]pyridine and l N sodium hydroxide solution in ethanol.
Yield: 57.0% of theory, Melting point: sinters from 96C
C30H34N4o4 x 0-5 H20 (532.65) Calculated: C 68.82 H 6.74 N 10.70 Found: 68.99 6.67 10.58 Example 11 2-n-Propyl-5 (l-methyl benzimidazol-2-yl)-7-methyl-3-[4-[(~-carboxy)benzyloxy]benzyl]imidazo[4,5-b]pyridine Prepared analogously to Example lb from 2-n-propyl-5-(1-methyl-benzimidazol-2-yl)-7~methyl-3-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl-imidazo~4,5-b]pyridine and 1 N sodium hydroxide solution in ethanol.
Yield: 41.4% of theory, Melting point: 242-244C

.
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2~73~3~ 1.

C33~l3~N5O3 (545-65) Calculated: C 72.6~ ~l 5.73 N 12.83 Found: 72.51 5.75 12.97 Example 12 2-n-Propyl-6~ methyl-benzimiclazol-2-yl)-4-methyl-1-[4-[(~-carboxy)benzyloxy]benzyl]benzimidazole Prepared analogously to Example! lb from 2-n-propyl-6-(1-methyl~benzimidazol-2-yl)-4-methyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]benzimidazole and 1 N
~`~ sodium hydroxide solution in ethanol.
Yield: 41.0% of theory, Melting point: amorphous C34H32N4O3 (544-66) Calculated: C 74.98 H 5.92 N 10.28 Found: 74.55 6.06 10.08 Mass spectrum: (M ~ H)~ = 545 Example 13 2-Methyl-4-[4'-[(~-carboxy)benzyloxy]benzyloxy]quinoline a) 2~Methyl-4-[4'-[(~-ethoxycarbonyl)benzyloxy]-^~ benzyloxy]quinoline Prepared analogously to Example la ~rom 4-hydroxy-quinaldine and 4-[(~-ethoxycarbonyl)benzyloxy]benzyl-bromide.
Yield: 19.8~ of theory, Oil, Rf value: 0.55 (silica gel; eluant: methylene chloride/ethanol = 19:1) b) 2-Methyl-4-[4'-[(~-carboxy)benzyloxy]benzyloxy]-quinoline Prepared analogously to Example lb from 2-methyl-4-[4'- .
[(~-ethoxycarbonyl)benzyloxy]benzyloxy-quinoline and 1 N
sodium hydroxide solution in ethanol.

., :', . ~ , :

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2~3~

~ 6~ -Yield: 66.6% of theory, Melting point: 142 143JC
C25H2lNO4 (399 50) Calculated: C 73.17 H 5.30 N 3.51 Found: 73.56 5.25 3.34 Mass spectrum: (M -~ H)~ = 400 _xample 14 2-n-Propyl-5-n-butyrylamino-3-[4-[(l-carboxy-3-methyl)-butyloxy]benzyl]imidaæo[4,5-b]E)yridine a) 2-n-Propyl-5-n-butyrylamino-3-[4-[(1-methoxycarbonyl-3-methyl)butyloxy]benzyl]imidazo[4,5-blpyridine _ _ Prepared analogously to Example la from 2-n-propyl-5-n-butyrylamino-imidazo[4,5-b]pyridine and 4-[(1-methoxycarbonyl-3-methyl)butyloxy]benzylbromide, with subsequent chromatographic separation of the 2-n-propyl-5-n-butyrylamino-1-[4-[(1-methoxycarbonyl-3-methyl)-butyloxy]benzyl]imidazo[4,5-b]pyridine.
Yield: 47.0% of theory, Oil, Rf value~ 0.30 (silica gel; eluant: methylene chloride/ethanol = 19:1) b) 2-n-Propyl-5-n-butyrylamino-3-[4~ carboxy-3-methyl)-butyloxy]benzyl~imidazo[4c5-b]pyridine Prepared analogously to Example lb from 2-n-propyl-5-n-butyrylamino-3-[4-(1-methoxycarbonyl-3-methyl)-butyloxy]benzyl]imidazo[4,5-b]pyridine and 1 N sodium hydroxide solution in ethanol.
Yield: 59~0% of theory, Melting point: 147-148C
C26H34N404 (466.59) Calculated:C 66.93H 7.35 N 12.01 Found: 66.69 7.48 11.85 ... .. . . . .

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Example 15 2-n-Butyl~1-[4-[(~-carboxy)cyclohexylmethyloxy]-benzyl]benzimidazole Prepared analogously to Example lb from 2-n-butyl-1-[4-[(~-methoxycarbonyl)cyclohexylmethyloxy]benzyl]-benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 92.0% of theory, Melting point: 208C (decomp.) C26H32~2O3 (420-56) Calculated: C 74.25 H 7 . 66 N 6.66 Found: 73.98 7.52 6.41 Example 16 2-n--Butyl-4-chloro-5-hydroxymethyl-1-[4-[(~-carboxy)-benzyloxy]benzyl]imidazole . . . _ . .
a) 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[4-[(~-methoxvcarbonyl)benzyloxylbenzyl]imidazole Prepared analogously to Example la from 2-n-butyl-4-chloro-5-hydroxymethyl-imidazole and 4-[(~-methoxycarbonyl)benzyloxy]benzylbromide, with subsequent chromatographic separation of the 2 n-butyl-5-chloro-4-hydroxymethyl-1-[4-[(~-methoxycarbonyl)benzyloxy]-benzyl]imidazole.
Yield: 21.0% of theory, Oil, Rf value: 0.70 (silica gel; eluant: methylene chloride/methanol = 6:1) b) 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[4-[(~-carboxy)-benzyloxy]benzyllimidazole-h,vdrochloride Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxymethyl-1-[4-[(Q-methoxycarbonyl)-benzyloxy]benzyl]imidazole and 1 N sodium hydroxide soIution in ethanol.

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Yield: 34.0% of theory, Melting point: 176~C
C23H2sClN20~, HCl (465.38) Calculated: C 59.36 H 5.63 N 6.02 Found: 59.53 5.43 5.97 Exam~le 17 2-n--Butyl-5-chloro-4-hydroxymelhyl-1-[4-[(1-carboxy-3-methyl)butyloxy]benzyl]imidazo:Le . . _ Prepared analogously to Example lb from 2-n-butyl=5-chloro-4-hydroxymethyl-1-[4-[(1-methoxycarbonyl-3 methyl)butyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 66.0% of theory, Melting point: 175-176'C
C2lH2sClN204 (408-93) Calculated: C 61.68 H 7.14 N 6.84 Found: 61.34 7.11 6.58 Example 18 2-n-Butyl-5-chloro-4-hydroxymethyl-1-[4-[(1-carboxy)-n-propyloxy]benzyl]imidazole _ Prepared analogously to Example lb from 2-n-butyl-5-chloro-4-hydroxymethyl-1-[4-[(1-methoxycarbonyl~-n-propyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 70.0% of theory, Melting point: 182-184C
C19H25ClN204(380-88) Calculated:C 59.91 H 6.61 N 7.35 Found:59v67 6.53 7.22 :
.
: ,:

2~73(~

Example 19 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[4-[(1-carboxy)-n-propyloxy]benzyl]imidazole Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxymethyl-1-[4-[(1-methoxycarbonyl)-n-propyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 66.0% of theory, Melting point: 125-127C
C19H2sClN2O,~ (380.88) Calculated: C 59.91 H 6.61 N 7.35 Found: 59.74 6.60 6.90 Example 20 2-n-Butyl-4-chloro-5-methoxymethyl-l-[4-[(~-carboxy)~
benzyloxy]benzyl]imidazole .
Prepared analogously to Example lb from 2-n-butyl-4-chIoro-5-methoxymethyl-1-[4-C(~-methoxycarbonyl)-benzyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 45.0% of theory, Melting point: 156-158C
C24H27ClN2o4 (4~2.95) Calculated: C 65.08 H 6.14 N 6.32 Found: 64.70 6.38 6.03 Example 21 2-n-Butyl-4-chloro 5-hydroxymethyl-1-[4-[(1-carboxy-3-methyl)butyloxy]benzyl]imidazole Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxy-methyl-1-[4-[(1-methoxycarbonyl-3-methyl)butyloxy]benzyl]imidazole and 1 N sodium . - . .
- : , - :

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2~7~

hydroxicle solution in ethanol.
Yield: 57.0% of theory, Melting point: 16~-165~C
C2lH2~ClN20~, (408.93) Calculated: C 61.68 H 7.14 N 6.84 Found: 61.63 7.09 6.71 Example 22 2-n-Butyl-4-hydroxymethyl-5-chloro-1-[4-[(~-carboxy)-benzyloxy]benzyl]imidazole .. . . . _ ..
Prepared analogously to Example lh from 2-n-butyl~4-hydroxymethyl-5-chloro-1-[4-[(~-me-thoxycarbollyl)-benzyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 18.0% of theory, Melting point: 193C
C23H2sClN20~ (428.92) Rf value: 0.10 (silica gel; eluanto methylene chloride/methanol = 9:1) Mass spectrum: ~M + H)+ = 394/396 (Cl) Example 23 2-n-Butyl-5-chloro-4-hydroxymethyl-1-[4-[(1-carboxy)-n-~utyloxy]benzyl]imidazole .... _ .
Prepared analogously to Example lb from 2-n-butyl-5-chloro-4-hydroxymethyl-1-[4-[(1-methoxycarbonyl)-n-butyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 27.0% of theory, Melting point: 154C
CzoHz7ClN204 (394 90) Rf value: 0.20-0.30 (silica gel; eluant: methylene chlori~e/methanol = 9:1) Mass spectrum: (M + H)~ = 394/396 (Cl) , ' : ' ~73~

Example 24 2-n-Butyl-4-hydroxymethyl-5-chloro-1-[4-[(~-carboxy)-p-phenyl-benzyloxy]benzyl]imidazole Prepared analogously to Example lb from 2-n-bu-tyl-4-hydroxymethyl-5-chloro-1-[4-[(~-methoxycarbonyl)-p-phenyl-benzyloxy]benzyl]imidazole and 1 N sodiu~
hydroxide solution in ethanol.
Yield: 72.0% of theory, Melting point: 182~C
C29H29ClN20~, (505.02) Calculated: C 68.97 H 5.78 N 5.54 Found: 68.50 5.83 5.46 Example 25 2-n--Butyl-4-chloro-5-hydroxyme-thyl-1-[4-[(a-carboxy)-p-phenyl-benzyloxy]benzyl]imidazole .
Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxymethyl-1-[4-[(~-methoxycarbonyl)-p-phenyl-benzyloxy3benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 75.0% of theory, Melting point: 185-186C (decomp.) C29H29ClN2O4 (505.02) Calculated: C 68.97 H 5.78 N 5.54 Found: 68.87 5.80 5.42 Example 26 2-n-Butyl-4-hydroxymethyl-5-chloro-1-[4-[(~-carboxy)-2-naphthylmethyloxy]benzyl]imidazole-semihydrate . . _ Prepared analogously to Example lb from 2-n-butyl-4-hydroxymethyl-5-chloro-1-[4-[(~-methoxycarbonyl)-2-naphthylmethyloxy]benzyl]imidazole and 1 N sodium .,: . .

: '. , - '~ ' ' ' 2 ~ 7 .~

hydroxide sollltion in ethanol.
Yield: 69.0% of theory, Melting point: from 188UC (decomp.) C27H27clN2o4 x 0-5 H20 (487 Calculated: C 66.~5 H 5.78 ~ 5.74 Found: 66.63 5.66 5.75 Example 27 2-n-Butyl-4-chloro-5-hydroxymet:hyl-1-[4-[(~-carboxy)-2-naphthylmethyloxy]benzyl]imidazole-semihydrate Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxymethyl-1-[~-[(~-methoxycarbonyl)-2-naphthylmethyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 82.0% of theory, Melting point: from 142C (decomp.) C27H27ClN204 x 0.5 H20 (487.99) Calculated: C 66.45 H 5.78 N 5.74 Found: 66.62 5.66 6.12 Example 28 2-n-Butyl-4 hydroxymethyl-5-chloro-1-[4-[(~-carboxy)-1-naphthylmethyloxy]benzyl]imidazole-hydrate Prepared analogously to Example lb from 2-n-butyl-4-hydroxymethyl-5-chloro-1-[4-[(~-methoxycarbonyl)-1-naphthylmethyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 91.0% of theory, Melting point: from 110C (decomp.) C27H27ClN204 x H20 (497-00) Calculated: C 65.25 H 5.88 N 5.63 Found: 65.58 5.89 5.83 .,. . : . .. .

2~3g~

Example 29 2-n-Butyl-4-chloro-5-hydroxymethyl-1-~4-[(~-carboxy)-1-naphthylmethyloxy]benzyl]imidazole-hydrate . . _ . . _ . . .
Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxymethyl-1-[4-[(~-methoxycarbonyl)-1-naphthylmethyloxy]benzyl~imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 42.0% of theory, Melting point: rrom 100C (decomp.) C27H27ClN2o4 x H2O (497.00) Calculated: C 65.25 H 5.88 N 5.63 Found: 65.21 5.70 6.10 Example 30 2-n~Butyl-4-chloro-5-hydroxymethyl-1- L 4-[(~-carboxy)-p-methoxy-benzyloxy]benzyl]imidazole Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxymethyl-1-[4-[(~-methoxycarbonyl)-p-methoxy-benzyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 58.0% of theory, Melting point: 165C
C24H27ClN2Os (458.95) Calculated: C 62.81 H 5.93 N 6.10 Found: 62.69 6.02 5.g3 Example 31 2-n-Butyl~4-chloro-5-methoxymethyl-1-[4-[(1-carboxy)-n-pentyloxy]benzyl]imidazole _ _ Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-methoxymethyl-1-[4~ methoxycarbonyl~-n-pentyloxy]benzyl]imidazole and 1 N sodium hydroxide -:

, .

~3~3~

solution in ethanol.
Yield: 84.0% of theory, Melting point: ~6~C
Cz2H3lClN2O4 (422-96) Calculated: C 62.45 H 7.38 N 6.62 Found: 62.23 7.47 6.79 Example 32 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[4-[(1-carboxy)-n-butyloxy]benzyl]imidazole Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxymethyl--1-[4-[(1-methoxycarbonyl)-n-butyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 50.0% of theory, Melting point: 137-138C
C20H27ClN24 (394 90) Calculated: C 60.83 H 6.89 N 7.09 Found: 60.67 6.94 6.67 Example 33 2 n-Butyl-4-chloro-5-hydroxymethyl-1-[4-[(1-carboxy)-n-pentyloxy]benzyl]imida~ole . .
Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxymethyl-1-[4-[(1-methoxycarbonyl)-n-pentyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 61.0% of theory, Melting point: 150C
C21H29ClN2O4 t408-93) Calculated: C 61.65 H 7.14 N 6.85 Found: 62.31 6.85 7.21 .:
. ~ ,~' :

.

2~73~

Example 2-n-sutyl-4-hydroxymethyl-5-chloro-l-[4-[(l-carboxy)-n pentyloxy]benzyl]imidazole Prepared analogously to Example lb from 2-n-butyl-4-hydroxymethyl-5-chloro-1-[4-[(1-methoxycarbonyl)-n-pentyloxy]benzyl]imidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 57.0% of theory, Melting point: 168C
C21Hz9ClN2O4 (408.93) Calculated: C 61.65 H 7.14 N 6.85 Found: 61.59 7.11 6.91 Example 35 2-n-Bu-tyl-8-methyl-3-[4-[~-carboxy)benzyloxy]benzyl]-quinazolin-4-one-semihydrate a) 2-n-Butyl-8-methyl-3-[4-[(~-ethoxycarbonyl)-benzyloxy]benzyl]quinazolin-4-one Prepared analogously to Example la from 2-n-butyl-8-methyl-quinazolin-4(lH)-one and 4-(~-ethoxycarbonyl-benzyloxy)benzylbromide.
Yield: 37% of theory, Oil~ Rf value: 0.45 (silica gel; eluant: petroleum ether/ethyl acetate = 4:1) b) 2-n-Butyl-8-methyl-3-[4-[(~-carboxy)benzyloxy]-benzyl]quinazolin-4-one-semihydrate . _ _ Prepared analogously to Example lb from 2-n-butyl-8-methyl-3-[(~-ethoxycarbonyl)benzyloxy]benzyl]-quinazolin-4-one and lN sodium hydroxide solution in ethanol.
Yield: 84% of theory, Melting point: 201-204C

... . . . .
.
: : :
~ , , ~73~3~

C2s~2~N2O~ x 0-5 H2O (~65.56) Calculated: C 72.2~ H 6.28 N 6.02 Found: 72.4~ 6.33 5.75 Example 36 2-n-Butyl-4-chloro-5-hydroxymethyl~1-[~[(1-carboxy-2-cyclohexyl)ethoxy]benzyl]imidazole Prepared analogously to Example lb from 2-n-butyl-4-chloro-5-hydroxymethyl-1-[4-[(1-methoxycarbonyl-2-cyclohexyl)ethoxy]benzyl]imidazole and lN sodium ~
hydroxide solution in ethanol.
Yield: 67.1% of theory, Melting point: 145-150C
C24H33clN2O4 (448.96) Calculated: C 64.20 H 7.40 N 6.24 Found: 63.97 7.38 6.01 Example 37 2-n-Butyl~4-hydroxymethyl-5-chloro-1-[4-[(1-carboxy-2-cyclohexyl)ethoxy]benzyl]imidazole Prepared analogously to Example lb from 2-n-butyl-4-hydroxymethyl-5-chloro-1-[4~[(1-methoxycarbonyl-2-cyclohexyl)ethoxy]benzyl]imidazole and lN sodium hydroxide solution in ethanol.
Yield: 59.1% of theory, Melting point: 180-183C
C24H33ClN2O4 (448.96) Calculated: C 64.20 H 7.40 N 6.24 Found: 63.99 7.20 6.27 Mass spectrum: m/e = 448/450 (Cl) : - .

