161
Claims
1. Compounds of general formula
<IMG>
R denotes a saturated, monounsaturated or, in the case of the 6- and 7-
membered heterocyclic groups, a diunsaturated 5- to 7-membered aza, diaza,
triaza, oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza-heterocyclic group,
while the abovementioned heterocyclic groups are linked via a carbon or
nitrogen atom and
contain one or two carbonyl groups, which are linked to at least one
nitrogen atom,
may be substituted by an alkyl group at one of the nitrogen atoms,
may be substituted at one or two carbon atoms in each case by an alkyl,
phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl,
thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-
methyl-
pyrazolyl, imidazolyl or 1-methylimidazolyl group, while the substituents
may be identical or different,
and wherein a double bond of one of the abovementioned unsaturated
heterocyclic groups may be fused to a benzene, pyridine, diazine,
162
1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole or
quinoline ring, to a 2(1H)-oxoquinoline ring optionally substituted by an
alkyl group at the nitrogen atom or to an imidazole or N-methyl-imidazole
ring, or also two olefinic double bonds of one of the abovementioned
unsaturated heterocyclic groups may be fused to a benzene ring in each
case,
while the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl,
1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-
methylimidazolyl groups contained in R as well as benzo-, thieno-,
pyrido- and diazino-fused heterocyclic groups in the carbon skeleton
may additionally be mono-, di- or trisubstituted by fluorine, chlorine,
bromine or iodine atoms, by alkyl, alkoxy, nitro, alkylthio, alkylsulphinyl,
alkylsulphonyl, alkylsulphonylamino, phenyl, trifluoromethyl,
difluoromethyl, difluoromethoxy, alkoxycarbonyl, carboxy, dialkylamino,
hydroxy, amino, acetylamino, propionylamino, aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl, (4-morpholinyl)carbonyl,
(1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-
1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy,
aminocarbonylamino, alkanoyl, cyano, trifluoromethoxy,
trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl
groups, while the substituents may be identical or different,
X denotes an oxygen atom or, if Z denotes the group -NR1-, it may also
denote one of the groups =N-CN or =N-SO2-R6, wherein
R6 denotes an alkyl group with 1 to 4 carbon atoms or a phenyl group
optionally substituted by a halogen atom, a methyl or a methoxy group,
Z denotes one of the groups ~CH2, wherein the hydrogen atoms may be
replaced independently of one another by a fluorine atom or a C1-3-alkyl
group,
or ~NR1, wherein
163
R1 denotes the hydrogen atom, an alkyl group which may be substituted in
the alkyl moiety with the exception of position 1 by an amino, C1-3-alkyl-
amino or di-(C1-3-alkyl)-amino group, or a phenylalkyl group which may be
mono- or disubstituted in the phenyl moiety by fluorine, chlorine, bromine or
iodine atoms, by a C1-3-alkyl, trifluoromethyl, difluoromethyl, cyclopropyl,
hydroxy, C1-3-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, nitro,
amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxycarbonyl,
aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl,
amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-
alkyl group, while the substituents may be identical or different,
A denotes a carbon atom substituted by a hydrogen atom or by a C1-3-alkyl
group
n denotes the number 1 or 2,
R2 denotes the group
<IMG>
wherein
one of the groups R a, R b and R c denotes the hydrogen, fluorine, chlorine,
bromine or iodine atom, a branched or unbranched alkyl group, a hydroxy,
alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy,
trifluoromethylthio, amino, acetylamino, dialkylaminoalkyl,
dialkylaminoalkoxy, nitro, methylsulphonyloxy, aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano,
trifluoromethylsulphinyl or trifluoromethylsulphonyl group,
164
a second of the groups R a, R b and R c denotes the hydrogen, fluorine,
chlorine, bromine or iodine atom, a branched or unbranched alkyl group, a
hydroxy, alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy,
difluoromethoxy, trifluoromethylthio, amino, acetylamino, alkanoyl,
aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group and
the third of the groups R a, R b and R c denotes the hydrogen, fluorine,
chlorine, bromine or iodine atom, a branched or unbranched alkyl group, a
hydroxy, alkoxy, trifluoromethyl, difluoromethyl, difluoromethoxy, or
trifluoromethoxy group, while the substituents may be identical or
different,
R3 and R4, which may be identical or different, in each case denote the
hydrogen atom, a C1-4-alkyl, amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or
di-(C1-3-alkyl)-amino-C1-3-alkyl group,
a phenyl or naphthyl group which in each case may be mono- or disubstituted
by R d, while the substituents may be identical or different and R d denotes a
fluorine, chlorine, bromine or iodine atom, a C1-3-alkyl, trifluoromethyl,
difluoromethyl, cyclopropyl, hydroxy, C1-3-alkoxy, difluoromethoxy,
trifluoromethoxy, cyano, nitro, amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-
amino,
carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl
or
di-(C1-3-alkyl)-amino-C1-3-alkyl group or a 4- to 7-membered
cycloalkyleneimino-carbonyl group wherein
one or two hydrogen atoms may each be replaced by a C1-3-alkyl
group and/or
in each case the methylene group in the 4 position of a 6- or 7-
membered cycloalkyleneimino moiety may be replaced by an oxygen
165
or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl) or
-N(C1-3-alkyl-carbonyl) group,
a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the
carbon skeleton by a C1-3-alkyl, amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-
amino,
carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl
or
di-(C1-3-alkyl)-amino-C1-3-alkyl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen
atoms and may optionally additionally be substituted by a fluorine,
chlorine, bromine or iodine atom, a C1-3-alkyl, C1-3-alkoxy, amino, C1-3-
alkylamino or di-(C1-3-alkyl)amino group and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a C1-3-alkyl, acetyl, trifluoroacetyl, C1-3-alkoxy-carbonyl,
aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl,
amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-
alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a C1-3-alkyl, acetyl,
trifluoroacetyl, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-
amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group or an oxygen or
sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C1-3-alkyl, acetyl,
trifluoroacetyl, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-
amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group and two nitrogen
atoms,
166
or R3 and R4 together (denote) a 1,3-butadien-1,4-ylene group wherein
one, two or three methyne groups may each be replaced by a nitrogen
atom,
a hydrogen atom may be replaced by a fluorine, chlorine, bromine or
iodine atom, by a C1-3-alkyl, trifluoromethyl, difluoromethyl, cyclopropyl,
hydroxy, C1-3-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, nitro,
amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxy-
carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-
aminocarbonyl, di-(C1-3-alkyl)-amino-C2-3-alkyl-aminocarbonyl, amino-C1-3-
alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group
or
by a 4- to 7-membered cycloalkyleneimino-carbonyl group wherein
one or two hydrogen atoms may each be replaced by a C1-3-alkyl
group and/or
in each case the methylene group in the 4 position of a 6- or 7-
membered cycloalkyleneimino moiety may be replaced by an oxygen
or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl) or
-N(C1-3-alkyl-carbonyl)- group,
and optionally additionally a second hydrogen atom may be replaced by a
fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, trifluoromethyl,
difluoromethyl, cyclopropyl, hydroxy, C1-3-alkoxy, difluoromethoxy or
trifluoromethoxy group, and
R5 denotes the group ~(CH2)m-R e, wherein
m denotes the number 0 and
R e denotes a hydrogen atom,
167
a phenyl or naphthyl group which in each case may be mono- or
disubstituted by R f, while the substituents may be identical or different and
R f denotes a fluorine, chlorine, bromine or iodine atom, a C1-3-alkyl,
trifluoromethyl, difluoromethyl, cyclopropyl, hydroxy, C1-3-alkoxy,
difluoromethoxy, trifluoromethoxy, cyano, nitro, amino, C1-3-alkyl-amino,
di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-
alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-
alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group, or
a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group
optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein
a hydrogen atom bound to a nitrogen atom may be replaced by a
C1-3-alkyl or acetyl group, or
a C3-7-cycloalkyl group, while
a hydrogen atom of the C3-7-cycloalkyl group may be replaced by an
amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino, amino-C1-3-alkyl, C1-3-
alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group and/or
the methylene group in the 3 position of the cyclopentyl group and the
methylene group in the 4 position of the cyclohexyl and cycloheptyl
group may each be replaced by an oxygen or sulphur atom, by a
sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl) or -N(C1-3-alkyl-carbonyl)-
group,
or m denotes one of the numbers 1 to 5 and
R e denotes a hydrogen atom, an aminomethylene,
C1-3-alkylaminomethylene, di-(C1-3-alkyl)-aminomethylene, aminocarbonyl,
168
C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or C3-7-cycloalkyl
group, while
a hydrogen atom of the C3-7-cycloalkyl group may be replaced by an
amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino, amino-C1-3-alkyl, C1-3-
alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group and/or
the methylene group in the 3 position of the cyclopentyl group and the
methylene group in the 4 position of the cyclohexyl and cycloheptyl
group may each be replaced by an oxygen or sulphur atom, by a
sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl) or -N(C1-3-alkyl-carbonyl)-
group,
a 4- to 7-membered cycloalkyleneimino group wherein
one or two hydrogen atoms may each be replaced by a C1-3-alkyl
group and/or
in each case the methylene group in the 4 position of a 6 or 7-
membered cycloalkyleneimino group may be replaced by an oxygen
or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl) or
-N(C1-3-alkyl-carbonyl)- group,
a phenyl or naphthyl group which may be mono- or disubstituted by R g in
each case independently of one another, while the substituents may be
identical or different and R g denotes a fluorine, chlorine, bromine or iodine
atom, a C1-3-alkyl, trifluoromethyl, difluoromethyl, cyclopropyl, hydroxy,
C1-3-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, nitro, amino, C1-3-
alkyl-amino, di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxy-carbonyl,
aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl,
amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-
alkyl group,
169
or a monocyclic 5- or 6-membered heteroaryl group optionally substituted
in the carbon skeleton by a C1-3-alkyl, amino, C1-3-alkyl-amino, di-(C1-3-
alkyl)-amino, carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-
amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen
atoms and may optionally additionally be substituted by a fluorine,
chlorine, bromine or iodine atom, a C1-3-alkyl, C1-3-alkoxy, amino, C1-3-
alkylamino or di-(C1-3-alkyl)amino group and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a C1-3-alkyl, acetyl, trifluoroacetyl, C1-3-alkoxy-carbonyl,
aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-
aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-
alkyl)-amino-C1-3-alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a C1-3-alkyl, acetyl,
trifluoroacetyl, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-
alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group or an
oxygen or sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C1-3-alkyl, acetyl,
trifluoroacetyl, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-
alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group and two
nitrogen atoms,
170
while the abovementioned alkyl groups or the alkyl groups contained in the
abovementioned groups, unless otherwise stated, contain 1 to 5 carbon
atoms and may be branched or unbranched,
the tautomers, diastereomers, enantiomers, mixtures and salts thereof.
