U.S. patent application number 10/685921 was filed with the patent office on 2004-07-08 for cgrp antagonists.
This patent application is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Arndt, Kirsten, Bauer, Eckhart, Doods, Henri, Dreyer, Alexander, Lustenberger, Philipp, Mueller, Stephan Georg, Rudolf, Klaus, Schindler, Marcus, Stenkamp, Dirk.
Application Number | 20040132716 10/685921 |
Document ID | / |
Family ID | 32103088 |
Filed Date | 2004-07-08 |
United States Patent
Application |
20040132716 |
Kind Code |
A1 |
Rudolf, Klaus ; et
al. |
July 8, 2004 |
CGRP antagonists
Abstract
CGRP antagonists of theformula 1 of which the following are
exemplary: (1)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbo-
xylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pipe-
razin-1-yl]-2-oxo-ethyl}-amide, (2)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbo-
xylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-pipe-
ridin-1-yl]-2-oxo-ethyl}-amide.
Inventors: |
Rudolf, Klaus; (Warthausen,
DE) ; Mueller, Stephan Georg; (Warthausen, DE)
; Stenkamp, Dirk; (Biberach, DE) ; Lustenberger,
Philipp; (Warthausen, DE) ; Dreyer, Alexander;
(Ochsenhausen, DE) ; Bauer, Eckhart; (Biberach,
DE) ; Schindler, Marcus; (Biberach, DE) ;
Arndt, Kirsten; (Biberach, DE) ; Doods, Henri;
(Warthausen, DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG
Ingelheim
DE
55216
|
Family ID: |
32103088 |
Appl. No.: |
10/685921 |
Filed: |
October 15, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60426167 |
Nov 14, 2002 |
|
|
|
Current U.S.
Class: |
514/211.15 ;
514/227.8; 514/326; 540/488; 544/126; 544/360; 544/60; 546/208;
546/209 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
43/00 20180101; A61P 25/36 20180101; A61P 19/02 20180101; C07D
401/14 20130101; A61P 1/02 20180101; A61P 31/04 20180101; C07D
471/08 20130101; A61P 3/10 20180101; A61P 17/00 20180101; A61P
11/06 20180101; C07D 495/04 20130101; A61P 1/12 20180101; A61P
17/16 20180101; A61P 9/10 20180101; A61P 27/16 20180101; A61P 25/06
20180101; A61P 29/00 20180101; A61P 11/00 20180101; C07D 471/04
20130101 |
Class at
Publication: |
514/211.15 ;
514/227.8; 514/326; 540/488; 544/060; 544/360; 544/126; 546/208;
546/209 |
International
Class: |
A61K 031/554; A61K
031/541; A61K 031/454 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 25, 2002 |
DE |
DE 102 50 082.7 |
Claims
What is claimed is:
1. A compound of the formula (I) 277wherein A denotes an oxygen or
sulphur atom, a phenylsulphonylimino or cyanimino group, X denotes
an oxygen or sulphur atom, an imino group optionally substituted by
a C.sub.1-6-alkyl group or a methylene group optionally substituted
by a C.sub.1-6-alkyl group, Y and Z independently of one another
each denote a straight-chain or branched C.sub.1-6-alkyl group
wherein each methylene group may be substituted by up to 2 fluorine
atoms and each methyl group may be substituted by up to 3 fluorine
atoms, while the above-mentioned alkyl groups together with the
carbon atoms to which they are bound may be joined to one another,
forming a 4- to 8-membered ring, R.sup.1 denotes a saturated, mono-
or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza,
thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocyclic group, in
which the above-mentioned heterocycles are linked via a carbon or
nitrogen atom, contain one or two carbonyl or thiocarbonyl groups
adjacent to a nitrogen atom, may be substituted at one of the
nitrogen atoms by an alkyl group, may be substituted at one or at
two carbon atoms by an alkyl group, by a phenyl, phenylmethyl,
naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl,
pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl,
1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, while
the substituents may be identical or different, and while an
olefinic double bond of one of the above-mentioned unsaturated
heterocycles may be fused to a phenyl, naphthyl, pyridine, diazine,
1,3-oxazole, thienyl, furan, thiazole, pyrrole, N-methylpyrrole or
quinoline ring, to a 1H-quinolin-2-one ring optionally substituted
at the nitrogen atom by an alkyl group or to an imidazole or
N-methylimidazole ring or also two olefinic double bonds of one of
the above-mentioned unsaturated heterocycles may each be fused to a
phenyl ring, 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.sup.1 as well as benzo-, thieno-, pyrido- and
diazino-fused heterocycles 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, difluoromethyl,
trifluoromethyl, alkoxycarbonyl, carboxy, hydroxy, amino,
alkylamino, dialkylamino, acetyl, 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, difluoromethoxy,
trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or
trifluoromethylsulphonyl groups, while the substituents may be
identical or different, R.sup.2 denotes the hydrogen atom, a
phenylmethyl group or a C.sub.2-7-alkyl group which may be
substituted in the .omega. position by a cyclohexyl, phenyl,
pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino,
carboxy, alkoxycarbonyl, aminocarbonyl, aminocarbonylamino,
acetylamino, 1-pyrrolidinyl, 1-piperidinyl,
4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl,
hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino,
4-alkyl-1-piperazinyl or
4-(.omega.-hydroxy-C.sub.2-7-alkyl)-1-piperaziny- l group, a phenyl