. .
:

- 79 - 2~3~
Example 3~

2-n-Butyl-l-[~-[(l-c~rboxy-3-methyl)butyloxy]benæyl]-benzimidazole Prepared analogously to Example lb from 2-n-butyl-1-[4-[(l-methoxycarbonyl-3-methyl)butyloxy]benzyl]-benzimidazole and 1 N sodium hydroxide solution in ethanol. ~
Yield: 82.3% of theory, Melting point: 150-152JC
C24~3~N2O3 (394.52) Calculated: C 73.07 H 7.66 N 7.10 Found: 72.83 7.37 7.14 Mass spectrum: m/e = 394 Example 39 2-n-Butyl-1-[4-[(1-carboxy-2-cyclohexyl)ethoxy]benzyl]-benzimidazole Prepared analogously to Example lb from 2-n-butyl-1~[4-[(1-methoxycarbonyl-2-cyclohexyl)ethoxy]benzyl]-benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 82.0% of theory, Melting point: 165-170C
C27EI34N2O3 (434.58) Calculated: C 74.63 H 7.88 N 6.44 Found~ 74.46 7.77 6.30 Mass spectrum: m/e = 434 Example 40 .
2-n-Butyl-6-propionylamino-1-[4-[(1-carboxy-3-methyl)-butyloxy]benzyl]benzimidazole Prepared analogously to Example lb from 2-n-butyl-6-:;

.

: :

2~7~
-- ~o --propionylamino-1-[4 [(1-methoxycarbonyl-3-methyl)-butyloxy]benzyl]benzim:idazole and L N sodium hydroY.ide solution in e-thanol.
Yield: 80.3% of theory, Melting point: 120-130C
C27~3sN304 (465.59) Calculated: C 69.65 H 7.58 N 9.02 Found: 69.30 7.8~ 8.83 Mass spectrum: m/e = 465 Example 41 2-n-Butyl-5-propionylamino-1-[4-[(1-carboxy-3-methyl)-butyloxy]benzyl]benzimidazole-semihydrate . _ _ _ _ Prepared analogously to Example lb from 2-n-butyl-5-propionylamino-1-[4-[(1-methoxycarbonyl-3-methyl)~
butyloxy]benzyl]benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 82.9% of theory, Melting point: 165-170C
C27H35N3O4 x 0.5 H2O (474 Calculated: C 68.32 H 7.64 N 8.85 Found: 68.63 7.72 8.90 - ~
Example 42 2-n-Butyl-6-cyclohexylaminocarbonylamino-1-[4-[(1-carboxy-3-methyl)butyloxy]benzyl]benzimidazole _ Prepared analogously to Example lb from 2-n-butyl-6-cyclohexylaminocarbonylamino-1-[4-[11-methoxycarbonyl-3-methyl)butyloxy]benzyl]benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 90.8% of theory, Melting point: 155-160C
C3lH42N4o4 (534-71) Calculated: C 69.64 H 7.9~ N 10.48 . ~

~ 0 73 Found: 69.58 ~.03 10.36 Mass spectrum: (M + H)+ - 535 Example 43 2-n-Butyl-5-cyclohexylaminocarbonylamino-1-[4-[(1-carboxy-3-methyl)butyloxy]benzyl]benzimidazole -Prepared analogously to Example lb from 2-n-bu~yl-5-cyclohexylaminocarbonylamino-1-[4-[tl-methoxycarbonyl-3-methyl)butyloxy]benzyl~benzimiclazole and 1 N sodium hydro~ide solution in ethanol.
Yield: 95.7% o~ theory, Melting point: 220-225C
c31H42N44 (534-71) Calculated: C 69.64 H 7.92 N 10.48 Found: 69.49 7.99 10.52 Mass spectrum: (M-tH)+ = 535 Example 44 2-n-Butyl-6-(N-propionyl-methylamino)-1-[4-[tl-carboxy-3-methyl)butyloxy]benzyl]benzimidazole Prepared analogously to Example lb from 2-n-butyl-6-(N-propionylmethylamino)-1-[~-[(1-methoxycarbonyl-3-methyl)butyloxy]benzyl]benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 66.8% of theory, Melting point: 170-175C
C28H37N304 (47g.63) Calculated: C 70.12 H 7.78 N 8.76 Found: 70.35 7.85 8.91 ;

. ~ . - . ~ , 2 ~

-~ 82 -Examp~e fi5 2-n-Butyl-5-(N-propionyl-methylamino)-1-[4-[(]-carboxy-3-methyl)butyloxy]benzyl]benzimidazole . _ _ .. . .
Prepared analogously to Example lb from 2-n-butyl-5-(N
propionylmethylamino)-l-[4-[(1--methoxycarbonyl-3-methyl)butyloxy]benzyl]benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 62.0% of theory, Melting point: 172-175~C
C2sH37N3O4 (479.63) Calculated: C 70.12 H 7.78 M 8.76 Found: -~0.11 7.80 8.63 Mass spectrum: m/e = 479 Example 46 2-n-Butyl-6-(N-cyclohexylaminocarbonyl-methylamino)-l-[4-[(1-carboxy-3-methyl)butyloxy]benzyl]benzimidazole Prepared analogously to Example lb from 2-n-butyl-6-(N-cyclohexylaminocarbonyl-methylamino)-l-[4-[(1-methoxycarbonyl-3-methyl)butyloxy]benzyl]benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 76.1% of theory, Melting point: 170-175C
C32H44N4O4 (548.73) Calculated: C 70.04 H 8.08 N 10.21 Found: 69.95 8.10 10.22 Example 47 2-n-Butyl-5-(N-cyclohexylaminocarbonyl-methylamino)-l-[4-[(1-carboxy-3-methyl)butyloxy]benzyl]benzimidazole . _ Prepared analogously to Example lb from 2-n-butyl-5-(N-cyclohexylaminocarbonyl-methylamino)-l-[4-[(1-.
' . : .

:~
, : , . :`

2 ~

- ~3 -methoxycarbonyl-3-methyl)butyloxy]benzyl]benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 72.9% of theory, Melting point: 178-1~2C
C32H44N4O4 (548.73) Calculated: C 70.04 H 8.08 N 10.21 Found: 69.77 7.97 10.04 Mass spectrum: m/e = 548 Example 48 2-n-Butyl-3-[4-[(~-carboxy)benzyloxy]benzyl]-5-methyl-6-dimethylaminocarbonylamino-imidazo[4,5-b]pyridine Prepared analogously to Example lb from 2-n-butyl-3-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-5-methyl-6-dimethylaminocarbonylamino-imidazo[4,5-b3pyridine and 2 N sodium hydroxide solution in ethanol.
Yield: 80.0% of theory, Melting point: 191-193C
C29H33N5O4 (515.62) Calculated: C 67.55 H 6.45 N 13.58 Found: 67.49 6.62 13.57 Example 49 2-n-Butyl-3-~4-[(~~carboxy)benzyloxy]benzyl] 5-methyl-6-~3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-imidazo[4,5-b]pyridine Prepared analogously to Example lb from 2-n-butyl-3-[4-[(~-ethoxycarbonyl)benzyloxy]henzyl]-5-methyl-6-(3-ben7yl-3,4,5,6-tetrahydro-2(lH) pyrimidinon~l-yl)-imidazo[4,5-b]pyridine and 2 N sodium hydroxide solution in ethanol.
Yield 87.5% of theory, Melting point: 157-160C
C37H3gN504 (617.75) . - ,. . . . ..
' ' ., ' . ...

~73~
- n4 -Calculated: C 71.9~ H 6.36 N 11.3~
Found: 71.71 6.3610.96 Example 50 2-n-Butyl-6-(N-methylaminocarbonyl-n-pentylamino)-1-[4-[(~-carboxy)benzyloxy]benzyl]benzimidazole -Prepared analogously to Example lb from 2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino)-1-[4-[((x-methoxycarbonyl)benzyloxy]benzyl~benzimidazole and 1 N
sodium hydroxide solution in ethanol.
Yie]d: 76.0% of theory, Melting point: 170-172C
C33H40N~O4 t556-71) Calculated: C 71.20 H 7.2a N10.07 Found: 70.80 7.34 9.96 Example 51 2-n-Butyl-6 (N-cyclohexylaminocarbonyl-n-pentylamino)-l-[4-[(~-carboxy)benzyloxy]benzyl]benzimidazole .
Prepared analogously to Example lb from 2-n-butyl-6-(N-cyclohexylaminocarbonyl-n-pentylamino)-1-[4-[(~-methoxycarbonyl)benzyloxy]benzyl]benzimidazole and 1 N
sodium hydroxide solution in ethanol.
Yield: 65.0% of theory, Melting point: 83C
C38H48N4o4 (624-83) Calculated: C 73.05 H 7.74 N 8.97 Found:72.80 7.51 8.59 : . . . ~ .

:
.

- ~5 -Example 52 2-n-Butyl-4-hydroxymethy],-5-ch'Loro-1-[4-[(~-carboxy-~-phenyl)benzyloxy]benzyl]benzim:idaæole Prepared analogously to Example lb from 2-n-butyl-4-hydroxymethyl-5-chloro-l-[4-[(c~-methoxycarbonyl-~-phenyl)benzyloxy]benzyl]benzimidazole and 7 N sodium hydroxide solution in ethanol.
Yield: 50.0% of theory, Melting point: 165~C (decomp.) Cz9H29ClN204 (505-02) Calculated: C 68.97 H 5.79 N 5.55 Found: 68.50 5.72 5.51 Example 53 2-n-Butyl-6-(p-methyl--phenylsulphonylamino)-1-[4-[(~-carboxy)benzyloxy]benzyl]benzimidazole Prepared analogously to Example lb from 2-n-butyl-6-(p-methyl-phenylsulphonylamino)-1-[4-[(~-methoxycarbonyl)-benzyloxy]benzyl]benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 81.0% of theory, Melting point: 150C
C33H33N30sS (583.71~
Calculated: C 67.90 H 5.70 N ~.20 Found: 67.18 5.70 6.96 Example 54 2-n-Butyl-6-~N-methyl-p-methyl-phenylsulphonylamino)-1-[4-[(Q-carboxy)benzyloxy]benzyl]benzimidazole _ _ Prepared analogously to Example lb from 2-n-butyl-6-(N-methyl-p-methyl-phenylsulphonylamino)-1-[4-[(~-methoxycarbonyl)-benzyloxy]benzyl]benzimidazole and 1 N

2~3~ ~
- ~6 -sodium hydroxide solution in ethanol.
Yield: 96.0% of -theory, Melting point: 218C
C34H3sN3sS (597.71) Calculated: c 68.32 H 5.90 N 7.03 Found: 67.82 5.84 6.85 Example 55 2-n-Butyl-6-(N-n-pentyl-p-methyl-phenylsulphonylamino)-1-[4-[(~-carboxy)henzyloxy]benzyl]benzimidazole Prepared analogously to Example lb from 2-n-butyl-6-(N-n-pentyl-p-methyl-phenylsulphonylamino)-l-[4-[(~-methoxycarbonyl)-benzyloxy]benzyl]benzimidazole and 1 N
sodium hydroxide solution in ethanol.
Yield: 94.0% of theory, Melting point: 202~C
C3sH43N3sS (653.81) Calculated: C 69.80 H 6.63 N 6.43 Found: 69.47 6.57 6.64 Example 56 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]-(~-methyl)-.~, benzyl]-benzimidazole a) 4-[(~-Ethoxycarbonyl~benzyloxylacetophenone Prepared analogously to Example la from ethyl 2-bromo-phenylacetate and 4-hydroxyacetophenone.
Yield: 78.0% of theory, Rf value: 0.58 (silica gel; eluant: toluene/ethyl acetate = 85:15) b) 1-[4-[(~-Ethoxycarbonyl)benzyloxylphen~llethanol 2.3 g (7.7 mMol) of 4-[(~-ethoxycarbonyl)benzyloxy]-acetophenone are dissolved in 50 ml of ethanol and at ambient temperature 0.28 g (7.7 mMol) of sodium , ~ ~ .

, '.. ' : ' ' '~
. ~ : - . .

.' .
. .

2 ~ r~

borohydride are ad~ed thereto in batches. The react;on mixture is stirred at ~0~C for 2 hours. After cooling to ambient temperature it is concentrated by evaporation and the residue is mixed with water arld dilute hydrochloric acid. After extraction with ethyl acetate the organic phase is drie~ with sodium sulphate. The solution is evaporated down and the residue is chromatographed over a silica gel column (particle size:
0.063-0.02 mm) using toluene/ethyl acetate (7:3). The uniform fractions are combined and evaporated down.
Yield: 1.0 g (~3% of theory), Oil, Rf value: 0.50 (silica gel; eluant: toluene/ethyl acetate = 7:3) c) l-[~-[(~-Ethoxycarbonyl)benzyloxy]phenyl]-1-ethanesulphonyloxyethane _ _ 0.5 g (1.7 mMol) of l-[~-[(~-ethoxycarbonyl)benzyloxyJ-phenyl]ethanol and 0.22 g (2.2 mMol) of triethylamine are dissolved in 10 ml of methylene chloride. At 5C, 0.23 g (2.0 mMol) of mesyl chloride are added dropwise with stirring. After one hour at ambient temperature the reaction mixture is poured onto ice water, extracted with methylene chloride and dried over sodium sulphate.
The crude product obtained is reacted directly without any further purification.

d) 2-n-Butyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]-(~
methyl)benzyl]benzimidazole A mixture of 0.26 g ~1.5 mMol) of 2-n-butyl-benzimidazolel 3 ml (1.7 mMol) of triethylamine and 1-[4-[(~-ethoxycarbonyl)benzyloxy]phenyl]-1-methanesulphonyloxyethane (crude) is heated to 80C for 30 minutes. After cooling, water is added and the mixture is extracted twice with ethyl acetate. The organic phases are combined, dried and evaporated down.
The crude product is chromatographed over a silica gel column (particle size: 0.063-0.02 mm) with toluene/ethyl , : ' ' ' ' ~ ' . ~ :
;i - , ' `~ :

2073~ 1 acetate (~:2). The uniform fractions are combi.ned and evaporated down.
Yield: O.lo g (15% of theory), Rf value: 0.35 (silica gel; eluant: to:Luene/ethyl acetate - 8:2) e) 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]-(~-methyl)-benzylJbenzimidazole Prepared analogously to Example lb from 2-n-butyl-1-[4-[(~-ethoxycarbonyl~benzyloxy]-(~-methyl)benzy].]-benzimidazole and l N sodium hydroxide solution in ethanol.
Yield: 82% of theory, Melting point: 109C
C27H28N2o3 (4~8.51) Calculated: C 75.67 H 6.59 N 6.54 Found: 75.93 6.76 6.32 Example 57 2-n-Butyl-1- E 4-[~ (lH-tetrazol-5-yl)benzyloxy]benzyl]-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)pyrimidinon-l-yl)-benzimidazole a) ~
Prepared from benzylcyanide and sodium azide/ammonium chloride in dimethylformamide.
Yield: 70% of theory, Melting point: 130-132C

b) N-Triphenylmethyl-5-benzyl-tetrazole Prepared from 5-benzyl-lH-tetrazole and triphenylmethyl-chloride.
Yield: 84% of theory, Melting point: 158-160C

c) N-TriPhenylmethyl-5-f -bromo)benzyl-tetrazole 2.0 g (5 mMol) of N-triphenylmethyl-5-benæyl-tetrazole, : :
~, ; : ~ :

, -. . . ,, .... :

:: :

2~73~ 1 _ ~9 _ 0.89 g (5 mMol) of N-bromosuccinimide and 30 mg of azo-bisisobutyronitrile are dissolved in 25 ml of carbon tetrachloride and heated to boiling for one hour under UV-irradiation. After cooling~ -the succinimide formed is filtered off and the filtrate is evaporated down.
Yield: 74.6% of theory, Melting point: 160-162C

d) 2-n-Butyl-1-[(4-benzyloxy)benzyl]-6-(3-benzyl-3,~,5,6-tetrahydro-2(lH)pyrimidinon-1-yl)-benzimi__zole _ Prepared analogously to Example la from 2-n-butyl-6-(3-benzyl-3,~,5,6-tetrahydro-2(lH)pyrimidinon~1-yl)-benzimidazole and ~-benzyloxybenzyl chloride.
Yield: 65.5% of theory, Rf value: 0.45 (silica gel; eluant: methylene chloride/ethanol = 19:1) e) 2-n-Butyl-1-[(4-hydroxy)benzyl]-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-benzimidazole 2.4 g of 2-n-butyl-1-[(4-benzyloxy)benzyl]-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-1-yl)-benzimidazole are dissolved in 100 ml of ethanol and 30 ml of dimethylformamide, mixed with 2.4 g of (10%) palladium on activat~d charcoal and hydrogenated with 5 bars of hydrogen at ambient temperature. The catalyst is filtered off, the filtrate is evaporated down and the residue is chromatographed over a silica gel column (particle size: 0.063-0.02 mm) with methylene chloride/ethanol. The uniform fractions are combined and evaporated down and the residue is triturated with ether and suction filtered.
Yield: 1.1 g (55% of theory), Melting point: 190-191C

. . .