2. Compounds of general formula I according to claim 1, wherein
R denotes a saturated or monounsaturated 5- to 7-membered aza, diaza,
oxaza or thiaza heterocyclic group,
while the abovementioned heterocyclic groups are linked via a nitrogen
atom and
contain a carbonyl group linked to one or two nitrogen atoms of the
heterocyclic group,
may be substituted by an alkyl group at one of the nitrogen atoms,
may be substituted at one of the carbon atoms by an alkyl, phenyl,
pyridinyl, furyl, thienyl or pyrrolyl group,
and wherein a double bond of one of the abovementioned unsaturated
heterocyclic groups may be fused to a benzene, pyridine or thiophene
ring,
while the phenyl, pyridinyl, furyl, thienyl, pyrrolyl groups contained in R
as well as the benzo-, thieno- and pyrido-condensed heterocyclic
groups in the carbon skeleton may additionally be mono- or
disubstituted by fluorine, chlorine, bromine or iodine atoms, by alkyl,
alkoxy, nitro, alkylthio, trifluoromethyl, difluoromethyl, alkoxycarbonyl,
carboxy, dialkylamino, hydroxy, amino, acetylamino, aminocarbonyl,
171
alkylaminocarbonyl, alkanoyl, cyano or trifluoromethoxy groups, while
the substituents may be identical or different,
X denotes an oxygen atom or, if Z the group -NR1- denotes, it may also
denote the group =N-CN,
Z denotes one of the groups -CH2 or -NR1, wherein
R1 denotes the hydrogen atom or an alkyl group,
A denotes a carbon atom substituted by a hydrogen atom or by a C1-3-alkyl
group,
n denotes the number 1 or 2,
R2 denotes the group
<IMG>
wherein
one of the groups R a, R b and R c denotes the hydrogen, fluorine, chlorine,
bromine or iodine atom, a branched or unbranched alkyl group, a hydroxy,
alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino,
acetylamino, dialkylaminoalkyl, dialkylaminoalkoxy, aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano or
trifluoromethylsulphonyl group,
172
a second of the groups R a, R b and R c denotes the hydrogen, fluorine,
chlorine, bromine or iodine atom, a branched or unbranched alkyl group,
an alkoxy, trifluoromethyl, amino, acetylamino or alkanoyl group and
the third of the groups R a, R b and R c denotes the hydrogen, fluorine,
chlorine, bromine or iodine atom or a branched or unbranched alkyl
group, while the substituents may be identical or different,
R3 denotes the hydrogen atom or a C1-3-alkyl group,
R4 denotes the hydrogen atom, a C1-4alkyl, amino-C1-3-alkyl, C1-3-alkyl-amino-
C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group,
a phenyl group which may be mono- or disubstituted by R d, while the
substituents may be identical or different and R d denotes a fluorine,
chlorine,
bromine or iodine atom, a C1-3-alkyl, trifluoromethyl, difluoromethyl,
cyclopropyl, hydroxy, C1-3-alkoxy, difluoromethoxy, trifluoromethoxy, amino,
C1-3-alkylamino, di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxy-carbonyl,
aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl,
amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-
alkyl
group, or
a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl,
pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group optionally
substituted in the carbon skeleton by a C1-3-alkyl group, wherein a hydrogen
atom bound to a nitrogen atom may be replaced by a C1-3-alkyl or acetyl
group,
or R3 and R4 together denote a 1,3-butadien-1,4-ylene group wherein
a hydrogen atom may be replaced by a fluorine, chlorine, bromine or
iodine atom, by a C1-3-alkyl, trifluoromethyl, difluoromethyl, cyclopropyl,
173
hydroxy, C1-3-alkoxy, amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino,
carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl, di-(C1-3-alkyl)-amino-C2-3-alkyl-
aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl, di-(C1-3-alkyl)-
amino-C1-3-alkyl group or by a 5- to 7-membered
cycloalkyleneimino-carbonyl group wherein
one or two hydrogen atoms may each be replaced by a C1-3-alkyl
group and/or
in each case the methylene group in the 4 position of a 6- or 7-
membered cycloalkyleneimino moiety by an oxygen or sulphur atom,
may be replaced by a -NH, -N(C1-3-alkyl) or -N(C1-3-alkyl-carbonyl)-
group,
and optionally a second hydrogen atom may additionally be replaced by a
fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl or trifluoromethyl
group, and
R5 denotes the group -(CH2)m-R e, wherein
m denotes the number 0 and
R e denotes a hydrogen atom or a C5-6-cycloalkyl group, while
the methylene group in the 3 position of the cyclopentyl group and the
methylene group in the 4 position of the cyclohexyl group may each
be replaced by a -NH, -N(C1-3-alkyl) or -N(C1-3-alkyl-carbonyl) group,
or m denotes one of the numbers 1 to 5 and
174
R e denotes a hydrogen atom, an aminomethylene,
C1-3-alkylaminomethylene, di-(C1-3-alkyl)-aminomethylene, aminocarbonyl,
C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-amino carbonyl or C5-6-cycloalkyl
group, while
the methylene group in the 3 position of the cyclopentyl group and the
methylene group in the 4 position of the cyclohexyl group may each
be replaced by a -NH, -N(C1-3-alkyl) or -N(C1-3-alkyl-carbonyl) group,
a 5- to 6-membered cycloalkyleneimino group, while
the methylene group in the 4 position of a 6-membered
cycloalkyleneimino group may be replaced by a -NH, -N(C1-3-alkyl) or
-N(C1-3-alkyl-carbonyl)- group,
a phenyl group which may be mono- or disubstituted by R9, while the
substituents may be identical or different and R9 denotes a fluorine,
chlorine, bromine or iodine atom, a C1-3-alkyl, trifluoromethyl,
difluoromethyl, hydroxy, C1-3-alkoxy, amino, C1-3-alkyl-amino, di-(C1-3-
alkyl)-amino, aminocarbonyl- C1-3-alkyl-aminocarbonyl, amino-C1-3-alkyl,
C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group,
or a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group
optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein
a hydrogen atom bound to a nitrogen atom by a C1-3-alkyl or acetyl group
may be replaced,
while the abovementioned alkyl groups or the alkyl groups contained in the
abovementioned groups, unless otherwise stated, contain 1 to 4 carbon
atoms and may be branched or unbranched,
175
the tautomers, diastereomers, enantiomers, mixtures and salts thereof.
