- 130 -
Claim:
1. Compounds of formula I
<IMG>
(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
<IMG>
- 131 -
<IMG>
- 132 -
<IMG>
or
<IMG>
(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
- 133 -
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
- 134 -
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
- 135 -
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
- 136 -
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,
- 137 -
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
- 138 -
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,
- 139 -
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
- 140 -
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
- 141 -
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
- 142 -
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
- 143 -
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
- 144 -
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
- 145 -
(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
- 146 -
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
<IMG>
<IMG>
<IMG>
<IMG>
<IMG> or
- 147 -
<IMG>
(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-,
- 148 -
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
- 149 -
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
- 150 -
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
- 151 -
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
- 152 -
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
- 153 -
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,
- 154 -
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,
- 155 -
methylimino or acetylimino group;
Ra denotes a group of the formula
<IMG>
or
- 156 -
(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
- 157 -
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
- 158 -
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-
- 159 -
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.
- 160 -
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
<IMG>
(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
<IMG> (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-
- 161-
alkylene group and
Z2 represents a nucleophilic leaving group) with a
compound of formula V
<IMG>
(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
<IMG> (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
<IMG> (VII)
- 162 -
(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
<IMG>
(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
<IMG> (IX)
(wherein
Ra, Rc, Rd, Re, Rf, A, B and n are as defined in any one
of claims 1 to 6 and
- 163 -
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
<IMG>
(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
<IMG>
cyclising a compound of formula XI
<IMG> (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
<IMG>
- 164 -
and the other group X1 or Y1 represents a group of
formula
<IMG>
(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
<IMG> (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
- 165 -
<IMG> (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
- 166 -
be identical or different) acylating a compound of
formula XIV
<IMG> (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
- 167 -
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
<IMG>
(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
- 168 -
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
- 169 -
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.