.. ..
-' 2073~

f) ~-n-Butyl-l-[~-[(~-(N-triphenylmethyl~tetrazol-5-yl) benzyloxy]benzyl]-6-(3-benzyl-3,~,5,6-tetrahydro-2(1~l)pyrimidinon-1-yl)-ben~lmidazole _ __ O.5 g (1.1 mMol) of 2-n-butyl-1-[(4-hydroxy)benzyl]-6-(3-benzyl-3,4,5,6-tetrahydro-2(1ll)pyrimidinon-1-yl)-benzimidazole, 0.74 g (5.4 mMol) of potassium carbonate and 0.93 g (1.1 mMol) of N-triphenylmethyl-5-[(~-bromo)-benzyl]tetrazole are dissolved in 10 ml of dimethylsulphoxide and stirred for 2 hours at ambient temp~rature. The product is precipitated by the addition of saline solution, suction filtered, washed with water and dried.
Yield: 0.9 g (97~ of theory), Melting point: from 150C (decomp.) g) 2-n-Butyl-1-[4-[~-(lH-tetrazol-5-yl)benzyloxy]-benzyl]-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-~yrimidinon-1-yl)-benzimidazole O.9 g (1.0 mMol) of 2-n-butyl-1-[4-[(~-N-triphenyl-methyl)tetrazol-5-yl)benzyloxy]benzyl]-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)pyrimidinon-1-yl)-benzimidazole are dissolved in 40 ml of ethanol, 10 ml of methylene chloride and 12 ml of 4N hydrochloric acid and stirred for 2 hours at ambient temperature. After the addition of 30 ml of water, the mixture is extracted with methylene chloride. The organic phase is washed with lN
sodium hydroxide solution, acidified with dilute acetic acid and dried over sodium sulphate. The crude product is chromatographed over a silica gel column (particle size: 0.063-0.02 mm) with methylene chloride/ethanol (50:1 and 19:1). The unified fractions are combined and evaporated down.
Yield: 0.22 g (34~ of theory), Melting point: from 134C (decomp.) C37H38N8o2 (626-76) Calculated:C 70.90 H 6.11 N 17.88 Found:70.72 6.00 17.68 , . .. . . .

:
,~ ' .

2~73~ ~

Example 58 2-n-Propyl-4-methyl-1-[4-[~-(lH-tetrazol-5-yl)benzyloxy]benzyl]benzimidazole a) 2-n-Propyl-~methyl-1-[4-[~-((N-triphenylmethyl)-tetrazol-5-yl)benzy]oxy]benzY11benzimidazole Prepared analogously to Example 57~ from 2-n-propyl-4-methyl-l-[t4-hydroxy)benzyl]benzimidazole and N~
triphenylmethyl-5-[(~-bromo)benzyl]tetrazole.
Yield: 99% of theory, Rf value: 0.68 (silica gel; eluant: methylene chloride/methanol = 19:1) b) 2-n-Propyl-4-methyl-1-[4-[~-(lH-tetrazol-5-yl)-benzyloxy]benzyl] enzimidazole Prepared analogously to Example 57g from 2-n-propyl-4~
methyl-l-[4-[~-((N-triphenylmethyl)tetrazol-5-yl)-benzyloxy]benzyl]benzimidazole and methanolic hydrochloric acid.
Yield: 63% of theory, Melting point: amorphous C26H26N6 (438.54) Calculated: C 71.21 H 5.98 N 19.17 Found: 70.99 5.98 18.96 Example 59 2-n-Propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-[4-[~-~lH-tetrazol-5-yl)benzyloxy]benzyl]benzimidazole _ .
a) 2-n-Propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl) 1-[4-[~-((N-triphenylmethyl)tetrazol-5-yl3benzyloxy]-benzyl]benzimidazole Prepared analogously to Example 57f from 2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-[(4-hydroxy)-benzyl]benzimidazole (synthesised analogously to Examples 58d and 58e) and N-triphenylmethyl-5-(~ bromo)-.' ` ~
! . ' , `` ' ' `~ ' " , ' .', '. ' 2~73~

benzyl--tetrazole.
Yield: 94% of theory, f value: 0.70 (silica gel; eluant: methylene chloride/~ethanol = 9:1) b) 2-n-Propyl 4-methyl-6-(1-methyl-benzimidazol-2-yl)-l-[4-[~-(lH-tetrazol-5-yl)benzyloxy]benzyl]-benzimidazole . . .
Prepared analogously to Example 57g from 2-n-propyl-~-methyl-6-(1-methyl~benzimidazol-2-yl)~ 4-[~-((N-triphenylmethyl)-tetrazol-5-yl)benzyloxy]benzyl]-benzimidazole and methanolic hydrochloric acid.
Yield: 62% of theory, Melting point: 165-166'C
C3~H32Ns (568.69) Calculated: C 71.81 H 5.67 N 19.71 Found: 71.68 5.60 19.55 Example 60 2-n-Propyl-5~n-butyrylamino-3-[4-~(1-(lH-tetrazol-5-yl)-3-methyl)butyloxy]benzyl]imidazo[4,5-b]pyridine _ .
a) 2-n-Propyl-5-n-butyrylamino-3-[4-[(1-cyano-3~methyl)-butyloxy]benzyllimidazo[4 5-blpyridine Prepared analogously to Example 57f from 2-n-propyl-5-n-butyrylamino-3-[(4-hydroxy)benzyl]imidazo[4,5-b]-pyridine and 2-bromo-4-methyl-valeronitrile.
Yield: 85% of theory, Rf value: 0.40 (silica gel; eluant: ethyl acetate/petroleum ether = 1:1) b) 2-n-Propyl-5-n-butyrylamino-3-[4-[(1-(lH-tetrazol-5-yl)-3-methyl)butyloxy]benzyllimidazor4.5-blpyridine A mixture of 800 mg (1.78 mMol) of 2-n-propyl-5-n-butyrylamino-3-[4-[(l-cyano-3-methyl)butyloxy)benzyl]-imidazo[4,5-b]pyridi.ne, 2.2 g (3.3 mMol) of sodium azide and 1.8 g (3.3 mMol) of ammonium chloride in 8 ml of - -:.

2~3~

dimethylformamide is s-tirred for 5 hours at î30c with stirring. It is then stirrecl into ice water, the product precipitated is suction filtered, washed with water, dried and purified over a silica yel column (methylene chloride/ethanol = 19:1). The fractions containing the desired substance are evaporated down, the residue obtained is triturated with ether, suction filtered and dried. When the purification step described above is repeated, 370 mg (42% of theory) of the product are obtained, m.p. 175-177C.
C26H34N~o2 (490-61) Calculated: C 63O65 l-l 6.99 N 22.84 Found: 63.61 7.03 22.83 Example 61 2-n-Butyl-4-hydroxymethyl-5-chloro-1-[4-[1-(lH-tetrazol-5-yl)propyloxy]benzyl]benzimidazole sesqui-hydrochloride Prepared analogously to Example 60b from 2-n-butyl-4-hydroxymethyl-5-chloro-1-[4-(1-cyano-propyloxy)benzyl]-imidazole and sodium azide/ammonium chloride in dimethylformamide.
Yield: 78% of theory, Oil, C~9H2sClN602 x 1.5 HCl (459.59) Calculated: C 49.65 H 5.81 N 18.28 Found: 49.41 6.03 18.52 Example 62 2-n-Butyl -5-hydroxymethyl-4-chloro-1-[4-[1-(lH-tetrazol-5-yl)propyloxy]benzyl]benzimidazole sesqui-hydrochloride Prepared analogously to Example 60b from 2-n-butyl-5-hydroxymethyl-4-chloro-1-[4-(1-cyano-propyloxy)benzyl]-imidazole and sodium azide/ammonium chloride in dimethylformamide.
Yield: 70% of theory, , . . . .

, .

2~73~1 9~ -Oil, C~9H2sClN6O2 x 1.5 HC~ (459.59) Calculated: C 49.65 H 5.81 N L8.28 Found: 49.86 5.76 18.26 Example 63 2-n-Butyl-1-[4 [(~-carboxy)benzylamino]benzyl]-benzimidazole semihydrate a) 2-n-Butyl-1-[4-[(Q-ethoxycarbonyl)benzylamino]-benzvl~benzimidazole 1.0 g (3.6 mMol) of 2-n-butyl-1-[(4-amino)benzyl]-benzimidazole, 0.87 g (3.6 mMol) of ethyl 2-bromo-phe.nylacetate and 0.5 g of sodium acetate-trihydrate are dissolved in 20 ml of ethanol and stirred for 18 hours at ambient temperature. Then the reaction mixture is refluxed for a further 4 hours. The solvent is evaporated down, water is added to the residue which is made alkaline with dilute ammonia solution and extracted with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate and concentrated by evaporation. The residue is purified over a silica gel column (particle size: 0.063-0.02 mm), using petroleum ether with 10-15~ ethyl acetate as eluant. The uniform fractions are combined and evaporated down.
Yield: 1.0 g (63% of theory), Rf value. 0.53 (silica gel; eluant: petroleum ether/ethyl acetate = 3:1) b) 2-n-Butyl-l- E 4 - E (Q-carboxy)benzylamino]benzyl]-benzimidazole semihydrate Prepared analogously to Example lb from 2-n-butyl-1-[4-[(Q-ethoxycarbonyl)henzylamino]benzyl]benzimidazole and lN sodium hydroxide solution in ethanol.
Yield: 99% of theory, C26H27N3O2 x 0-5 HzO (422.54) Calculated: C 73.91 H 6.68 N 9.95 :

2~3c~

Eound: 7~.05 6.55 9.91 Exam~le 6~

2-n-Butyl-1-[4-[(~-carboxy)-N-acetyl-benzylaminoJ
benzyl]benzimidazole a) 2-n-Butyl-1-[4-[(~-ethoxycarbonyl)-N-acetyl-benzylamino~benzylJbenzimidazole O.5 g (1.1 mMol) of 2-n-butyl-:l-[4-[(~-ethoxycarbonyl)-benzylamino]benzyl]benzimidazo:Le are dissolved in 5 ml of ace-ticanhydride and stirred a-t 120C :for 3 hours.
The solvent is eliminated, the residue is purified over a silica gel column (particle size: 0.063-0.02 mm), using ethyl acetate as eluant. The uniEorm fractions are combined and evaporated down.
Yield: 0.35 g (64% of theory), Rf value: 0.50 (silica gel; eluant: methylene chloride/ethanol = 95:5) b) 2~n-Butyl-1-[4-[(~-carboxy) N-acetyl benzylamino]-benzyl]benzimidazole Prepared analogously to Example lb from 2-n-butyl-1-[4-[(~-ethoxycarbonyl)-N-acetyl-benzylamino]benzyl]-benzimidazole and lN sodium hydroxide solution in ethanol.
Yield: 74% of theory, Melting point: 212-214C
Cz8H29N3O3 (455.56) Calculated: C 73.82 H 6.42 N 9.12 Found: 73.50 6.5~ 9.28 Example 65 ... , ~ , , .
~ , 2g~3~

2-n-Butyl-1-[4-[(2-carboxy-3-phenyl)propyllbenzyl]
benzimidazole a) 2-n-Butyl-1-[(4-hydroxymethyl)benzylJbenzimidazole 1.2 g (30 mMol) of lithium aluminium hydride are suspended in 200 ml of absolute tetrahydrofuran. At ambient temperature a solution of 10.6 y (30 mMol) of 2-n-butyl-1-[(4-ethoxycarbonyl)benzyl]benzimidazole in lO0 ml of absolute tetrahydrofuran is added dropwise.
The mixture is stirred for 2 hGurs at ambient temperature and then slowly hydrolysed, with cooling, with aqueous sodium hydroxide solution. The crystallised salts are suction filtered and the filtrate is concentrated by evaporation. The residue is mixed with water and ex-tracted wi-th ethyl acetate. The combined organic phases are washed with water, dried and concentrated by evaporation. The residue is purified over a silica gel column (particle size: 0.063-0.02 mm), using methylene chloride/methanol (30:1) as eluant. The uniform frac-tions are combined and evaporated down.
Yield: 6.5 g (74% of theory), Rf value: 0.60 (silica gel; eluant: methylene chloride/methanol = 19:1) b) 2-n-Butyl-1-[(4-chloromethyl)benzyl]benzimidazole 6.2 g (21 mMol) of 2-n-butyl-l-[(4-hydroxymethyl)-benzyl]benzimidazole are dissolved in 10 ml of thionylchloride and refluxed for 10 minutes. Then the excess thionylchloride is distilled off and the residue is mixed with ice water. After neutralisation with saturated sodium hydrogen carbonate solution, the mixture is extracted with ethyl acetate. The combined organic phases are washed with water, dried and evaporated down.
Yield: 6.0 g (91% of theory), Rf value: 0.65 (silica gel; eluant: methylene chloride/methanol = 19:1) i : , .

2~3~ ~

c) 2-n-Butyl-1-[~-[(2,2-bls-ethoxycarbonyl-3~phenyl)-propyllbenzyllbenzimidazole 2.4 g (9.6 mMol) of diethyl benzylmalonate are dissolved in 25 ml of dimethylsulphoxide, mixed with 1.1 y (9.6 mMol) of potassium -tert.butoxide and stirred for 30 minutes at ambient temperature~ Then a solution of 3.0 g (9.6 mMol) of 2-n-butyl-:L--[(4-chloromethyl) benzyl]ben~imidazole in 25 ml of dimethyl~ulphoxide is added dropwise. After one hour at ambient temperature the mixture is heated to 100C for 15 minutes. The reaction mixture is combined with ice water. 'rhe product which crystallises out is suction fi.ltered and extracted with ethyl acetate. The combined organic phases are washed with water, dried and evaporated down.
Yield: 4.2 g (83% of theory), Rf value: 0.15 (silica gel; eluant: methylene chloride/methanol = 30:1) d) 2-n-Butyl-1-[4-[(2-carboxy~3-phenyl)propyl]benzyl]-benzimidazole 0.44 g (0.8 mMol) of 2-n~butyl-1-[4-[(2,2-bis~
ethoxycarbonyl-3-phenyl)propyl]benzyl]benzimidazole and 0.12 g of sodium hydroxlde are taken up in 30 ml of water and refluxed for 8 hours. The mixture is then acidified with glacial acetic acid. The product which crystallises out is suction filtered and purified over a silica gel column (particle size: 0.063-0.02 mm), using methylene chloride/methanol (19:1) as eluant~ The uniform fractions are combined, evaporated down, triturated with ethe~, suction filtered and dried.
Yield: 0.1 g (39% of theory), Melting point: 139-140C
C28H30N22 (426-56) Calculated: C 78.84 H 7.09 N 6.57 Found: 78.72 6.96 6.56 Example 66 - - :

;
;, .
~ .
. :; : ' :
. i .. ..

2~73~

9~
2-n-Butyl-1-[4-[(2-carboxy-2-phenyl)ethyl]benzy]]-benzimidazole .
a) 2-n-Butyl-1-[4-[(2,2-bis-ethoxycarbonyl-2-phenyl)-ethyllbenzyl]benzimidazole Prepared analogously to Example 65c from 2-n-butyl-1-[(4-chloromethyl)benzyl]benzimidazole and diethyl-phenylmalonate/potassium tert.butoxide.
Yield: 82% of theory, R~ value: 0.20 (silica gel; el~lant: methylene chloride/methanol = 40:1) b) 2-n-Butyl-1-[4-[(2-carboxy-2-phenyl)ethyl]benzyl]-benzimidazole .
Prepared analogously to Example 65d from 2-n-butyl-1-[4-[(2,2-bis-ethoxycarbonyl-2-phenyl)ethyl]benzyl]-benzimidazole and aqueous sodium hydroxide solution in ethanol.
Yield: 37% of theory, Melting point: 171-172C
C27H28N2o2 (412-54) Calculated: C 78.44 H 6.66 N 6.88 Found: 78.61 6.84 6.79 Example 67 2-n-Propyl-5-(N-ethyl-cyclohexylcarbonylamino)-3-[4-[(~-carboxy)benzyloxy]benzyl~imidazo[4,5-b]pyridine . .
Prepared analogously to Example lb from 2-n-propyl-5-(N-ethyl-cyclohexylcarbonylamino)-3-[4-[(~-ethoxycarbonyl)-benzyloxy]benzyl]imidazo[4,5-b]pyridine and lN sodium hydroxide solution in ethanol.
Yield: 87% of theory, Melting point: 113-115C
C33H3gN44 (554.70) Calculated: C 71.46 H 6.91 N 10.10 Found- 71.60 6.99 lO.00 .
. .
-, , : . ' .. ' :
:- . ; . :
.. .
: . , ' ' , .
.