3. Compounds of general formula I according to claim 2, wherein
R denotes a monounsaturated, 5- to 7-membered diaza heterocyclic group
linked via a nitrogen atom,
while the abovementioned heterocyclic groups contain a carbonyl group
linked to both nitrogen atoms of the heterocyclic group,
may each be substituted independently of one another at one of the
nitrogen atoms and one of the saturated carbon atoms by a C1-3-alkyl
group,
and wherein the double bond of the abovementioned unsaturated
heterocyclic groups is fused to a benzene ring optionally substituted by a
fluorine, chlorine, bromine or iodine atom, or by a C1-3-alkyl, C1-3-alkoxy,
trifluoromethyl, carboxy, C1-3-alkoxy-carbonyl, amino, acetylamino,
hydroxy, aminocarbonyl or alkanoyl group,
X denotes an oxygen atom,
Z denotes one of the groups -CH2 or -NR1 wherein
R1 denotes the hydrogen atom or a C1-3-alkyl group,
A denotes a carbon atom substituted by a hydrogen atom or by a C1-3-alkyl
group,
n denotes the number 1,
R2 denotes the group
176
<IMG>
wherein
one of the groups R a, R b and R c denotes the hydrogen, fluorine, chlorine,
bromine or iodine atom, a C1-3-alkyl, trifluoromethyl, hydroxy, alkoxy or
amino group,
a second of the groups R a, R b and R c denotes the hydrogen, fluorine,
chlorine, bromine or iodine atom, a C1-3-alkyl or trifluoromethyl group and
the third of the groups R a, R b and R c denotes the hydrogen, fluorine,
chlorine, bromine or iodine atom, while the substituents may be identical
or different,
R3 denotes the hydrogen atom or a C1-3-alkyl group,
R4 denotes a phenyl group optionally substituted by a fluorine, chlorine,
bromine or iodine atom, by a C1-3-alkyl, trifluoromethyl, hydroxy, C1-3-
alkoxy,
amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, carboxy or C1-3-alkoxy-carbonyl
group,
or R3 and R4 together denote a 1,3-butadien-1,4-ylene group wherein
a hydrogen atom may be replaced by a fluorine, chlorine, bromine or
iodine atom, by a C1-3-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy,
C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-
alkyl)-aminocarbonyl or di-(C1-3-alkyl)-amino-C2-3-alkyl-aminocarbonyl
group or by a 5- to 7-membered cycloalkyleneimino-carbonyl group, while
177
the methylene group in the 4 position of the 6-membered
cycloalkyleneimino moiety may be replaced by a -NH, -N(C1-3-alkyl) or
-N(C1-3-alkyl-carbonyl)- group,
and optionally a second hydrogen atom may additionally be replaced by a
fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl group, and
R5 denotes the group -(CH2)m-R e, wherein
m denotes the number 0 and
R e denotes a hydrogen atom,
or m denotes one of the numbers 1 to 3 and
R e denotes a hydrogen atom, an aminomethylene,
C1-3-alkylaminomethylene or di-(C1-3-alkyl)-aminomethylene group,
while the abovementioned alkyl groups or the alkyl groups contained in the
abovementioned groups, unless otherwise stated, may be branched or
unbranched,
the tautomers, diastereomers, enantiomers, mixtures and salts thereof.
4. Compounds of general formula I according to claim 1, wherein
R, X, Z, A, n, R2, and R5 are defined as in claim 1 and
R3 denotes the hydrogen atom or a C1-4-alkyl group and
178
R4 denotes the hydrogen atom, a C1-4-alkyl, amino-C1-3-alkyl, C1-3-alkyl-amino-
C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group,
a phenyl or naphthyl group which may be mono- or disubstituted by R d in
each case independently of one another, while the substituents may be
identical or different and R d denotes a fluorine, chlorine, bromine or iodine
atom, a C1-3-alkyl, trifluoromethyl, difluoromethyl, cyclopropyl, hydroxy,
C1-3-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, nitro, amino, C1-3-
alkyl-
amino, di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl,
C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-
3-
alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group, or
a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the
carbon skeleton by a C1-3-alkyl, amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-
amino,
carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl
or
di-(C1-3-alkyl)-amino-C1-3-alkyl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen
atoms and
die 5-membered heteroaryl group contains an imino group optionally
substituted by a C1-3-alkyl, acetyl, trifluoroacetyl, C1-3-alkoxy-carbonyl,
aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl,
amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-
alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a C1-3-alkyl, acetyl,
trifluoroacetyl- C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-
amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group or an oxygen or
sulphur atom and additionally a nitrogen atom or
179
an imino group optionally substituted by a C1-3-alkyl, acetyl,
trifluoroacetyl- C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-
aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino-C1-3-alkyl, C1-3-alkyl-
amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group and two nitrogen
atoms,
the tautomers, diastereomers, enantiomers, mixtures and salts thereof.
5. Compounds of general formula I according to claim 2, wherein
R, X, Z, A, n, R2, and R5 are defined as in claim 2 and
R3 denotes the hydrogen atom or a C1-3-alkyl group and
R4 denotes a phenyl group which may be mono- or disubstituted by R d, while
the substituents may be identical or different and R d denotes a fluorine,
chlorine, bromine or iodine atom, a C1-3-alkyl, trifluoromethyl,
difluoromethyl,
cyclopropyl, hydroxy, C1-3-alkoxy, difluoromethoxy, trifluoromethoxy, amino,
C1-3-alkyl-amino, di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxy-carbonyl,
aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl,
amino-C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-
alkyl
group, or
a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl,
pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group optionally
substituted in the carbon skeleton by a C1-3-alkyl group, wherein a hydrogen
atom bound to a nitrogen atom may be replaced by a C1-3-alkyl or acetyl
group,
the tautomers, diastereomers, enantiomers, mixtures and salts thereof.
180
6. Compounds of general formula I according to claim 3, wherein
R, X, Z, A, n, R2, and R5 are defined as in claim 3 and
R3 denotes the hydrogen atom or a C1-3-alkyl group and
R4 denotes a phenyl group optionally substituted by a fluorine, chlorine,
bromine or iodine atom, by a C1-3-alkyl, trifluoromethyl, hydroxy, C,-3-
alkoxy,
amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, carboxy or C1-3-alkoxy-carbonyl
group,
the tautomers, diastereomers, enantiomers, mixtures and salts thereof.
7. Compounds of general formula I according to claim 1, wherein
R, X, Z, A, n, R2, and R5 are defined as in claim 1 and
R3 and R4 together denote a 1,3-butadien-1,4-ylene group wherein
one, two or three methyne groups may each be replaced by a nitrogen
atom,
a hydrogen atom may be replaced by a fluorine, chlorine, bromine or
iodine atom, by a C1-3-alkyl, trifluoromethyl, difluoromethyl, cyclopropyl,
hydroxy, C1-3-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, nitro,
amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxy-
carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-
aminocarbonyl, di-(C1-3-alkyl)-amino-C2-3-alkyl-aminocarbonyl, amino-C1-3-
alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group
or
by a 4- to 7-membered cycloalkyleneimino-carbonyl group wherein
181
one or two hydrogen atoms may each be replaced by a C1-3-alkyl
group and/or
in each case the methylene group in the 4 position of a 6- or 7-
membered cycloalkyleneimino moiety may be replaced by an oxygen
or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl)
or-N(C1-3-alkyl-carbonyl)- group,
and a second hydrogen atom may optionally additionally be replaced by a
fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, trifluoromethyl,
difluoromethyl, cyclopropyl, hydroxy, C1-3-alkoxy, difluoromethoxy or
trifluoromethoxy group,
the tautomers, diastereomers, enantiomers, mixtures and salts thereof.
8. Compounds of general formula I according to claim 2, wherein
R, X, Z, A, n, R2, and R5 are defined as in claim 2 and
R3 and R4 together denote a 1,3-butadien-1,4-ylene group wherein
a hydrogen atom may be replaced by a fluorine, chlorine, bromine or
iodine atom, by a C1-3-alkyl, trifluoromethyl, difluoromethyl, cyclopropyl,
hydroxy, C1-3-alkoxy, amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino,
carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl,
di-(C1-3-alkyl)-aminocarbonyl or di-(C1-3-alkyl)-amino-C2-3-alkyl-
aminocarbonyl group or by a 5- to 7-membered
cycloalkyleneimino-carbonyl group wherein
one or two hydrogen atoms may each be replaced by a C1-3-alkyl
group and/or
182
in each case the methylene group in the 4 position of a 6- or 7-
membered cycloalkyleneimino moiety may be replaced by an oxygen
or sulphur atom, by a -NH, -N(C1-3-alkyl) or-N(C1-3-alkyl-carbonyl)-
group,
and a second hydrogen atom may optionally additionally be replaced by a
fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl or trifluoromethyl
group,
the tautomers, diastereomers, enantiomers, mixtures and salts thereof.
9. Compounds of general formula I according to claim 3, wherein
R, X, Z, A, n, R2, and R5 are defined as in claim 3 and
R3 and R4 together denote a 1,3-butadien-1,4-ylene group wherein
a hydrogen atom may be replaced by a fluorine, chlorine, bromine or
iodine atom, by a C1-3-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy,
C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-
alkyl)-aminocarbonyl or di-(C1-3-alkyl)-amino-C2-3-alkyl-aminocarbonyl
group or by a 5- to 7-membered cycloalkyleneimino-carbonyl group, while
the methylene group in the 4 position of the 6-membered
cycloalkyleneimino moiety may be replaced by a -NH, -N(C1-3-alkyl)
or-N(C1-3-alkyl-carbonyl) group,
and a second hydrogen atom may optionally additionally be replaced by a
fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl group,
the tautomers, diastereomers, enantiomers, mixtures and salts thereof.
183
10. The following compounds of general formula I according to claim 1:
(1) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-(1-(3-
dimethylamino-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(2) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[1-(2-
dimethylamino-ethyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(3) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[(R)-2-(4-amino-3,5-dibromo-phenyl)-1-(1-methyl-1H-
benzimidazol-2-yl)-ethyl]-amide,
(4) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[(R)-2-(4-amino-3,5-dibromo-phenyl)-1-(1H-
benzimidazol-2-yl)-ethyl]-amide,
(5) methyl 2-((R)-2-(4-amino-3,5-dibromo-phenyl)-1-{[4-(2-oxo-1,4-dihydro-
3H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-ethyl)-1H-
benzimidazole-5-carboxylate,
(6) methyl 2-((R)-2-(4-amino-3,5-dibromo-phenyl)-1-{[4-(2-oxo-1,2,4,5-
tetrahydro-1, 3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-ethyl)-
1H-benzimidazole-5-carboxylate,
(7) 2-((R)-2-(4-amino-3,5-dibromo-phenyl)-1-{[4-(2-oxo-1,2,4,5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-ethyl)-1H-
benzimidazole-5-carboxylic acid,
184
(8) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[6-(4-methyl-
piperazin-1-carbonyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(9) 2-((R)-2-(4-amino-3,5-dibromo-phenyl)-1-{[4-(2-oxo-1,2,4,5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-ethyl)-1H-
benzimidazole-5-carboxylic acid-(3-dimethylamino-propyl)-amide,
(10) 2-((R)-2-(4-amino-3,5-dibromo-phenyl)-1-{[4-(2-oxo-1,2,4,5-tetrahydro-
1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-ethyl)-1H-
benzimidazole-5-carboxylic acid-(2-dimethylamino-ethyl)-amide,
(11) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carboxylic acid-{(R)-