2 ~ J
_ 99 _ ExampLe 6~

2-n-Propyl-5-(N-cyclohexylaminocarbony:L-ethylamino)-3-[4-[(~-carboxy)b~nzyloxy]benzyl]imidazo[4,5-b]pyridine Prepared analogously to Example lb from 2-n-propyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]benzimidazole and lN
sodium hydroxide solution in ethanol.
~'ield: 20~ of theory, Meltiny point: 183 D C
C33E~39Ns 4 ( 569.72) Calculated: C 69.57 H 6.90 N 12.29 Found: 69.80 6.69 11.97 Example 69 2-n-Butyl-4-methyl-7-[ Q- ( lH-tetrazol-5-yl)benzyloxy]-1-[4-[~-(lH-te-trazol-5-yl)benzyloxy]benzyl]benzimidazole .
Prepared analogously to Example 57g from 2-n-butyl-4-methyl-7-[ Q- ( 1-triphenylmethyl-tetrazol-5-yl)benzyloxy]-1-[4-[~-((1-triphenylmethyl)tetrazol-5-yl)benzyloxy]-benzyl]benzimidazole and 4N hydrochloric acid.
Yield: 52% of theory, Melting point~ from 166C (decomp.) C3sH34N1 02 ( 626.72) Calculated: C 67.68 H 5.46 N 22.35 Found: 67.70 5.52 22.66 . ~
: , . :, , ~ .

: ~ .

~7.~g(~

Example 70 2-n-Butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinon-1-yl)-3-[4-[~-(lH-tetrazol-5-yl)benzyloxy]-benzyl]imidazo~4,5-b]pyridine Prepared analogously to Example 57g from 2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(lH)pyrimidinon-l-yl)-3-[4-[~-((1-triphenylmethyl)tetrazol-5-yl)benzyloxy]benzyl]imidazo[4,5-b]pyridine and 4N
hydrochloric acid.
Yield: 75% of theory, ~elting point: 185-187C
C37H39N902 (661-79) Calculated: C 69.24 H 6.12 N 19.64 Found: 68.97 6.17 19.91 Example 71 2-n-Butyl-5-dimethylaminocarbonylamino-1 [4-[~-(lH-tetrazol-5-yl)benzyloxy]benzyl]benzimidazole Prepared analogously to Example 57g from 2-n-butyl-5-dimethylaminocarbonylamino-1-[4-[~-((1-triphenylmethyl)-tstrazol-5-yl)benzyloxy~benzyl]benzimidazole and 4N
hydrochloric acid.
Yield: 66% of theory, Melting point: 207-209~C
C29H32N802 (524-68) Calculated: C 64.19 H 6.31 N 20.65 Found: 63.~5 6.33 2C.44 Example 72 2-Ethyl-5,7-dimethyl-3-[4-[~-(lH-tetrazol-5-yl)-benzyloxy]benzyl]imidazo[4,5-b]pyridine semihydrate . _ Prepared analogously to Example 57g from 2-ethyl-5,7-.:
.

.

~:

2 0 l 3 ~

-- .I O :L
dimethyl-3-[~-L~ -triphenylmethyl)tetrazol-5-y])-benzyloxy]benzyl]imidazo[4,5-b]pyridine-~emihydrate and 4N hydrochloric acid.
Yield: 83% of theory, Melting point: 104-105C
C25H2sN7o x 0 5 H20 (448.53) Calculated: C 66.95 H 5.89 N 21.83 Found: 67.05 5.94 22.36 Exam~_e 73 2~n-Propyl-4-methyl-1-[4-[~-(0-ethyl-phosphono)-benzylamino~benzyl]benzimiclazole hydrate a) 2-n-Propyl-4-methyl-1-[~-[~-(0,0-diethyl-phosphono)-benzylamino]benzyllbenzimidazole 6.5 g (23.3 mMol) of 2-n-propyl-4-methyl-1-[(4-amino)-benzyl]benzimidazole are stirred into 4.2 g (40 mMol) of benzaldehyde. The mixture is stirred at ambient temperature for 2 hours. Then 10.72 g (77.6 mMol) of diethylphosphite are added and the mixture is heated to 100C for 45 minutes. The precipitate formed after cooling to ambient temperature is triturated with 250 ml of ether, suction filtered and dried in air. It is then recrystallised from 150 ml of petroleum ether/isopropanol (2:1).
Yield: 8.7 g (74% of theory), Melting point: 110-115C

b) 2-n-Propyl-4-methyl-1-[4-[~-(0-ethyl-phosphono)-benzylaminolbenzyllbenzimidazole hYdrate 0.5 g (1 mMol) of 2-n-propyl-4-methyl-1-[4-[~-(0,0-diethylphosphono)benzylamino]benzyl]benzimidazole and 1.0 g of pulverised potassium hydroxide ar~ dissolved in ~0 ml of methanol and refluxed for 9 hours. After cooling to ambient temperature, 25 ml of ice water are added. The pH is adjusted to 6.5 by the addition of glacial acetic acid and conc. ammonia solution. After ' : ~

2~1~3~ ~

the addition of solid sodium chloride, extraction is carried out six times, each time using lOo ml of ethyl acetate. The combined organic phases are washed with saturated saline solution and dried over magnesium sulphate. After evaporation of the solvent i vacuo the residue is triturated wi-th ether and dried over potassium hydroxide.
Yield: 0.35 g t73% of theory), Melting point: from 158C (decomp.) C27H32N3O3P x H2O (495.57) Calculated: C 65.44 H 6.92 N 8.48 Found: 65.66 6.52 8.49 Example 74 2-n-Butyl-1-[4-[~-(O-ethyl-phosphono)benzylamino]-benzyl]benzimidazole a) 2-n-Butyl-1-[4-[~-(O,O-diethyl-phosphono)-benzylamino]benzyl]benzimidazole Prepared analogously to Example 73a from 2-n-butyl-1-~(4-amino)benzyl]benzimidazole, benzaldehyde and diethylphosphite.
Yield: 51% of theory, Melting point: 149-153C
. ~, b) 2-n-Butyl-1-[4-[~-(O~ethyl-phosphono)benzylamino]-benzyl]benzimidazole Prepared analogously to Example 73b from 2-n-butyl-1-[4-[~-(O,O-diethyl-phosphono)benzylamino]benzyl]
benzimidazole and methanolic potassium hydroxide solution.
Yield: 67% of theory, Melting point: 118-123C (decomp.) Cz7H32N3O3P (477-55) Calculated: C' 67.91 H 6.76 N 8.80 Found: 67.74 7.02 8.64 '' 2~J3,~

Exam~l~ /5 2-n-Butyl-l-[4-[(~-carboxy)benzyloxy]benzyl]-benzimidazole a) 2-n-Butyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]-benzyl]benzimidazole Prepared analogously to Example la from 2-n-butyl-benzimidazole and 4-[(~-ethoxycarbonylbenzyloxy)-benæyl]bromide.
Yield: 22.0% of theory, Oil, Rf value: 0.65 (silica yel; eluant: ethyl acetate/ethanol = 9~1) C2B~30N23 ( 442.60) Calculated: C 75.99 H 6.83 N 6.33 Found: 75.97 6.79 5.99 b) 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-benzimidazole Prepared analogously to Example lb from 2-n-butyl-1-[4-[(a-ethoxycarbonyl)benzyloxy]benzyl]benzimidazole and 1 N sodium hydroxide solution in ethanol.
Yield: 38.0% of theory, Melting point: 223-225C
C26H26N23 ( 414.51) Calculated: C 75.34 H 6.32 N 6.76 Found: 75.03 6.34 6.73 Example 76 2-n~Propyl-7-methyl-3-[4-[(~-carboxy)benzyloxy]benzyl]-imidazo[4,5-b]pyridine _ _ a) 2-n-Propyl-7-methyl-3-E4-[(~-ethoxycarbonyl)-benzyloxy]benzyl]imidazo~4 5-blpyridine Prepared analogously to Example la from 2-n-propyl~
methyl-imidazo[4,5-b]pyridine and 4 [(~-ethoxycarbonyl)-benzyloxy]benzylbromide.

, . . .

. . ~ , .-, . ~ ;,, , 20r~3~
-- 10~ --Yield: 34.0% of thPory, Oil, Rf value: 0.40 (silica gel; eluant: methylene chloride/ethanol - 25:1) b) 2-n-Propyl-7-me-thyl-3-[4-[(cY-carboxy)benzyloxy]-benzyl]imidazo~4 5~b]~yridine _ _ _ _ Prepared analogously to Example lb from 2-n-propyl-7-methyl-3-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-imidazo[4,5-b]pyridine and 1 N sodium hydroxidë solution in ethanol.
Yield: 66.4% of theory, Melting point: 108C
C2sH2sN3O3 (415.50) Calculated: C 72.27 ~l 6.06 N 10.11 Found: 72.25 6.03 9.87 Example 77 5,7-Dimethyl-2-ethyl-3-~4-[(c~-carboxy)benzyloxy]benzyl]-imidazo[4,5-b]pyridine semihydrate .
Prepared analogously to Example lb from 5,7-dimethyl-2-ethyl-3-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]~
imidazo[4,5-b]pyridine and lN sodium hydroxide solution in ethanol.
Yield: 89.3% of theory, Mèlting point: 251 253C
C2sH25N3O3 x 0-5 ~2 (424 Calculated: C 70.73 H 6.17 N 9.B9 Found: 71.00 5.97 9.79 Example 78 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]-3,5-dichloro-benzyl]-6-cyclohexylaminocarbonylamino-benzimidazole Prepared analogously to Example lb from 2-n-butyl-1-[4-[(cY-ethoxycarbonyl)benzyloxy]-3,5-dichlorobenzyl]-6-. . : . , , ~ - , , -.

, ~: . . : . , 21~73~

cyclohexylaminoca~bonylamino-benzimidaZole and lN sodium hydroxicle sol~ltlon in ethanol.
Yield: 95.6% of theory, Melting poin-t: 251-253C
C33H36Cl~N4O4 (623-53) Calculated: C 63.56 H 5.82 ~~.98 Cl 11.37 Found: 63.39 5.88 8.8711.85 Example 79 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]-3-methoxybenzyl]-6-dimethylaminocarbonylamino-benzimidazole Prepared analogously to Example lb from 2-n-butyl-1-[4-[(~-ethoxycarbonyl)benzyloxyl-3-methoxybenzyl]-6-dimethylaminocarbonylamino-benzimidazole and 2N sodium hydroxide solution in ethanol.
Yield: 87.5% of theory, Melting point: 170-172C
C30H34N4s (530-62) Calculated: C 67.90 H 6.46 N 10 . 56 Found: 67.64 6.25 10.33 Example 80 2-n-Butyl-1-[4-[(~-carboxy)benzyloxy]-3-methoxybenzyl]-5-dimethylaminocarbonylamino-benzimidaæole . _ _ _ . . . _ . . . ~ . .
Prepared analogously to Example lb from 2-n-butyl-1 t4-~ ethoxycarbonyl)benzyloxy]-3-methoxybenzyl]-5-dimethylaminocarbonylamino-benzimidazole and 2N sodium hydroxide solution in ethanol.
YieldO 78.6% of theory, Melting point: 154-156C
C30H34N4Os (530-62) Calculated:C 67.90 H 6.46 N 10.56 Found:67.74 6.37 10.24 '' ' : ' ,' ' ' ' ~' '~ ' :

.. ~ . ' ' . . . . , ,, ~ .
. , . ~ .:

21~3~
- ~06 -E ~lmple 8:L

2-n-Propyl-1-[4-[(~-carboxy)benzyloxy] 3,5-dimethoxybenzyl]-6-(1-methyl-benzimidazol-2-yl)-4-methyl-benzimidazole hydrate _ _ . _ _ Prepared analogously to Example lb from 2-n-propyl~l-[4-[(~-ethoxycarbonyl)benzyloxy]-3,5-dimethoxybenzyl]-6-(l-methyl~benzimidazol-2-yl)-4-methyl-benzimidazole and 2N
sodium hydroxide solution in ethanol.
Yield: 91.4% of theory, Melting point: 148-150C
C36H36N40s x HzO (622.72) Calculated: C 69.44 H 6.25 N 9.00 Found: 69.77 6.09 8.92 Example 82 2-n-Propyl-l-[4-[(~-carboxy)benzyloxy]-3,5-dibromobenzyl]-6-(l-methyl-benzimidazol-2-yl)-4-methyl-benzimidazole hydrate _ Prepared analogously to Example lb from 2-n-propyl-l-[4-[(~-ethoxycarbonyl)benzyloxy]-3,5-dibromobenzyl]-6-(1-methyl-benzimidazol-2-yl)-4-methyl-benzimidazole and 2N
sodium hydroxide solution in ethanol.
Yield: 58.4~ of theory, Melting point: 229-230~C
C34H30Br2N4o3 x H20 (720.46) Calculated:C 56.68 H 4.47 N 7.77 Found:56.78 4.64 7.75 , . : .
' ~ ~

: . , :
, .

2~7~
~07 -Example 83 2-n-Propyl-6~(2,3-dimethylsuccinimino)-1-[4-[(~-carboxy)benzyloxy]-3,s-dimetho~ybenæyl]-benzimid~zole semihydrate Prepared analogously to Example lb from 2-n-propyl-6-(2,3-dimethylsuccinimino)-1-[4--[(~-ethoxycarbonyl)-benzyloxy]-3,5-dimethoxybenzyl]-benzimidazole and 2N
sodium hydroxide solution in et:hanol.
Yield: 13.8% of theory, Melting point: 129-13:L~C
C34H37N307 x 0-5 H20 (608.69) Calculated: C 67.09 H 6.29 N 6.90 Found: 67.29 6.37 6.86 Example 84 2-n-Butyl-6-(1-cyclohexen-1,2-dicarbonylimino)-1-[4-[(~-carboxy)benzyloxy]benzyl]benzimidazole semihydrate Prepared analogously to Example lb from 2-n-butyl-6-(1-cyclohexen-1,2-dicarbonylimino)~ 4-[(~-ethoxycarbonyl)benzyloxy]benzyl~benzimidazole and lN
sodium hydroxide solution in ethanol.
Yield: 23.3% of theory, Melting point: 247-249C
C34H33N305 x 0-5 H20 (572.66) Calculated: C 71.30 H 5.98 N 7.33 Found: 71.47 6.05 7.15 Example 85 2-n-Propyl-4-methyl-1-[~-[(~-carboxy)-2-chloro-benzyloxy]benzyl]benzimidazole : .
Prepared analogously to Example lb from 2-n-propyl-4-methyl-l-[4-[(~-ethoxycarbonyl)-2-chlorobenzyloxy]-: ~, :: `~ ',' ' '` , . : . : , . , .

.:

2~73~
-- 10~ --benzyl]ben~imidazole and 2N sodium hydroxide solution in ethanol.
Yield: 40.7% of theory, Melting point: sinters from 105~C
C26H2sClN2O3 (448.97) Calculated: C 70.00 H 5.62 N 6.28 Cl 7.91 Found: 69.94 5.72 6.29 7.92 Example 86 2-n-Propyl-4-chloro-6-(1-oxo-2-isoindolin-2~yl)-l-[4-[(~-carboxy)benzyloxy]benzyl~benzimidazole _ Prepared analogously to Example lb from 2-n-propyl-4-chloro-6-(1-oxo-2-isoindolin-2-yl)-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]benzimidazole and 2N
sodium hydroxide solution in ethanol.
Yield: 61.0% of theory, Melting point: 252-254C
C33H28ClN3O4 (566.06) Calculated: C 70.00 H 5.02 N 7.42Cl 6.25 Found: 69.81 5.22 7.876.54 Example 87 2-n-Butyl-6-(1-cyclohexen-1,2-dicarbonylimino)-1-[4-[~-(lH-tetrazol-5-yl)benzyloxy]benzyl]benzimidazole .
Prepared analogously to Example 57g from 2-n-butyl-6-(1-cyclohexen-1,2-dicarbonylimino)-l-[4-[(~-(N-triphenylmethyl)tetrazol-5-yl)benzyloxy]benzyl]-benzimidazole and 85% formic acid in methylene chloride.
Yield: 43.7% of theory, Melting point: 149-151C
C34H33N7O3 ~587.68) Calculated. C 69.49 H 5.66 N 1~.68 Found: 69.40 5.83 16.31 . , ~ . . .

- . . .

.

': :

2~3~1 xample 88 2-n-Butyl-5-methyl-6-dimethylaminocarbonylamino-3-[4-[c~-(lH-tetrazol-5-yl)benzyloxy]benzyl]imidazolL4,5-b]-pyridine Prepared analogously to Example 57g from 2-n-butyl-5-methyl-6-dimethylaminocarbonylamino-3-[4-[(~-(N-triphenylmethyl)tetrazol-5-yl)benzyloxy]benzyl]imidazo-[4,5-b]pyridine and 4N hydrochloric acid in ethanol.
Yield: 75% oE theory, Melting point: 198-200UC
C29H33N902 (539-64) Calculated: C 64.54 H 6.16 N 23.36 Founcl: 64.37 6.24 23.57 Example 89 2-n-Butyl-6-(cyclohexylaminocarbonyl-N-methylamino)-l-[4-[~-(lH-tetrazol-5-yl)benzyloxy]benzyl]benzimidazole Prepared analogously to Example 57g from 2-n-butyl-6-(cyclohexylaminocarbonyl-N-methylamino)-1-[4-[(~-(N-triphenylmethyl)-tetrazol--5-yl)benzyloxy]benzyl]-benzimidazole and 4N hydrochloric acid in ethanol~
Yield: 85.-l~6 of theory, Melting point: 195-197C
C34H40N8o2 (592-74) Calculated: C 68.89 H 6.80 N 18.90 Found: 68.82 6.91 18.77 Example 90 5,7-Dimethyl-2 ethyl-3-[4-[~-(lH-tetrazol-5-yl)-benzyloxy]-3,5-dichlorobenzyl]imidazo[4,5-b]pyridine hydrate Prepared analogously to Example 57g from 5,7 dimethyl-2-~ . . , ,:
~ :
:' - ~ , -2~3~

ethyl-3-[4-[(~-(N-triphenylmethy])tetrazol-5-yl)benzyloxyl-3,5-dichlorobenzyl]imidazo[4,5-b]pyridine and 85~ formic acid in methylene chloride.
Yield: 77~2% of theory, Melting point: 143-145C
C2sH23cl2N7o x H2O (526.42) Calculated: C 57.04 H 4.78 N18.62 Cl 13.47 Found: 57~51 4.82 19.03 13.38 Examp1e 91 2-n-Butyl-6-cyclohexylaminocarbonylamino-1-[4-[~--(lH-tetrazol-5-yl)benzyloxy]-3,5-dichlorobenzyl]-benzimidazole semihydrate ___ Prepared analogously to Example 57g from 2-n-butyl-6-cyclohexylaminocarbonylamino-1-[4~[t~-(N-triphenyl-methyl)tetrazol-5-yl)benzyloxy]-3,5-dichlorobenzyl]~
benzimidazole and 85% formic acid in methylene chloride.
Yield: 83% of theory, Melting point: 129-131C
C33H36cl2Nso2 x 0-5 H2O (655.62) Calculated: C 60.36 H 5.68 N 17.07 Found: 60.40 5.78 17.19 Example 92 2-n-Butyl-6-dimethylaminocarbonylamino-1-[4-[~-(lH-tetrazol-5-yl)benzyloxy]-3-methoxybenzyl]benzimidazole Prepared analogously to Example 57g from 2-n-butyl-6-dimethylaminocarbonylamino-1-[4-[(~-(N-triphenylmethyl)-tetrazol-5-yl)benzyloxy~-3-methoxybenzyl]benzimidazole and 4N hydrochloric acid in ethanol. -Yield: 75~ of theory, Melting point: 158-162C
C30H34N8O3 (554.65) Calculated: C 64.97 H 6.18 N 20.20 .
, ' :

~73~

-- 11.1 --Found. 6~.71 6.20 19.91 Example 93 2-n-Propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-[4-[~-(lH-tetrazol-5-yl)benzyloxy]-3,5-dimethoxybenzyl]~
benzimidazole hydrate Prepared analogously to Example 57g from 2-n-propyl--4-methyl-6 (1-methyl-benzimidazo:L-2~yl)-1-[4 [(~-(N-triphenylmethyl)tetrazol-5-yl)benzyloxy]-3,5-dimethoxybenzyl]benzimidazole and 85% formic acid~in methylene chloride.
Yield: 83% of theory, Melting point: 152-154C
C36H36N~03 x ~I20 (646.75) Calculated: C 66.86 H 5.97 N 17.33 Found: 67.08 5.9~ 16.97 Example 94 2-n-Propyl-4-methyl-6-(2,3-dimethylsuccinimino) 1-[4-[a-(lH-tetrazol-5-yl)benzyloxy~-3,5-dimethoxybenzyl]-benzimidazole semihydFate Prepared analogously to Example 57g from 2-n-propyl-4-methyl-6-(2,3-dimethylsuccinimino) 1-t4-[(~-(N-triphenylmethyl)tetrazol-5-yl)benzyloxy~-3,5-dimethoxybenzyl]benzimidazole and 85% formic acid in methylene chloride.
Yield: 74.6% of theory, Melting point: 192-144C
C34H37N705 x 0-5 H20 (632.71~
Calculated: C 64.54 H 6.05 N 15.50 ~ound: 64.46 6.10 15.25 :
' . -- ~ . .
- : : :. , .:
:, ~
. ;, . ~ ~ :: ; . - - .. . . . . . .

:

2~73~
~ 112 -Example 95 2-n-Propyl-4~methyl-6-(1-methyl-berlzimidazol-2-yl)-1-[4-[~ LH-tetrazol-5~yl)benzyloxy]-3,5-dibromobenzyll-benzimidazole ___ _ .
Prepared analogously to Example 57g from 2-n~propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-[4-[(~-(N-triphenylmethyl)tetrazol-5-yl)benzyloxy]-3,5- ~
dibromobenzyl]benzimidazole and 8S~ formic acid in methylene chloride.
Yield: 21.6% of theory, Melting point: 132-134C
C34H30Br2N~0 (726.47) Calculated: C 56.21 H 4.16 N 15.42Br 21.99 Found: 56.53 4.50 15.42 22.03 Example g6 2-n-Butyl-5-dimethylaminocarbonylamino-1-[4-[Q-(lH-tetrazol-5-yl)benzyloxy]-3-methoxybenzyl]-benzimidazole Prepared analogously to Example 57g from 2-n-butyl-5-dimethylaminocarbonylamino-1-[4-[(~-(N-triphenylmethyl)-tetrazol~5-yl)benzyloxy]-3-methoxybenzyl]benzimidazole and 4N hydrochloric acid in ethanol.
Yield: 88.2% of theory, Melting point: 181-185C
C30H34N8O3 (554-66) Calculated: C 64.96 H 6.18 N 20.20 Found: 65.18 5.92 19.97 :

' : ~: '. , :, .: . ' .

2 ~
~ 113 Exan)ple 97 5,7-Dimethyl-2-ethyl-3-[4-[~-(0-ethyl-phosphono)-benzyloxy]benzyl]imidazo[4,5-b]pyridine sodium salt-semihydrate _ _ Prepared analogously to Example 73b from 5,7-dimethyl~2-ethyl-3-[4-[~-(0,0-diethylphosphono)benzyloxy]benzyl~-imidazo[4,5-b]pyridine and potassium hydroxide in methanol.
Yield: 52% of theory, Melting point: from 150C (decomp.) H30N4NaO3p x 0-5 H20 (509-Calculated: C 61.29 H 6.33 N 11.00 Found: 60.95 6.34 lO.9B

Example 98 2-n-Propyl-4-methyl-1-[4-[~-(0-ethyl-phosphono)-N-methyl-benzylamino]benzyl]benzimidazole semihydrate . _ a) 2-n-Propyl-4-methyl-1-[4-[~-(0,0-diethylphosphono)-N-methyl-benzylaminolbenzyl]benzimidazole 1.1 g ~2 mMol) of 2-n-propyl-4~methyl-1-[4-[~-(0,0-diethylphosphono)-benzylamino]benzyl]benzimidazole are dissolved in 1 ml of formic acid and mixed with 2 ml of a 37~ formalin solution. The mixture is stirred for 2 hours at 100C, cooled and poured onto ice. After the addition of conc. ammonia the mixture is extracted twice with ethyl acetate. The combined organic phases are washed with saturated saline solution and dried over magnesium sulphate. The organic phase is evaporated down ln vacuo and the residue obtained is purified over a silica gel column (particle size: 0.063-0.02 mm, ethyl acetate~petroleum ether = 1:1 to 1:2). The uniform fractions are combined and evaporated down in vacuo.

. ~

.

2~73~ 1 Yield: 0. 60 g (58% of theory), Rf value: 0.45 (silic~ y~l; eluan-t: petroleum ether/ethyl acet~te = 1:1) b) 2-n-Propyl-4-methyl-1-[~-[~ (0-ethyl-phosphono)-N-methyl-henzylamino]benzyl~enzlmldazole semih~drate Prepared analoyously to Example 73b from 2-n-propyl-4-methyl-l-[4-[~-(0,0-diethylphosphono)-N-methyl-benzylamino]benzyl]benzimidazole and potassium hydroxide in methanol.
Yield: 77% of theory, Melting point: from 106C (decomp.) C28H34N303P x 0-5 H20 (500-Calculated: C 67.18 H 7.05 N 8.40 Found: 67.25 7.02 8.42 Example 99 2-n-Propyl-4-methyl-1-[4-[~-(0-ethyl-phosphono)benzyl-amino]benzyl]benzimidazole hydrobromide . _ _ 0.5 g (1.0 mMol) of 2-n-propyl-4-methyl-1-[4-t~-(0,0-diethylphosphono)benzylamino]benzyl]benzimidazole are dissolved in 10 ml of 48% hydrobromic acid and refluxed for 5 hours. After cooling at ambient température, the pH is adjusted to 6 by the addition of concentrated ammonia and glacial acetic acid. ~he precipitate formed is suction filtered and dried over potassium hydroxide at 40C.
Yield: 47% of theory, Melting point: from 140C (decomp.) sH2sN33P x HBr (530.42) Calculated: C 56.61 H 5.51 N 7.92 Found: 56.48 5.80 8 05 .

. . : -. ::.: , . ~ :.

2~73(~

Example 100 2-n-Propyl-~-methyl-1-[4-[(~-methanesulphonylamino-carbonyl)benzyloxy]benzyl]benzimidazole . _ 410 mg (1 mMol) of 2-n-propyl-4-methyl-1 [4-[(~-carboxy)benzyloxy]benzyl]benzimidazole are dissolved in 100 ml of thionylchloride, mixed with 1 drop of dimethylformamide and refluxed for 1 hour. Then, after the addition of -toluene, the mixture is evaporated to dryness and taken up in 30 ml of acetone. After the addition of 1 ml of triethylamine and 150 mg (1.58 mMol) of methanesulphonic acid amide the mixture is stirred for 2 hours at ambient temperature. The reaction mixture is then evaporated down and the residue is purified over a silica gel column (particle size:
0.063-0.02 mm; methylene chloride/ethanol = 50:1, 19:1, 9:1 and 4:1). The uniform fractions are combined, evaporated down and the residue obtained is triturated with ether and dried.
Yield: 15.3% of theory, Melting point: 139-141C
Cz7N29N3O4S (491.60) Calculated: C 65.g5 H 5.94 N 8.54 Found: 65.67 6.27 8.89 Example 101 2-Ethyl-4-methyl-1-[4-[(~-carboxy)benzyloxy]benzyl]-6 (n-butanesultam-l-yl)benzimidazole Prepared analogously to Example lb ~rom 2-ethyl-4-methyl 1-[4-~[(~-ethoxycarbonyl)benzyloxy]benzyl]-6-(n-butanesultam-l-yl)-benzimidazole and 2N sodium hydroxide solution in ethanol.

.,. ~ ~ ~ - . .

.: ~ , :, , . ,;
, ' , . ' .

2~3~

Example 102 2-Ethyl-4-methyl-1-[~-[~ H-tetrazol-5-yl)benzyloxy]-benzyl]-6-(n-butanesultam-1-yl)benzimidazole . ~
Prepared analogously to Example 57g from 2-ethyl-4-methyl-1-[4 [(~-(N-triphenylmethyl)tetrazol-5~yl)-benzyloxy]benzyl]-6-(n-butanesultam-1-yl)-benzimidazole and 4N hydrochloric acid in ethanol.

Example 103 2-n-Butyl-1-[4-[~-(ethoxycarbonyl)-~-(2-pyridyl)-methoxy]benzyl]-6-(N-cyclohexylaminocarbonyl-methylamino)-benzimidazole Prepared analogously to Example la from 2-n-butyl-1-(4-hydroxybenzyl)-6-(N-cyclohexylaminocarbonyl-methylamino)-benzimidazole and ethyl ~-bromo-pyridyl-2-acetate.
Yield: 90.0% of theory, R~ value: 0.70 (silica gel; ethyl acetate/ethanol/
ammonia = 90:10:1) C33H44N504 (574.76) Calculated: C 70.20 H 7040 N 11.69 Found: 69.97 7.26 11.21 Example 104 2~n-Butyl-3-[4-[(~-carboxy)benzyloxy]-3-methoxybenzyl]-5-methyl-6-dimethylaminocarbonylamino-imidazo[4,5-b]-pyridine Prepared analogously to Example lb from 2-n-butyl-3-[4-[t~-ethoxycarbonyl)benzyloxy]-3-methoxybenzyl~-5-methyl-6-dimethylaminocarbonylamino-imidazo[4,5-b]pyridine and 2N sodium hydroxide solution in ethanol.
Yield: 91.8% of theory, - . .. . .

, i : , . :
.

: ' :
:~

Melting point: 174-176C
Rf value: 0.60 (sili~a gel; ethyl acetate/ethanol/
ammonia -- 50:45:5) C30H3sNsOs (545.65) Calculated: C 66.0~ H 6.~7 N 12.8~
Found: 66.25 6.39 12.95 Example 105 2-n-Butyl-1-[4-[~-(ethoxycarbonyl)-~-(2-pyridyl~meth-oxy]benzyl]-6 dimethylaminocarbonylamino-benzimidazole .. . . _ _ Prepared analogously to Example la ~rom 2-n-butyl-1-(4-hydroxybenzyl)-6-dimethylaminocarbonylamino-benzimidazole and ethyl ~-bromo-pyridyl-2-acetate.
Yield: 87.5% of theory, Rf value: 0.50 (silica gel; ethyl acetate/ethanol/
ammonia = 90:10:1) C30H3sNsO4 (529-65) Calculated: C 68.03 H 6.66 N 13.22 Found: 68.09 6.83 13.06 Example 106 2-n-Butyl-l-[4-[~-(ethoxycarbonyl)-Q- ( 2-pyridyl)meth-oxy]benzyl]-6-cyclohexylcarbonylamino-benzim.idazole Prepared analogously to Example la from 2-n-butyl-1-(4-hydroxybenzyl)-6-cyclohexylcarbonylamino-benzimidazole and ethyl ~-bromopyridyl-2-acetate.
Yield: 75.3% of theory, Rf value: 0.50 (silica gel; ethyl acetate/ethanol/
ammonia = 90:10:1) C34H40N404 (568-73~
Calculated:C 71.80 ~ 7.09 N 9.35 Found:71.82 7.21 9.83 :~ ' :

: , 2~3~

Exa~le_l07 2-n-Butyl-3-[~-[~ l-tetrazol-5-yl)benzyloxy]-3-methoxybenzyl]-5-methyl-6-dimethylaminocarbonylamino-imidazo[4,5-b]pyridine Prepared analogously to Example 57g from 2-n-butyl-3 [4-[~-((N-triphenylmethyl)-tetrazol-5-yl)benzyloxy]-3-methoxybenzyl]-5-methyl-6-dimethylaminocarbonyIamino-imidazo[4,5-b]pyridine and 4 N hydrochloric acid in ethanol.
Yield: 60.0% of theory, Melting point: 197-199C
Rf value: 0.60 (silica gel; ethyl acetate/ethanol/
ammonia = 50:45:5) C30H35N903 (569.68) Calculatedo C 63.25 H 6.19 N 22.13 Found: 62.94 6.13 21.87 Example 108 2-n-Butyl-1-[4-[~-(lH-tetrazol-5-yl)-~-(2-pyridyl)-methoxy]benzyl]-6-dimethylaminocarbonylamino-benzimidazole .. .. . _ , .
Prepared analogously to Example 57g from 2-n-butyl-1-[4-[~-((N-triphenylmethyl)-tetrazol-5-yl~-~-(2-pyridyl)methoxy]benzyl]-6-dimethylaminocarbonylamino-benzimidazole and 4 N hydrochloric acid in ethanol.
Yield: 25.0% of theory, Melting point: 197-203C
Rf value: 0.50 (silica gel; ethyl acetate/ethanol/
ammonia = 50:45:5) C28H31N902 (525.63) Mass spectrum: (M+H) = 526 .- , ~ . . , ,:
'' ' ' ' , 2~3~