2-(4-amino-3,5-dibromo-phenyl)-1-[1-(3-dimethylamino-propyl)-5-phenyl-
1H-imidazol-2-yl]-ethyl}-amide,
(12) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[(R)-2-(4-amino-3,5-dibromo-phenyl)-1-(1-butyl-1H-
benzimidazol-2-yl)-ethyl]-amide,
(13) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[1-(3-pyrrolidin-1-
yl-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(14) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[(R)-2-(4-amino-3,5-dibromo-phenyl)-1-(1-pyridin-3-
ylmethyl-1H-benzimidazol-2-yl)-ethyl]-amide,
(15) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[(R)-2-(4-amino-3,5-dibromo-phenyl)-1-(1-benzyl-1H-
benzimidazol-2-yl)-ethyl]-amide,
185
(16) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid {(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[1-(1-methyl-
piperidin-4-ylmethyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(17) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[1-(4-
dimethylamino-butyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(18) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[1-(1-methyl-
piperidin-4-yl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(19) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[(R)-2-(4-amino-3,5-dibromo-phenyl)-1-(1-cyclohexyl-
1H-benzimidazol-2-yl)-ethyl]-amide,
(20) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[(R)-2-(4-amino-3,5-dibromo-phenyl)-1-(1-cyclopentyl-
1H-benzimidazol-2-yl)-ethyl]-amide,
(21) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[1-(5-
dimethylamino-pentyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(22) methyl 4-[2-((R)-2-(4-amino-3,5-dibromo-phenyl)-1-{[4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-ethyl)-
benzimidazol-1-yl]-butyrate,
(23) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[6-chloro-1-(3-
dimethylamino-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
186
(24) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-(1-(3-
dimethylamino-propyl)-6-fluoro-1H-benzimidazol-2-yl]-ethyl}-amide,
(25) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[1-(3-
dimethylamino-propyl)-5-fluoro-1H-benzimidazol-2-yl]-ethyl}-amide,
(26) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(4-amino-3,5-dibromo-phenyl)-1-[5,6-dichloro-1-
(3-dimethylamino-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(27) methyl 2-((R)-2-(4-amino-3,5-dibromo-phenyl)-1-{[4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-ethyl)-
1-(3-pyrrolidin-1-yl-propyl)-1H-benzimidazole-5-carboxylate,
(28) 2-(2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-{[4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino)-ethyl)-
1-(3-pyrrolidin-1-yl-propyl)-1H-benzimidazole-5-carboxylic acid,
(29) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(3,5-dibromo-4-hydroxy-phenyl)-1-[1-(1-methyl-
piperidin-4-ylmethyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(30) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(3,5-dibromo-4-hydroxy-phenyl)-1-[1-(1-methyl-
piperidin-4-yl)-1H-benzimidazol-2-yl]-ethyl)-amide,
(31) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(3,5-dibromo-4-hydroxy-phenyl)-1-[1-(3-
dimethylamino-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
187
(32) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{(R)-2-(3,5-dibromo-4-hydroxy-phenyl)-1-[1-(3-
pyrrolidin-1-yl-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(33) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[1-[6-chloro-1-(3-dimethylamino-propyl)-1H-
benzimidazol-2-yl]-2-(3,4-dibromo-phenyl)-ethyl]-amide,
(34) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-dibromo-phenyl)-1-[5,6-dichloro-1-(3-
dimethylamino-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(35) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[1-[7-chloro-1-(3-dimethylamino-propyl)-1H-
benzimidazol-2-yl]-2-(3,4-dibromo-phenyl)-ethyl]-amide,
(36) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-dibromo-phenyl)-1-[1-(3-dimethylamino-propyl)-
6-fluoro-1H-benzimidazol-2-yl]-ethyl}-amide,
(37) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-dibromo-phenyl)-1-[1-(1-methyl-piperidin-4-yl)-
1H-benzimidazol-2-yl]-ethyl-amide,
(38) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-dibromo-phenyl)-1-[1-(3-pyrrolidin-1-yl-propyl)-
1H-benzimidazol-2-yl]-ethyl}-amide,
(39) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-dibromo-phenyl)-1-[1-(1-methyl-piperidin-4-
ylmethyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
188
(40) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[2-(3,4-dibromo-phenyl)-1-(1-pyridin-3-ylmethyl-1H-
benzimidazol-2-yl)-ethyl]-amide,
(41) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-dibromo-phenyl)-1-[1-(3-dimethylamino-propyl)-
1H-benzimidazol-2-yl]-ethyl}-amide,
(42) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-dibromo-phenyl)-1-[1-(4-dimethylamino-butyl)-
1H-benzimidazol-2-yl]-ethyl}-amide,
(43) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-diethyl-phenyl)-1-[1-(3-dimethylamino-propyl)-
1H-benzimidazol-2-yl]-ethyl}-amide,
(44) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-diethyl-phenyl)-1-(1-(4-dimethylamino-butyl)-1H-
(45) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-diethyl-phenyl)-1-[1-(1-methyl-piperidin-4-yl)-1H-
benzimidazol-2-yl]-ethyl}-amide,
(46) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-diethyl-phenyl)-1-[1-(3-pyrrolidin-1-yl-propyl)-1H-
benzimidazol-2-yl]-ethyl}-amide,
(47) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,4-diethyl-phenyl)-1-[1-(1-methyl-piperidin-4-
ylmethyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
189
(48) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[2-(3,4-diethyl-phenyl)-1-(1-pyridin-3-ylmethyl-1H-