Example 109 2-Ethyl-3-[4-[~-(lH-tetrazol-5-yl)benzyloxy]benzyl] 5-methyl-6-dimethylaminocarbonylamino-imidazo[4,5-b~-pyridine Prepared analogously to Example 57g from 2-ethyl-3-[4-[~-((N-triphenylmethyl)-tetrazol-5-yl)benzyloxy]benzyl]-5 methyl-6-dimethylaminocarbonylamino imidazo[4,5-b]-pyridine and 4 N hydrochloric acid in ethanol.
Yield: 50.0% of theory, Melting point: 234-236C
C27H29N902 (511-60) Calculated- C 63.39 H 5.71 N 2~.64 Found: 63.36 5.87 24.52 Example 110 2-n-Butyl-4-methyl-1-[4-[~-(lH-tetrazol-5-yl)benzyloxy]-benzyl]-6-(2,3-dimethylsuccinimino)benzimidazole Prepared analogously to Example 57g from 2-n-butyl-4-methyl-1-[4-[~-t(N-triphenylmethyl)-tetrazol-5-yl)-benzyloxy]benzyl]-6-(2,3-dimethylsuccinimino)-benzimidazole and 4 N hydrochloric acid in ethanol.
~ .~
Yield: 80.0~ of theory, Melting point: 175-177C
C33H3sN73 (577 703 Calculated: C 68.61 H 6.11 N 16.97 Found: 68.45 6.24 17.00 Example 111 2-n-Butyl-4-methyl-1-[4-~(~-carboxy)benzyloxy]benzyl]-6-cyclohexylcarbonylamino-benzimidazole . . _ _ Prepared analogously to Example lb from 2-n-butyl-~-methyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-6-,, . . ~

`:

2 ~ rl~ 3 ~

cyclohexylcarhonyLamino-benzimldazole and 2 N sodium hydroxide solution in ethanol.
Yield: 81.8% of theory, Melting point: 191-193 D C
C34H39N30,, (553.70) Calculated: c 73.75 H 7.10 N 7.58 Found: 73.70 6.94 7.48 Example 112 2-n Butyl-4-methyl-1-[4-[~-(lH-tetrazol-5-yl)benz~loxy]-benzyl]-6-cyclohexylcarbonylamino-benzimidazole -Prepared analogously to Example 57y from 2-n-butyl-4-methyl-1-[4-[~-((N-triphenylmethyl)-tetrazol-5-yl)-benzyloxy]benzyl]-6-cyclohexylcarhonylamino-benzimidazole and 4 N hydrochloric acid in ethanol.
Yield: 85.0% of theory, Melting point: 195-198C
C34H39N702 (577-72) Calculated: C 70.68 H 6.80 N 16.97 Found: 70.81 6.98 16.97 Example 113 Z-n-Butyl-4-methyl-1-[4-[~-(carboxy)benzyloxy]benzyl]-6-tert.butylcarbonylamino-benzimidazole Prepared analogously to Example lb from 2-n-butyl-4-methyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]benzyl]-6-tert.butylcarbonylamino-benzimidazole and 2 N sodium hydroxide solution in ethanol.
Yield: 78.6% of theory, Melting point: 179-181~C
C32H37N304 (527-67) Calculated: C 72.34 H 7.07 N 7.96 Found: 72.51 6.95 7.65 , .
' ' `' ~ ~ ' " "' , ~ .

~73$~

- ~21 -Exam~æ~ 114 2-n-Butyl~4-~ethyl-1-[4-[~-(tetrazol-5-yl)benzyloxy]-benzyl]-6-tert.butylcarbonylamino-benzimidazole . _ .. . . _ Prepared analogously to Example 57g from 2-n-butyl-4-methyl-1-[4 [-((N--triphenylmethyl)-tetrazol-5-yl)benzyloxy]benzyl]-6-tert.butylcarbonylamino-benzimidazole and 4 N hydrochloric acid in ethano].
Yield: 75.0% of theory, Melting point: 191-193C
C32H37N7O2 (551.70) Calculated: C 69.67 H 7.76 N 17.77 Found: 69.42 7.80 17.68 Example 115 2-Ethoxy-7-ethoxycarbonyl-1-[4-[(~-ethoxycarbonyl)-benzyloxy]benzyl~benzimidazole _ Prepared analogously to Example 63a from 2-ethoxy-7-ethoxycarbonyl-l-(4-hydroxy)benzyl-benzimidazole and ethyl 2-bromo-phenylacetate.
Yield: 45.5% of theory, Oil, Rf value: 0.30 (silica gel; ethyl acetate/petroleum ` ether = 30:70) Example 116 2-Ethoxy-7-carboxy-1-[4-(~-carboxy~benzyloxy]benzyl]-benzimidazole semihydrate Prepared analogously to Example lb from 2-ethoxy-7-ethoxycarbonyl-1-[4-[(~-ethoxycarbonyl)benzyloxy]-benzyl]benzimidazole and lN sodium hydroxide in ethanol at 80C.
Yield: 90.9% of theory, Melting point: 180-182C

:: ' ....

2~ ~33~.~

C2sH22N206 x 0.5 H20 (~55- ) Calcula-ted: C 65.92 H 5.09 N 6.15 Found: 65.8~ 4.97 6.17 Examp~e 117 2-Ethoxy-7-ethoxycarboxy~1-[4-(~-carboxy)benzyloxy]-benzyl]-benzimidazole Prepared analogously to Exampl~e lb from 2-ethoxy-7-ethoxycarbonyl-1-[4-[(~-ethoxycarbonyl)benzyloxy~=
benzyl]benzimidazole and lN sodium hydroxide in ethanol at room temperature.
Yield: 59.6% of theory, Melting point: 185-187C
C27H26N206 (474.50) Calculated: C 68.34 H 5.52N 5.90 Found: 67.84 5.64 5.90 Example 118 2-Ethoxy-7-carboxy-1-[4-[~-(lH-tetrazol-5-yl)-benzyloxy]benzyl]benzimidazole-semihydrate . . .
Prepared analogously to Example lb from 2-ekhoxy-7-ethoxycarbonyl-1-[4-[~-((N-triphenylmethyl)tetrazol-5-yl)benzyloxy]benzyl]benzimidazole and lN sodium hydroxide in ethanol.
Yield: 78.3~ of theory, Melting point: 154-156C (decomp.) C2sH22N6O4 x 0.5 H20 (47 Calculated: C 62.62 H 4.83 N 17.52 Found:62.76 4.92 17.24 . ~
- . : : , - .. ::~ , , ~
:

: ',, , ' ' .:, . ., .: .~: ~ ', , . ~

. .

2~73~
- I.23 -Example_119 2-Ethoxy-1-[4-[~-carboxy)benzyloxy]benzylJ-lH-benzimidazol-4-carboxylic acid . ~
Prepared analogously to Example lb from 2-ethoxy-1-[4-[(~-ethoxycarbonylbenzyloxy]benzyl]-4-ethoxycarbonyl~lH-benzimidazole and lN sodium hydroxide in ethanol.
Yield: 34.9~ of theory, Melting point: 131-133C
Rf value: 0.25 (silica gel; ethyl acetate/ethanol/
ammonia = 80:~0:2) - . ~

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.~ ' .

~3,5~4 L

- 12~ -In the Examples of Pharmaceutlcal Formulations which Eollow, any suitable compound of formula I, particularly compounds A to I o~ the pharmacological test report, m~y be used as the active substance:

Exam~le I

Ampoules containing 50 mg of active substance per 5 ml Composition:
Active substance 50 my KH2P04 2 mg Na2HP04 x 2H20 50 mg NaCl 12 mg Water ~or injections ad 5 ml Preparation:

The buffer suhstances and isotonic substance are dissolved in some of the water. The active substance is added and, once it has been completely dissolved, water is added to make up the required volume.

Example II

Ampoules containing 100 mg of active substance per 5 ml .. ... .. _ _ .
Composition:
Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene-glycol block polymer 250 mg Water for injections ad 5 ml 2 ~ 7 ,~

Pre~aration:

Methyl glucamine is dissolved ln some of the water and the active substance is dissolved with stirring and heating. After addition of the solvents, water is added to make up the desired volume.

Example III

Tablets containing 50 mg of active substance .

Composition:
Active substance 50.0 mg Calcium pho~phate 70.0 mg Lactose 40.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 1.5 mg 200.0 mg Preparation:

The active substance, CaHPO4, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50~C in a circulating air dryer and screened again.

After the lubricant has been added, the granules are compressed in a tablet making machine.

.
. :, ' ' '. ' . . ' .' . ; .

.

~3~1 Example IV

Coated table-ts containing 50 mg of active substance Composition:
Active substance 50.0 my Lysine 25.0 mg Lactose 60.0 mg Corn s-tarch 34.0 mg Gelatin 10.0 mg Magnesium stearate 180.0 mg Preparation:

The active substance is mixed with the excipienks and moistened with an a~ueous 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 m~ of active substance ... . . _ _ Composition:
Active substance 100.0 mg Lysine 50.0 mg Lactose 86.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 2.8 mg Microcrystalline cellulose 60.0 mg Magnesium stearate 1.2 mg 350~0 mg . ~:
.
' . ' ' ' `:' ` ~', ; :
~' : .

2~3~

_eparat]on:

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 ~5~C.
After drying, it is screened agairl and the magnesium stearate is added. This mixture is compressed into cores.

I'he cores thus produced are covered with a coating by known methods. Colourings may be added to the coating suspension or solution.

Example VI

Capsules containing 250 mg of active substance Composition:
Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 mg 320.0 mg Preparation:

The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The final mixture is packed into size ~ hard gelatin capsules.

.
- ' . :

.

3 ~ ~
- 12~ -Example VII

Oral suspension containing 50 mg O e active substance per 5 ml Composition:
Active substance 50.0 mg Hydroxyethylcellulose 50.0 my Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg Water ad 5.0 ml Preparation:

Distilled water is heated to 70C. Hydroxyethyl-cellulose 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 l00 mg of active substance -Composition:
Active substance l00.0 mg Solid fat (adeps solidus) 1600.0 mq 1700.0 mg ~ ~ ' . ':
:
.
`

2 ~ c ~

Pre~ar~atlon:

The hard fat is melted. At 40C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38C and poured into slightly chilled suppository moulds.

. .
.

:
:, :

Claims (18)

Claim:
1. Compounds of formula I

(I) (wherein n represents the number 0 or 1;

A represents a straight-chained or branched alkylene group;

B represents an oxygen atom, a carbonyl, hydroxy-methylene, sulphenyl, sulphinyl or sulphonyl group, a straight-chained or branched alkylene group, a C2-4-alkylidene group, a 1,1-cycloalkylene group or an imino group optionally substituted by an alkyl group or by a C1-4-alkanoyl group;

Ra represents a chlorine or bromine atom, a hydroxy, alkylsulphonyloxy, phenylsulphonyloxy or phenylalkyl-sulphonyloxy group or a group of the formula or (wherein one of the groups D1, D2 and D3 represents a methylene or imino group and the remaining groups of D1, D2 and D3 are each methine groups, whilst additionally a methine group may be replaced by a nitrogen atom and one of the methine groups may be substituted by a group R5 and, optionally, another of the methine groups may be substituted by a group R4;

none, one or two of the groups D4, D5, D6 and D7 represent a nitrogen atom and the remaining groups of D4, D5, D6 and D7 each represent methine groups, whilst additionally a methine group may be substituted by a group R4 and another methine group may be substituted by a group R5;

E represents a carbon-carbon bond, an oxygen or sulphur atom, a hydroxymethylene or carbonyl group or an imino group optionally substituted by a C1-6-alkyl group, by a cycloalkyl group, by a C2-5-alkanoyl group or by an allyl, phenyl or benzyl group;

X represents an oxygen or sulphur atom or an imino group optionally substituted by an alkyl, phenyl or phenylalkyl group;

R1 represents a straight-chained or branched C1-9-alkyl, C2-6-alkenyl or C2-6-alkynyl group optionally substituted by a cycloalkyl group, by a fluorine, chlorine or bromine atom, or by a hydroxy, amino, alkylamino, dialkylamino or .alpha.,.alpha.-difluoroethane group, or R1 may represent a C1-4-perfluoroalkyl group or a cycloalkyl group optionally mono- or di-substituted by a trifluoromethyl group or by an alkyl group;

R2 represents a hydrogen, fluorine, chlorine or bromine atom, a C1-5-alkyl or C1-5-perfluoroalkyl group, a cyano or nitro group;

R3 represents a hydrogen atom, a cyano group, a C1-6-alkyl group optionally substituted by a hydroxy or alkoxy group, a C1-6-perfluoroalkyl group, a C3-6-alkenyl group optionally substituted by fluorine atoms, a phenylalkyl or phenyl(C2-4-alkenyl) group, or a C1-5-alkyl group which is terminally substituted by an imidazol-l-yl, tetrazolyl, phthalimido, R6COO-, R7S-, R7SO-, R7SO2-, R7CO-, R7NHCOO-, R7NHCO-, R7NHCONR7-, R8CONR7- or R8SO2NR7-group or by a triazolyl group itself optionally mono- or disubstituted by an acetoxy or alkyl group;

R6 represents a C1-8-alkyl or C1-8-perfluoroalkyl group, or a cycloalkyl, phenyl, benzyl, phenylethyl, adamantyl, naphthyl, naphthylmethyl or naphthylethyl group;

R7 represents a hydrogen atom or a group R6;

R8 represents a group R7 or a piperazino group optionally substituted by an alkyl or phenyl group in the 4-position, or R8 represents a pyrrolidino, piperidino, hexamethyleneimino, morpholino, R7O- or (R7)2N-group;

R4 represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, a cycloalkyl group, a C1-6-alkyl group optionally substituted by a cycloalkyl, hydroxy, alkoxy, alkylamino, dialkylamino, alkoxycarbonyl, alkylaminocarbonyl or dialkylamino-carbonyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom, a straight-chained or branched C1-6-alkyl or C1-6-perfluoroalkyl group, a C2-6-alkenyl or C2-6-alkynyl group, in which the above-mentioned alkyl and alkenyl moieties may each be mono- or di-substituted by a heteroaryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, N-alkyl-alkylcarbonylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, piperidinocarbonyl, morpholinocarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazol-5-yl, tetrazol-5-yl-aminocarbonyl, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl, alkylsulphonylaminocarbonyl, heteroarylaminosulphonyl or alkylcarbonylaminosulphonyl group, or R5 represents a C1-7-alkoxy group substituted in the 2-, 3-, 4-, 5-, 6- or 7-position by an imidazolyl, tetrazolyl, benzimidazolyl or tetrahydrobenzimidazolyl group, or a phenylalkoxy group optionally substituted in the alkoxy moiety by a 1H-tetrazol-5-yl or 1-triphenylmethyl-tetrazol-5-yl group, or a carboxy group or a group which is metabolically converted into a carboxy group in vivo, or a C1-4-alkylsulphonyloxy group, a benzenesulphonyloxy or phenylalkylsulphonyloxy group, or an acylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenyl group, wherein the acyl moiety is a C1-7-alkanoyl group, a C2-4(alkoxycarbonyl) group, a C1-6-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenylalkanesulphonyl, naphthylenesulphonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl group, in which the above-mentioned phenyl nuclei may each be mono- or di-substituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group and the substituents may be identical or different, or a phthalimino, homophthalimino, 2-carboxyphenylcarbonyl-amino or 2-carboxyphenylmethylamino group, in which a carbonyl group in a phthalimino group may be replaced by a methylene, alkyl-methylene or dialkyl-methylene group and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups, wherein the phenyl nuclei in any of said groups may be additionally mono- or disubstituted by alkyl or alkoxy groups optionally wholly or partially hydrogenated, in which the substituents may be the same or different, or a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, wherein a methylene group of the alkyleneimino or alkenyleneimino group may be replaced by a carbonyl or sulphonyl group, or a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene moieties each contain 9 or 10 carbon atoms and may be substituted by 1, 2 or 3 methyl groups and may have an endomethylene group replaced by an oxygen atom, or a glutaric acid imino group in which the n-propylene group may be perfluorinated and may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a maleic acid imido or succinimido group optionally mono- or di-substituted by an alkyl or phenyl group, wherein the substituents may be identical or different, or a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group, which contains an imino group, an oxygen or sulphur atom, or which contains an imino group and an oxygen, sulphur or nitrogen atom, or R5 represents a 6-membered heteroaromatic ring bound via a carbon atom which contains 1 or 2 nitrogen atoms, which 5- or 6-membered heteroaromatic ring is attached via two adjacent carbon atoms to an n-propylene, n-butylene or 1,3-butadienyl group or via an imino group and an adjacent carbon atom to an n-propylene, n-butylene or 1,3-butadienyl group and, in an anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene group in the 3-, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or, in an anellated phenyl ring thus formed, one or two methine groups may be replaced by nitrogen atoms, whilst additionally the above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted in the carbon structure by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylamino-sulphonyl or dialkylaminosulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and any -NH- group present in an imidazole ring may be substituted by a C1-6-alkyl group or by a cycloalkyl group, or a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, wherein a phenyl group may be fused onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the nitrogen atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or an imidazolidinedione group optionally substituted by an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, or a pyridazin-3-one or dihydro-pyridazin-3-one group optionally substituted in the 2-position by an optionally phenyl-substituted alkyl group, and with the carbon structure additionally optionally substituted by 1 or 2 alkyl groups, or an R11-NR10-CO-NR9 group (wherein R9 represents a hydrogen atom, a C1-8-alkyl group or a phenylalkyl group, R10 represents a hydrogen atom, a C1-8-alkyl group, a C3-5-alkenyl group, a phenylalkyl group or a C5-7-cycloalkyl group, and R11 represents a hydrogen atom or a C1-6-alkyl group, and one of the groups R9, R10 and R11 may also represent a bicyclohexyl or biphenylyl group, and R10 and R11 together with the nitrogen atom between them may represent a straight-chained C4-6-alkyleneimino group or a morpholino group, and R9 and R11 together may represent a C2-4,-alkylene group));