benzimidazol-2-yl)-ethyl]-amide,
(49) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,5-bis-trifluoromethyl-phenyl)-1-[1-(1-methyl-
piperidin-4-yl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(50) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,5-bis-trifluoromethyl-phenyl)-1-[1-(3-pyrrolidin-1-yl-
propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(51) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,5-bis-trifluoromethyl-phenyl)-1-[1-(1-methyl-
piperidin-4-ylmethyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(52) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(3,5-bis-trifluoromethyl-phenyl)-1-[1-(3-
dimethylamino-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(53) methyl2-(2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-{[4-(2-oxo-
1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-
amino}-ethyl)-1-(3-pyrrolidin-1-yl-propyl)-1 H-benzimidazole-5-
carboxylate,
(54) 2-(2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-{[4-(2-oxo-1,2,4,5-
tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-ethyl)-
1-(3-pyrrolidin-1-yl-propyl)-1H-benzimidazole-5-carboxylic acid,
(55) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-[1-(1-
methyl-piperidin-4-yl)-1 H-benzimidazol-2-yl]-ethyl}-amide,
190
(56) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-[1-(3-
pyrrolidin-1-yl-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(57) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-[1-(1-
methyl-piperidin-4-ylmethyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(58) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-[2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-(1-
pyridin-3-ylmethyl-1H-benzimidazol-2-yl)-ethyl]-amide,
(59) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-
carboxylic acid-{2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-[1-(3-
dimethylamino-propyl)-1H-benzimidazol-2-yl]-ethyl}-amide,
(60) 3-(1-{4-(3,4-diethyl-phenyl)-3-[1-(3-dimethylamino-propyl)-1H-
benzimidazol-2-yl]-butyryl}-piperidin-4-yl)-1,3,4,5-tetrahydro-1,3-
benzodiazepin-2-one,
(61) 3-(1-{4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-[1-(3-pyrrolidin-1-
yl-propyl)-1H-benzimidazol-2-yl]-butyryl}-piperidin-4-yl)-1,3,4,5-
tetrahydro-1,3-benzodiazepin-2-one,
(62) 3-(1-{4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-[1-(3-imidazol-1-
yl-propyl)-1H-benzimidazol-2-yl]-butyryl}-piperidin-4-yl)-1,3,4,5-
tetrahydro-1,3-benzodiazepin-2-one,
(63) 3-(1-{4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-[5-(3-
dimethylamino-propyl)-1-ethyl-1H-benzimidazol-2-yl]-butyryl}-piperidin-
4-yl)-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
191
(64) 3-(1-{4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-[1-(3-
diethylamino-propyl)-1H-benzimidazol-2-yl]-butyryl}-piperidin-4-yl)-
1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
(65) 3-(1-{4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-[1-(4-hydroxy-
butyl)-1H-benzimidazol-2-yl]-butyryl}-piperidin-4-yl)-1,3,4,5-tetrahydro-
1,3-benzodiazepin-2-one,
(66) 3-(1-{4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-[1-(1-methyl-
piperidin-3-ylmethyl)-1H-benzimidazol-2-yl]-butyryl}-piperidin-4-yl)-
1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
(67) 3-[1-(4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-{1-[2-(4-methyl-
piperazin-1-yl)-ethyl]-1H-benzimidazol-2-yl}-butyryl)-piperidin-4-yl]-
1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
(68) 3-{1-(4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-
ylmethyl-1H-benzimidazol-2-yl)-butyryl]-piperidin-4-yl}-1,3,4,5-
tetrahydro-1,3-benzodiazepin-2-one,
(69) 3-{1-[4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-(1-piperidin-4
ylmethyl-1H-benzimidazol-2-yl)-butyryl]-piperidin-4-yl}-1,3,4,5
tetrahydro-1,3-benzodiazepin-2-one,
(70) 3-(1-{4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-[1-(3-
dimethylamino-2,2-dimethyl-propyl)-1H-benzimidazol-2-yl]-butyryl}-
piperidin-4-yl)-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
(71) 3-(1-{4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-[7-(3-
dimethylamino-propoxy)-1H-benzimidazol-2-yl]-butyryl}-piperidin-4-yl)-
1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
192
(72) 3-{1-[4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-(1-piperidin-4-
ylmethyl-1H-imidazo[4,5-c]pyridin-2-yl)-butyryl)-piperidin-4-yl}-1,3,4,5-
tetrahydro-1,3-benzodiazepin-2-one,
(73) 3-(1-{4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-[3-(3-pyrrolidin-1-
yl-propyl)-3H-imidazo[4,5-c]pyridin-2-yl]-butyryl}-piperidin-4-yl)-1,3,4,5-
tetrahydro-1,3-benzodiazepin-2-one,
(74) 3-{1-[4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-(1-methyl-6-
pyrrolidin-1-ylmethyl-1H-benzimidazol-2-yl)-butyryl]-piperidin-4-yl}-
1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,
their stereoisomers and salts.
11. Physiologically acceptable salts of the compounds according to at least
one of claims 1 to 10 with inorganic or organic acids or bases.
12. Pharmaceutical compositions containing a compound according to at least
one of claims 1 to 10 or a physiologically acceptable salt according to claim
11 optionally together with one or more inert carriers and/or diluents.
13. Use of a compound according to at least one of claims 1 to 11 for
preparing a pharmaceutical composition for the acute and prophylactic
treatment of headaches, particularly migraine or cluster headaches.
14. Process for preparing a pharmaceutical composition according to claim 12,
characterised in that a compound according to at least one of claims 1 to 11
is
incorporated in one or more inert carriers and/or diluents by a non-chemical
method.
193
15. Process for preparing the compounds according to claims 1 to 11,
characterised in that
a) in order to prepare compounds of general formula I wherein X denotes
the oxygen atom and Z denotes the -NR1 group, and wherein A, n, R, R1, R2,
R3 and R4 and A are defined as in claims 1 to 10,
an amine of general formula II,
<IMG> (II),
wherein
R is defined as in claims 1 to 10, is reacted with a carbonic acid derivative
of
general formula III,
<IMG> (III)
wherein
X1 denotes a nucleofugic group,
and with a compound of general formula IV,
<IMG> (IV),
wherein
R1, R2, R3, R4, R5, A and n are defined as in claims 1 to 10,
and subsequently, if necessary, any protecting groups are cleaved or precursor
functions are converted, or
b) In order to prepare compounds of general formula I wherein A, n, R,
R1, R2, R3 and R4 and A are defined as in claims 1 to 10 and R3 and R4
together represent a 1,3-butadien-1,4-ylene group wherein
one, two or three methyne groups may each be replaced by a nitrogen
atom,
a hydrogen atom may be replaced by a fluorine, chlorine, bromine or
iodine atom, by a C1-3-alkyl, trifluoromethyl, difluoromethyl, cyclopropyl,
hydroxy, C1-3-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, nitro,
amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxy-
carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-
aminocarbonyl, di-(C1-3-alkyl)-amino-C2-3-alkyl-aminocarbonyl, amino-C1-3-
alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group
or
by a 4- to 7-membered cycloalkyleneimino-carbonyl group wherein
one or two hydrogen atoms may each be replaced by a C1-3-alkyl
group and/or
in each case the methylene group in the 4 position of a 6- or 7-
membered cycloalkyleneimino moiety may be replaced by an oxygen
or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl) or
-N(C1-3-alkylcarbonyl)- group,
and a second hydrogen atom may optionally additionally be replaced by a
fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, trifluoromethyl,
difluoromethyl, cyclopropyl, hydroxy, C1-3-alkoxy, difluoromethoxy or
trifluoromethoxy group,
an amide of general formula
195
<IMG>
wherein R, X, Z, A, n, R2 and R5 are defined as in claims 1 to 10, R3' and R4'
together represent a 1,3-butadien-1,4-ylene group wherein
one, two or three methyne groups may each be replaced by a nitrogen
atom,
a hydrogen atom may be replaced by a fluorine, chlorine, bromine or
iodine atom, by a C1-3-alkyl, trifluoromethyl, difluoromethyl, cyclopropyl,
hydroxy, C1-3-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, nitro,
amino, C1-3-alkyl-amino, di-(C1-3-alkyl)-amino, carboxy, C1-3-alkoxy-
carbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-
aminocarbonyl, di-(C1-3-alkyl)-amino-C2-3-alkyl-aminocarbonyl, amino-C,1-3-
alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group
or
by a 4- to 7-membered cycloalkyleneiminocarbonyl group wherein
one or two hydrogen atoms may each be replaced by a C1-3-alkyl
group and/or
in each case the methylene group in the 4 position of a 6- or 7-
membered cycloalkyleneimino moiety may be replaced by an oxygen
or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl) or
-N(C1-3-alkyl-carbonyl) group,
and a second hydrogen atom may optionally additionally be replaced by a
fluorine, chlorine or bromine atom, by a C1-3-alkyl, trifluoromethyl,
196
difluoromethyl, cyclopropyl, hydroxy, C1-3-alkoxy, difluoromethoxy or
trifluoromethoxy group,
is anellated, or
c) In order to prepare compounds of general formula I wherein R, A, n and
R2 to R5 are defined as in claims 1 to 10 and X denotes the oxygen atom and Z
denotes the -CH2 group:
A carboxylic acid of general formula
<IMG>
wherein
R2 to R5, A and n are defined as in claims 1 to 10,
is coupled with a compound of general formula
<IMG>
wherein
R is defined as in claims 1 to 10, or
d) In order to prepare compounds of general formula I wherein R, A, n and
R2 to R5 are defined as in claims 1 to 10 and X denotes the oxygen atom and Z
denotes the -CH2 group:
197
a compound of general formula
<IMG>
wherein
A, n, and R2 to R5 are defined as in claims 1 to 10 and Nu denotes a leaving
group,
is coupled with a compound of general formula
<IMG>
wherein
R is defined as in claims 1 to 10, or
e) In order to prepare compounds of general formula I wherein R, A, n and
R2 to R5 are defined as in claims 1 to 10 and X denotes the oxygen atom and Z
denotes the group ~NH-:
an isocyanate of general formula VIII,
<IMG>
wherein
R2 to R5, A and n are defined as in claims 1 to 10
198
is reacted with amines of general formula II,
<IMG>
wherein
R is defined as in claims 1 to 10, and subsequently, if necessary, protecting
groups are cleaved or precursor functions are converted, or
f) In order to prepare compounds of general formula I wherein R, A, n and R2
to R5 are defined as in claims 1 to 10 and X denotes one of the groups =N-CN
or =N-SO2-R6 and Z denotes the group -NR1-, where R1 and R6 are defined as
in claims 1 to 10:
a compound of general formula
<IMG>
wherein A, n and R2 to R5 are defined as in claims 1 to 10, X' denotes one of
the groups =N-CN or =N-SO2-R6, Z' denotes the group -NR1, while R1 and R6
are defined as in claims 1 to 10, and Nu is a leaving group,
is reacted with secondary amines of general formula
<IMG>
wherein R is defined as in claims 1 to 10, and
any protecting groups for reactive groups such as hydroxy, carboxy, amino or
imino groups are cleaved and/or
199
a compound of general formula I thus obtained is resolved into the
stereoisomers thereof and / or
a compound of general formula I thus obtained is converted into the salts
thereof, particularly for pharmaceutical use into the physiologically
acceptable
salts thereof with an inorganic or organic acid or base.
16. Use of a compound according to at least one of claims 1 to 11 for
preparing a pharmaceutical composition for combating non-insulin-dependent
diabetes mellitus (NIDDM).
17. Use of a compound according to at least one of claims 1 to 11 for
preparing a pharmaceutical composition for the treatment of cardiovascular
diseases, morphine tolerance, skin diseases, particularly thermal and
radiation-induced skin damage including sunburn, inflammatory diseases
such as in particular inflammatory diseases of the joints such as arthritis,
inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied
by excessive vasodilatation and consequent reduced circulation of blood
through the tissues, such as particularly shock or sepsis, for relieving pain
in
general or for preventive or acute-therapeutic influence on the symptoms of
hot flushes caused by vasodilatation and increased blood flow in menopausal
oestrogen-deficient women and hormone-treated patients with prostate
carcinoma.