R6 represents a cyano, trifluoromethylcarbonylamino, trifluoromethylcarbonylaminomethyl, trifluoromethyl-sulphonylamino, trifluoromethylsulphonylaminomethyl, alkylsulphonylamino, alkylsulphonylaminomethyl, arylsulphonylamino, arylsulphonylaminomethyl, aralkylsulphonylamino, aralkylsulphonylaminomethyl, arylsulphonylaminocarbonyl, benzylsulphonylamino-carbonyl, sulpho, aminosulphonyl, alkylaminosulphonyl, aralkylaminosulphonyl, arylaminosulphonyl, alkylcarbonylaminosulphonyl, aralkylcarbonylamino-sulphonyl, arylcarbonylaminosulphonyl, sulphomethyl, aminosulphonylmethyl, alkylaminosulphonylmethyl, aralkylaminosulphonylaminomethyl, arylaminosulphonyl-methyl, alkylcarbonylaminosulphonylmethyl, aralkyl-carbonylaminosulphonylmethyl, arylcarbonylamino-sulphonylmethyl, phosphino, O-alkyl-phosphino, O-aralkyl-phosphino, O-aryl-phosphino, phosphono, O-alkyl-phosphono, O-aralkyl-phosphono, O-aryl-phosphono, O,O-dialkylphosphono, phosphono-methyl, O-alkyl-phosphono-methyl, O-aralkyl-phosphono-methyl, O-aryl-phosphono-methyl, O,O-dialkylphosphono-methyl, phosphato, O-alkyl-phosphato, O-aralkyl-phosphato, O-aryl-phosphato or O,O-dialkoxy-phosphoryl group, a 1H-tetrazolyl, 1H-tetrazolylalkyl, 1H-tetrazolylaminocarbonyl or triazolyl group optionally substituted by an alkyl, trifluoromethyl, phenylalkyl or triphenylmethyl group, or a (C1-6alkyl)sulphonylaminocarbonyl or perfluoro(C1-6alkyl)-sulphonylaminocarbonyl group, a carboxy group or a group which is metabolically converted into a carboxy group in vivo, or an aralkoxycarbonyl group;

Rc represents a hydroyen atom, an alkyl, aralkyl, aryl, carboxy or alkoxycarbonyl group;

Rd represents a straight-chained or branched C1-10 alkyl group, a straight-chained or branched C2-10-alkenyl or C2-10-alkynyl group, a cycloalkyl or cycloalkylalkyl group, a phenyl group optionally mono- or di-substituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, or a biphenyl, naphthyl or heteroaryl group;

Re and Rf represent hydrogen atoms, or if R5 represents a phthalimino, homophthalimino, 2-carboxyphenylcarbonyl-amino or 2-carboxyphenylmethyl-amino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene, alkyl-methylene or dialkyl-methylene group and a methylene group in a homophthalimino group can be substituted by one or two alkyl groups, wherein the phenyl nuclei in any of said groups may be additionally mono- or disubstituted by alkyl or alkoxy groups optionally wholly or partially hydrogenated, in which the substituents may be the same or different, or a carboxy group or a group which is metabolically converted into a carboxy group in vivo, or a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, wherein a methylene group of the alkyleneimino or alkenylenimino group may be replaced by a carbonyl or sulphonyl group, or a bicyeloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene moieties may each contain 9 or 10 carbon atoms and may be substituted by 1, 2 or 3 methyl groups and may have an endomethylene group replaced by an oxygen atom, or a glutaric acid imino group wherein the n-propylene group may be perfluorinated and may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a maleic acid imido or succinimido group optionally mono- or di-substituted by an alkyl or phenyl group, in which the substituents may be identical or different, or a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group and containing an imino group, an oxygen or sulphur atom or containing an imino group and an oxygen, sulphur or nitrogen atom, or a 6-membered heteroaromatic ring bound via a carbon atom and containing 1 or 2 nitrogen atoms, wherein the 5- or 6-membered heteroaromatic ring is attached via two adjacent carbon atoms to an n-propylene, n-butylene or 1,3-butadienyl group, or via an imino group and an adjacent carbon atom to an n-propylene, n-butylene or 1,3-butadienyl group, and in an anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene ring in the 3-, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or, in an anellated phenyl ring thus formed, one or two methine groups may be replaced by nitrogen atoms, whilst additionally the above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylamino-sulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups and any -NH- group present in an imidazole ring may be substituted by a C1-6-alkyl group or by a cycloalkyl group, or a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, wherein a phenyl group may be condensed onto the pyridine ring via two adjacent carbon atoms and a methylene group adjacent to the nitrogen atom in a pyrrolidine or piperidine ring may be replaced by a carbonyl group, or an imidazolidinedione group optionally substituted by an alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene group, or a pyridazin-3-one or dihydro-pyridazin-3-one group optionally substituted in the 2-position by an optionally phenyl-substituted alkyl group and additionally optionally substituted in the carbon skeleton by 1 or 2 alkyl groups, or an R11-NR10-CO-NR9 group (wherein R9, R10 and R11 are defined as hereinbefore), then Re may also represent a hydrogen, fluorine, chlorine or bromine atom or an alkyl or alkoxy group and Rf may also represent a fluorine, chlorine or bromine atom or an alkoxy group;

wherein, unless otherwise stated, any alkyl, alkylene or alkoxy moiety contains 1 to 4 carbon atoms and any cycloalkyl moiety contains 3 to 7 carbon atoms, any aryl group, unless otherwise specified is a phenyl group optionally mono- or di-substituted by a fluorine, chlorine or bromine atom or by a hydroxy, alkyl, alkoxy, phenylalkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylamino-sulphonyl group, wherein each alkyl moiety may contain 1 to 4 carbon atoms, or a naphthyl group, any heteroaryl group, unless otherwise specified is a 5-membered heteroaromatic ring which contains an imino group, an oxygen or sulphur atom, or contains an imino group and an oxygen, sulphur or nitrogen atom, or contains an imino group and 2 or 3 nitrogen atoms, and a 6-membered heteroaromatic ring which contains 1, 2 or 3 nitrogen atoms, whilst the above-mentioned rings may additionally be mono- or di-substituted by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylaminosulphonyl or dialkylamino-sulphonyl group), and the isomer mixtures, the tautomers, enantiomers and salts thereof with inorganic or organic acids or bases.
2. Compounds as claimed in claim 1 comprising as a group which is metabolically converted into a carboxy group in vivo an ester of formula -CO-OR', -CO-O-(HCR")-O-CO-R"' or -CO-O-(HCR")-O-CO-OR"' (wherein R' represents a straight-chained or branched C1-6-alkyl group, a C5-7-cycloalkyl group, a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, pivaloyloxymethyl,-phthalidylmethyl, (1,3-dioxa-2-oxo-4-methyl-cyclopenten-5-yl)-methyl, methoxymethyl or cinnamyl group, R" represents a hydrogen atom or a methyl group and R"' represents a straight-chained or branched C1-6-alkyl group, a C5-7-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group).
3. Compounds of formula I as claimed in either one of claims 1 and 2 wherein Ra, Rb, Rc, Rd, Re, Rf, A, B and n are as defined in claim 1 hereinbefore, with the proviso that D4, D5, D6 and D7 represent methine groups with the additional provisos (a) to (j), or D7 represents a nitrogen atom and the groups D4, D5 and D6 represent methine groups with the additional provisos (a) to (g) and (k) to (m) or (a) to (g) and (n) to (p), or one of the groups D4, D5 and D6 represents a nitrogen atom and the remaining groups of groups D4, D5, D6 and D7 represent methine groups, or two of the groups D4, D5, D6 and D7 represent nitrogen atoms and the remaining groups of groups D4, D5, D6 and D7 represent methine groups, with the additional provisos that either (a) n represents the number 1, or (b) E has the meanings given for E hereinbefore with the exception of the carbon-carbon bond, or (c) A has the meanings given for A hereinbefore with the exception of the methylene group, or (d) B has the meanings for B given hereinbefore with the exception of the oxygen atom, or (e) Rb has the meanings given for Rb hereinbefore with the exception of the carboxyl group, or (f) Rc has the meanings given for Rc hereinbefore with the exception of the hydrogen atom, or (g) Rd has the meanings given for Rd hereinbefore with the exception of the phenyl group, or (h) R1 has the meanings given for R1 hereinbefore with the exception of the n-butyl group, or (i) R4 has the meanings given for R4 hereinbefore with the exception of the methyl group in position 7, or (j) R5 has the meanings given for R5 hereinbefore with the exception of the hydrogen atom, or (k) R1 has the meanings given for R1 hereinbefore with the exception of the ethyl group, or (l) R4 has the meanings given for R4 hereinbefore with the exception of the methyl group in position 7, or (m) R5 has the meanings given for R5 hereinbefore with the exception of the methyl group in position 5, or (n) R1 has the meanings given for R1 hereinbefore with the exception of the n-propyl group, or (o) R4 has the meanings given for R4 hereinbefore with the exception of the hydrogen atom, or (p) R5 has the meanings given for R5 hereinbefore with the exception of the hydrogen atom, and the remaining groups have the meanings given hereinbefore, whilst additionally a methine group mentioned in the above definitions of groups D4, D5, D6 and D7 may be substituted by a group R4 and a further methine group mentioned in the above definitions of groups D4, D5, D6 and D7 may be substituted by a group R5, and the isomer mixtures thereof, the tautomers, enantiomers and salts thereof with organic or inorganic acids or bases.
4. Compounds of formula I as claimed in any one of claims 1 to 3 wherein n represents the number 0 or 1;

A represents a straight-chained or branched alkylene group;

B represents an oxygen atom, a straight-chained or branched C1-3-alkylene group or an imino group optionally substituted by an alkyl group or by a C1-4-alkanoyl group;

Ra represents a group of khe formula or (wherein none, one or two of the groups D4, D5, D6 and D7 represents a nitrogen atom and the remaining groups of D4, D5, D6 and D7 each represent methine groups, whilst additionally a methine group may be substituted by a group R4 and a further methine group may be substituted by a group R5;

E represents a carbon-carbon bond, an oxygen or sulphur atom or an imino group optionally substituted by a C1-4-alkyl group;

X represents an oxygen or sulphur atom;

R1 represents a straight-chained or branched C1-6-alkyl group, a straight-chained or branched C2-6-alkenyl or C2-6-alkynyl group, whilst the above-mentioned saturated and unsaturated alkyl moieties may each be substituted by a fluorine, chlorine or bromine atom or by a hydroxy or amino group, or R1 represents a C3-6-cycloalkyl group;

R2 represents a hydrogen, fluorine, chlorine or bromine atom, a C1-5-alkyl or C1-5-perfluoroalkyl group or a cyano or nitro group;

R3 represents a hydrogen atom, a cyano group, a C1-3-alkyl group optionally substituted by a hydroxy or alkoxy group, a C1-3-perfluoroalkyl group, a C3-6-alkenyl group optionally substituted by fluorine atoms, a C1-3-alkyl group which is substituted in the terminal position by an R6COO-, R7S-, R7S-, R7SO2-, R7CO-, R7NHCOO-, R7NHCO-, R7NHCONR7-, R8CONR7- or R8SO2NR7 group, (wherein R6 represents a C1-4-alkyl or C1-4-perfluoroalkyl group or a cycloalkyl, phenyl, benzyl or phenylethyl group;

R7 represents a hydrogen atom or a group R6; and R8 represents a group R7);

R4 represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, a cycloalkyl growp, a C1-6-alkyl group optionally substituted by a hydroxy, alkoxy or alkoxycarbonyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom, or a straight-chained or branched C1-6-alkyl or C1-6-perfluoroalkyl group, a C2-6-alkenyl or C2-6-alkynyl group, whilst the above-mentioned alkyl and alkenyl moieties may each be mono- or di-substituted by a heteroaryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, N-alkyl-alkylcarbonylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or tetrazol-5-yl group, or a C1-5-alkoxy group or an .alpha.-(1H-tetrazol-5-yl)-benzyloxy group, or a carboxy group or a group which is metabolically converted into a carboxy group in vivo, or a C1-4-alkylsulphonyloxy group or a benzenesulphonyloxy or phenylalkylsulphonyloxy group, or an acylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenyl, cycloalkyl, phenylalkyl or cycloalkylalkyl group, in which the acyl group is a-C1-5-alkanoyl group, a C2-4(alkoxycarbonyl) group, a C1-6-alkylsulphonyl group, a benzoyl, benzenesulphonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl group, whilst the above-mentioned phenyl nuclei may each be mono- or di-substituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group and the substituents may be identical or different, or a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene, alkyl-methylene or dialkyl-methylene group, and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups wherein the phenyl nuclei in any of said groups may be additionally mono- or disubstituted by alkyl or alkoxy groups optionally wholly or partially hydrogenated, in which the substituents may be the same or different, or a 5-, 6- or 7-membered alkyleneimino group optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, wherein a methylene group of the alkyleneimino group may be replaced by a carbonyl or sulphonyl group, or a maleic acid imido or succinimido group optionally mono- or di-substituted by an alkyl or phenyl group, wherein the substituents may be identical or different, or a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group, which contains an imino group, an oxygen or sulphur atom or which contains an imino group and an oxygen, sulphur or nitrogen atom, or a 6-membered heteroaromatic ring bound via a carbon atom which contains 1 or 2 nitrogen atoms, which 5- or 6-membered heteroaromatic ring is attached via two adjacent carbon atoms to an n-propylene, n-butylene or 1,3-butadienyl group or via an imino group and an adjacent carbon atom to an n-propylene, n-butylene or 1,3-butadienyl group and, in an anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene group in the 3-, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or, in an anellated phenyl ring thus formed, one or two methine groups may be replaced by nitrogen atoms, whilst additionally the above-mentioned fused aromatic or heteroaromatic rings may be monosubstituted in the carbon structure by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylamino-sulphonyl or dialkylaminosulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and any -NH- group present in an imidazole ring may be substituted by a C1-6-alkyl group, or an R11-NR10-CO-NR9 group (wherein R9 represents a hydrogen atom, a C1-6-alkyl group or a phenylalkyl group, R10 represents a hydrogen atom, a C1-6-alkyl group, a phenylalkyl group or a C5-7-cycloalkyl group, R11 represents a hydrogen atom or a C1-6-alkyl group, or R10 and R11 together with the nitrogen atom between them represent a straight-chained C4-6-alkyleneimino group or a morpholino group, or R9 and R11 together represent a C2-4-alkylene group));

Rb represents a cyano, carboxy, arylsulphonylamino-carbonyl, benzylsulphonylaminocarbonyl, sulpho, alkylcarbonylaminosulphonyl, aralkylcarbonylamino-sulphonyl, arylcarbonylaminosulphonyl, alkylcarbonyl-aminosulphonylmethyl, aralkylcarbonylaminosulphonyl-methyl, arylcarbonylaminosulphonylmethyl, phosphino, 0-alkyl-phosphino, phosphono, 0-alkyl-phosphono, 0,0-dialkylphosphono, phosphono-methyl, 0-alkyl-phosphono-methyl, 0,0-dialkylphosphono-methyl, phosphato or 0-alkyl-phosphato group, a 1H-tetrazolyl or 1H-tetrazolyl-alkyl group optionally substituted by a phenylalkyl or triphenylmethyl group, an (C1-6alkyl)sulphonylamino-carbonyl or perfluoro(C1-6alkyl)sulphonylaminocarbonyl group, a group which is metabolically converted into a carboxy group in vivo, or an aralkoxycarbonyl group;

Rc represents a hydrogen atom, a methyl, phenyl, benzyl, carboxy or alkoxycarbonyl group;

Rd represents a straight-chained or branched C1-6-alkyl group, a straight-chained or branched C2-6-alkenyl or C2-6-alkynyl group, a cycloalkyl or cycloalkylalkyl group, a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, or a biphenyl, naphthyl or heteroaryl group;

Re and Rf represent hydrogen atoms or, if R5 represents a phthalimino or homophthalimino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene, alkylmethylene or dialkylmethylene group, and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups, wherein the phenyl nuclei in any of said groups may be additionally mono- or disubstituted by alkyl or alkoxy groups optionally wholly or partially hydrogenated, in which the substituents may be the same or different, or a carboxy group or a group which is metabolically converted into a carboxy group in vivo, or a 5-, 6- or 7-membered alkyleneimino group optionally substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, wherein a methylene group the alkyleneimino group may be replaced by a carbonyl or sulphonyl group, or a maleic acid imido or succinimido group optionally mono- or di-substituted by an alkyl or phenyl group, the substituents being identical or different, or a 5-membered heteroaromatic ring bound via a carbon atom or via an imino group, which contains an imino group, an oxygen or sulphur atom or which contains an imino group and an oxygen, sulphur or nitrogen atom, or a 6-membered heteroaromatic ring bound via a carbon atom which contains 1 or 2 nitrogen atoms, which 5- or 6-membered heteroaromatic ring is attached via two adjacent carbon atoms to an n-propylene, n-butylene or 1,3-butadienyl group or via an imino group and an adjacent carbon atom to an n-propylene, n-butylene or 1,3-butadienyl group and, in an anellated pyridine ring thus formed, a methine group may be replaced by a nitrogen atom and a vinylene group in the 3-, 4-position relative to the nitrogen atom of the pyridine ring formed may be replaced by a sulphur atom or, in an anellated phenyl ring thus formed, one or two methine groups may be replaced by nitrogen atoms, whilst additionally the above-mentioned fused -aromatic or heteroaromatic rings may be monosubstituted in the carbon structure by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl, aminosulphonyl, alkylamino-sulphonyl or dialkylaminosulphonyl group or may be disubstituted by fluorine or chlorine atoms or by methyl, methoxy or hydroxy groups, and any -NH- group present in an imidazole ring may be substituted by a C1-6-alkyl group, or an R11-NR10-CO-NR9 group wherein R9 to R11 are defined as hereinbefore, then Re may also represent a hydrogen, fluorine, chlorine or bromine atom or an alkyl or alkoxy group and Rf may also represent a fluorine, chlorine or bromine atom or an alkoxy group;

whilst unless otherwise specified the expression "a group which is converted metabolically into a carboxy group in vivo" is defined as in claim 2, any alkyl, alkylene or alkoxy moiety contains 1 to 4 carbon atoms and any cycloalkyl moiety contains 3 to 7 carbon atoms, any aryl group, unless otherwise specified is a phenyl group optionally mono- or di-substituted by a fluorine, chlorine or bromine atom or by a hydroxy, alkyl, alkoxy, phenylalkoxy, phenyl or nitro group, wherein each alkyl moiety may contain from 1 to 4 carbon atoms, or a naphthyl group, and any heteroaryl group, unless otherwise specified is a 5-membered heteroaromatic ring which contains an imino group, an oxygen or sulphur atom or which contains an imino group and an oxygen, sulphur or nitrogen atom or which contains an imino group and 2 or 3 nitrogen atoms, and a 6-membered heteroaromatic ring which contains 1, 2 or 3 nitrogen atoms, whilst the above-mentioned rings may additionally be mono- or di-substituted by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, hydroxy, phenyl or nitro group, and the isomer mixtures, tautomers, enantiomers and salts thereof, with the exclusion of the following compounds:

(i) 2-n-butyl-1-[4-[(.alpha.-carboxy)benzyloxy]benzyl]-benzimidazole, (ii) 2-n-propyl-7-methyl-3-[4-[(.alpha.-carboxy)benzyloxy]-benzyl]imidazo[4,5-b]pyridine and (iii) 5,7-dimethyl-2-ethyl-3-[4-[.alpha.-carboxy)benzyloxy]-benzyl]imidazo[4,5-b]pyridine and their salts.
5. Compounds of formula I as claimed in any one of claims 1 to 4 wherein n represents the number 0;

A denotes a methylene, ethylene or ethylidene group;

B denotes an oxygen atom, a methylene, imino, methylimino or acetylimino group;

Ra denotes a group of the formula or (wherein none, one or two of the groups D4, D5, D6 and D7 represents a nitrogen atom and the remaining groups of D4, D5, D6 and D7 each represent methine groups, whilst additionally a methine group may be substituted by a group R4 and another methine group may be substituted by a group R5;

E represents an oxygen atom or a carbon-carbon bond;

R1 represents a straight-chained or branched C1-6-alkyl group;

R2 represents a hydrogen, fluorine, chlorine or bromine atom;

R3 represents a hydroxyalkyl group having 1 or 2 carbon atoms;

R4 represents a hydrogen atom or a C1-3-alkyl group; and R5 represents a hydrogen, fluorine, chlorine or bromine atom; or a straight-chained or branched C1-3-alkyl group or an .alpha.-(1H-tetrazol-5-yl)-benzyloxy group, or an amino or nitro group, or a carboxy group or a (C1-3alkoxy)carbonyl group, or an acylamino group optionally substituted at the nitrogen atom by a C1-5-alkyl group, wherein the acyl group represents a C1-5-alkanoyl group or a benzenesulphonyl group, the above-mentioned phenyl nucleus optionally being mono- or di-substituted by a methyl or methoxy group and the substituents being identical or different, or a 5-, 6- or 7-membered alkyleneimino group optionally substituted by- one or two methyl groups, wherein a methylene group of the alkyleneimino group may be replaced by a carbonyl or sulphonyl group, or a 2,3-dimethylsuccinimido, phthalimino, homophthalimino or isoindolin-1-on-yl group, or a benzimidazol-2-yl group optionally substituted in the 1-position by a C1-3-alkyl group, or an R11-NR10-CO-NR9 group (wherein R9 represents a hydrogen atom, a C1-5-alkyl group or a phenyl(C1-3alkyl) group, R10 represents a hydrogen atom, a C1-5-alkyl group or a cyclohexyl group, R11 represents a hydrogen atom, a benzyl group or a C1-5-alkyl group or R9 and R11 together represent a C2-3-alkylene group));

Rb represents a carboxy, 1H-tetrazolyl or 0-(C1-3alkyl)-phosphono or (C1-3alkyl)sulphonylaminocarbonyl group;

Rc represents a hydrogen atom or a phenyl group;

Rd represents a straight-chained or branched C1-4-alkyl group, a cyclohexyl, cyclohexylmethyl, phenyl, biphenyl, methoxyphenyl, chlorophenyl, pyridyl or naphthyl group;

Re and Rf represent hydrogen atoms or, if R5 represents a benzimidazol-2-yl group optionally substituted in the 1-position by a C1-3-alkyl group, or a 2,3-dimethylsuccinimino group, or a 5-, 6- or 7-membered alkyleneimino group optionally substituted by one or two methyl groups, wherein a methylene group of the alkyleneimino group may be replaced by a carbonyl or sulphonyl group, or an R11-NR10-CO-NR9 group, wherein R9 to R11 are defined as hereinbefore, then Re may also represent a hydrogen, chlorine or bromine atom or a methoxy group and Rf may also represent a chlorine or bromine atom or a methoxy group, and the isomer mixtures, tautomers, enantiomers and salts thereof, with the exclusion of the following compounds:

(i) 2-n-butyl-1-[4-[(.alpha.-carboxy)benzyloxy]benzyl]-benzimidazole, (ii) 2-n-propyl-7-methyl-3-[4-[(.alpha.-carboxy)benzyloxy]-benzyl]imidazo[4,5-b]pyridine and (iii) 5,7-dimethyl-2-ethyl-3-[4-[(.alpha.-carboxy)benzyloxy]-benzyl]imidazo[4,5-b]pyridine, and their salts.
6. A compound as claimed in claim 1 being:

(a) 2-n-propyl-4-methyl-1-[4-[(.alpha.-carboxy)benzyloxy]-benzyl]benzimidazole;

(b) 2-n-butyl-1-[4-[(.alpha.-carboxy)benzyloxy]benzyl]-6-dimethylaminocarbonylamino-benzimidazole;

(c) 2-n-propyl 6-(1-methyl-benzimidazol-2-yl)-4-methyl-1-[4 [(.alpha.-carboxy)benzyloxy]benzyl]berlzimidazole;

(d) 2-methyl-4-[4'-[(.alpha.-carboxy)benzyloxy]benzyloxy]-quinoline;

(e) 2-n-butyl-8-methyl-3-[4-[(.alpha.-carboxy)benzyloxy]-benzyl]quinazolin-4-one semihydrate;

(f) 2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-1-[4-[.alpha.-(1H-tetrazol 5-yl)benzyloxy]benzyl]-benzimidazole;

(g) 2-n-butyl-6-(N propionyl-methylamino)-1-[4-[(1-carboxy-3-methyl)butyloxy]benzyl]benzimidazole;

(h) 2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-3-[4-[.alpha.-(1H-tetrazol-5-yl)-benzyloxy]benzyl]imidazol[4,5-b]pyridine; or (i) 2-n-butyl-1-[4-[.alpha.-(.alpha.-ethyl-phosphono)benzylamino]-benzyl]benzimidazole;

or a salt thereof with an inorganic or organic acid or base.
7. A compound as claimed in any one of claims 1 to 6 being a physiologically acceptable salt of a compound of formula I as defined in any one of claims 1 to 6.
8. A pharmaceutical composition containing a compound of formula I as claimed in any one of claims 1 to 6 or a physiologically acceptable salt thereof together with at least one physiologically acceptable carrier or excipient.
9. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps:

a) reacting a compound of formula II

Ra - H (II) (wherein Ra is as defined in any one of claims 1 to 6) with a compound of formula III

(III) (wherein A, B, n, Rb, Rc, Rd, Re and Rf are as defined in any one of claims 1 to 6 and Z1 represents a nucleophilic leaving group) and if required hydrolysing the compound thus obtained;

b) reacting a compound of formula IV

(IV) (wherein Ra, Re, Rf and A are as defined in any one of claims 1 to 6, B' represents a straight-chained or branched C1-4-alkylene group and Z2 represents a nucleophilic leaving group) with a compound of formula V

(V) (wherein Rb, Rd and n are as defined in any one of claims 1 to 6 and Rc' represents an alkoxycarbonyl group) and optionally hydrolysing and/or decarboxylating the compound thus obtained;

c) to prepare compounds of formula I wherein B
represents an oxygen or sulphur atom or an optionally alkyl-substituted imino group) reacting a compound of formula VI

(VI) (wherein Ra, Re, Rf and A are as defined in any one of claims 1 to 6 and B" represents an oxygen or sulphur atom or an optionally alkyl-substituted imino group) with a compound of formula VII

(VII) (wherein Rb, Rc, Rd and n are as defined in any one of claims 1 to 6 and Z3 represents a nucleophilic leaving group) and optionally hydrolysing the compound thus obtained;

d) (to prepare a compound of general formula I wherein Rb represents a carboxy group) converting a compound of formula VIII

(VIII) (wherein Ra, Rc, Rd, Re, Rf, A, B and n are as defined in any one of claims 1 to 6 and Rb' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding compound of formula I by hydrolysis, thermolysis or hydrogenolysis;

e) (to prepare a compound of formula I wherein Rb represents a 1H-tetrazolyl group) cleaving a protective group from a compound of formula IX

(IX) (wherein Ra, Rc, Rd, Re, Rf, A, B and n are as defined in any one of claims 1 to 6 and Rb" represents a lH-tetrazolyl group protected in the 1-or 2-position by a protecting group);

f) (to prepare a compound of formula I wherein Rb represents a lH-tetrazolyl group) reacting a compound of formula X

(X) (wherein Ra, Rc, Rd, Re, Rf, A, B and n are as defined in any one of claims 1 to 6) with hydrazoic acid or a salt thereof;

g) (to prepare compounds of formula I wherein Ra represents a group of the formula cyclising a compound of formula XI

(XI) (wherein D4, D5, D6 and D7 are as defined in claims 1 to 6, one of the groups X1 or Y1 represents a group of formula and the other group X1 or Y1 represents a group of formula (wherein R1, A, B, E, n, Rb, Rc, Rd, Re and Rf are as defined in any one of claims 1 to 6, Z4 and Z5, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups, or Z4 and Z5 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C1-3-alkyl group, or a C2-3-alkylenedioxy or alkylenedithio group));

h) (to prepare compounds of formula I wherein R5 represents an R11-NR10-CO-NR9 group) reacting a compound of formula XII
(XII) (wherein Rb, Rc, Rd, Re, Rf, A, B and n are as defined in any one of claims 1 to 6, Ra' represents a group Ra as defined in any one of claims 1 to 6, wherein R5 is an amino group, a C1-8-alkylamino group or a phenyl(C1-4alkyl)amino group) with a compound of formula XIII

(XIII) (wherein R10 represents a hydrogen atom, a C1-8-alkyl group, a C3-5-alkenyl group, a phenylalkyl group or a C5-7-cycloalkyl group, R11 represents a hydrogen atom or a C1-6-alkyl group, or one of the groups R10 or R11 may also represent a bicyclohexyl or biphenylyl group, or R10 and R11 together with the nitrogen atom between them represent a straight-chained C4-6 alkyleneimino group, or a morpholino group, and Z6 represents a nucleophilic leaving group or, if one of the groups R10 or R11 represents a hydrogen atom, Z6 together with R10 or R11 may represent a nitrogen-carbon bond);

i) (to prepare compounds of formula I wherein R5 represents an acylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group, by a phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl, bicyclohexyl or biphenyl group, wherein the acyl group is a C1-7-alkanoyl group, a C2-4(alkoxycarbonyl) group, a C1-6-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenylalkanesulphonyl, naphthalenesulphonyl, cycloalkylcarbonyl, phenylalkanoyl or cycloalkylalkanoyl group, whilst the above-mentioned phenyl nuclei may each be mono- or di-substituted by a fluorine, chlorine or bromine atom, by a methyl or methoxy group and the substituents may be identical or different, a phthalimino or homophthalimino group wherein the phenyl nucleus in each case may be mono- or di-substituted by C1-3-alkyl or C1-3-alkoxy groups, or a maleic acid imido or succinimido group optionally mono- or di-substituted by an alkyl or phenyl group, wherein the substituents may be identical or different) acylating a compound of formula XIV

(XIV) (wherein Rb, Rc, Rd, Re, Rf, A, B and n are as defined in any one of claims 1 to 6 and Ra" represents a group Ra as defined in any one of in claims 1 to 6, wherein R5 represents an amino group optionally substituted by a C1-6-alkyl group, by a phenyl, cycloalkyl, phenylalkyl, cycloalkyalkyl, bicyclohexyl. or biphenyl group) with a compound of formula XV

HO - U - R12 (XV) (wherein U represents a carbonyl or sulphonyl group and R12 represents a C1-6 alkyl group, a C1-3-alkoxy group, a phenyl, phenylalkyl, naphthyl or cycloalkyl group, wherein the above-mentioned phanyl nuclei may each be mono- or di-substituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group and the substituents may be identical or different, or, if U
represents a carbonyl group, R12 may also represent a hydrogan atom, a phenyl group which is substituted in the o-position by a carboxy or carboxymethyl group and wherein the phenyl nucleus may be mono- or disubstituted by C1-3-alkyl or C1-3-alkoxy groups and may additionally be wholly or partially hydrogenated, a 2-carboxy-ethyl or 2-carboxy-ethenyl group in which the ethyl and ethenyl moiety may each be mono- or di-substituted by an alkyl or phenyl group) or with a reactive derivative thereof;

j) (to prepare compounds of formula I wherein Rb represents a phosphono or O-alkyl-phosphono group) hydrolysing a compound of formula XVI

(XVI) (wherein A, B, Ra, Rc, Rd, Re, Rf and n are as defined in any one of claims 1 to 6 and Rb"' represents an O-alkyl- or O,O-dialkyl-phosphono group in which each alkyl moiety may contain 1 to 5 carbon atoms);

k) resolving a compound of formula I by isomer separation into the isomers or enantiomers thereof;

1) converting a compound of formula I into a salt thereof, more particularly, for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound; and m) performing a process as defined in any one of steps (a) to (1) above on a corresponding protected compound and subsequently removing the protecting group used.
10. Use of a compound of formula I as claimed in any one of claims 1 to 6 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent with an angiotensin antaganistic activity.
11. Use of a compound of formula I as claimed in any one of claims 1 to 6 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
120 Use of a compound of formula I as claimed in any one of claims 1 to 6 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy as well as other pulmonary diseases.
13. Use of a compound of formula I as claimed in any one of claims 1 to 6 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function and other nervous system disorders.
14. A method of treatment of the human or non-human animal body to combat hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 6 or a physiologically acceptable salt thereof.
15. A method of treatment as claimed in claim 14 to combat hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of -the progression of cardiac insufficiency after myocardial infarction and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
16. A method of treatment as claimed in claim 14 to combat depression, Alzheimer's disease, Parkinson syndrome, bulimia, disorders of cognitive function and other nervous system disorders.
17. A compound of formula I as claimed in claim l or a pharmaceutical composition thereof substantially as herein disclosed in any one of the Examples.
18. Each and every novel compound, composition, process, use and method as herein disclosed.
CA 2073841 1991-07-15 1992-07-14 Phenylalkyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them Abandoned CA2073841A1 (en)

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DEP4142366.6 1991-12-20
DE19914142366 DE4142366A1 (en) 1991-07-15 1991-12-20 New phenylalkyl derivs. - are angiotensin II antagonists used to treat hypertension, coronary insufficiency, angina, cns disorders etc.

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