or pyridinyl group, while the above-mentioned heterocyclic groups
and phenyl groups may additionally be mono- di- or trisubstituted
in the carbon skeleton by fluorine, chlorine, bromine or iodine
atoms, by methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy,
amino, C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino,
acetylamino, aminocarbonyl, cyano, methylsulphonyloxy,
difluoromethoxy, trifluoromethoxy, trifluoromethylthio,
trifluoromethylsulphinyl, trifluoromethylsulphonyl,
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.s- ub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl groups and the
substituents may be identical or different, R.sup.3 denotes the
hydrogen atom or a C.sub.1-3-alkyl group optionally substituted by
a phenyl or pyridinyl group, while the C.sub.1-3-alkyl group may be
linked to an alkyl group present in R.sup.2 or a phenyl or pyridyl
ring present in R.sup.2 and the nitrogen atom to which they are
bound, forming a ring, or R.sup.2 and R.sup.3 together with the
enclosed nitrogen atom denote a group of general formula 278wherein
Y.sup.1 denotes the carbon atom or, if R.sup.5 is a pair of free
electrons, it may also denote the nitrogen atom, q and r, if
Y.sup.1 denotes the carbon atom, represent the numbers 0, 1 or 2,
or q and r, if Y.sup.1 denotes the nitrogen atom, represent the
numbers 1 or 2, R.sup.4 denotes the hydrogen atom, an amino,
alkylamino, dialkylamino, alkyl, cycloalkyl, amino-C.sub.2-7-alkyl,
alkylamino-C.sub.2-7-alkyl, dialkylamino-C.sub.2-7-alkyl,
aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino,
cycloalkylaminocarbonyl amino, phenylaminocarbonyl amino,
aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl or carboxyalkyl group, or, if Y.sup.1 does not
denote the nitrogen atom, the carboxy, aminomethyl,
alkylaminomethyl or dialkylaminomethyl group, a phenyl, pyridinyl,
diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or
phenylcarbonyl group which may each be mono-, di- or trisubstituted
in the carbon skeleton by fluorine, chlorine, bromine or iodine
atoms, by alkyl, alkoxy, methylsulphonyloxy, difluoromethyl,
trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl,
aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy,
alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl,
.omega.-(dialkylamino)alkanoyl, .omega.-(dialkylamino)alkyl,
.omega.-(dialkylamino)hydroxyalkyl, .omega.-(carboxy)alkanoyl,
difluoromethoxy, trifluoromethoxy, trifluoromethylthio,
trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, while
the substituents may be identical or different, a 4- to 10-membered
azacycloalkyl group, a 6- to 10-membered oxaza, thiaza or
diazacycloalkyl group, a 6- to 10-membered azabicycloalkyl group, a
1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl
group, while the above-mentioned mono- and bicyclic heterocycles
are bound via a nitrogen or carbon atom, in the above-mentioned
mono- and bicyclic heterocycles any methylene group not directly
bound to a nitrogen, oxygen or sulphur atom may be substituted by
one or two fluorine atoms, the above-mentioned mono- and bicyclic
heterocycles as well as the 1-alkyl-4-piperidinylcarbonyl- and
4-alkyl-1-piperazinylcarbonyl group in the ring may be mono- or
polysubstituted by a C.sub.1-7-alkyl group, monosubstituted by a
phenyl-C.sub.1-3-alkyl, alkanoyl, dialkylamino, phenylcarbonyl,
pyridinylcarbonyl, carboxy, carboxyalkanoyl, carboxyalkyl,
alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl,
alkylaminocarbonyl, alkylsulphonyl, cycloalkyl or cycloalkylalkyl
group, or substituted by a cycloalkylcarbonyl,
azacycloalkylcarbonyl, diazacycloalkylcarbonyl or
oxazacycloalkylcarbonyl group optionally alkyl-substituted in the
ring, while the alicyclic moieties contained in these substituents
each comprise 3 to 10 ring members and the heteroalicyclic moieties
each comprise 4 to 10 ring members and the phenyl and pyridinyl
groups contained in the above-mentioned groups may in turn be
mono-, di- or trisubstituted by fluorine, chlorine, bromine or
iodine atoms, by alkyl, alkoxy, methylsulphonyloxy, difluoromethyl,
trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl,
aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy,
alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl,
.omega.-(dialkylamino)alkanoyl, .omega.-(carboxy)alkanoyl,
difluoromethoxy, trifluoromethoxy, trifluoromethylthio,
trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, while
the substituents may be identical or different, R.sup.5 denotes a
hydrogen atom, a C.sub.1-4-alkyl group, while an unbranched alkyl
group may be substituted in the .omega. position by a phenyl,
pyridinyl, diazinyl, amino, alkylamino, dialkylamino,
1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl,
4-morpholinyl or hexahydro-1H-1-azepinyl group, an alkoxycarbonyl,
the cyano or aminocarbonyl group or also, if Y.sup.1 denotes a
nitrogen atom, a pair of free electrons, or, if Y.sup.1 does not
denote a nitrogen atom, also the fluorine atom, or R.sup.4 together
with R.sup.5 and Y.sup.1 denote a 4- to 7-membered cycloaliphatic
ring, in which a methylene group may be replaced by a --NH or
--N(alkyl)- group while a hydrogen atom bound to a nitrogen atom
within the above-mentioned group R.sup.4 may be replaced by a
protecting group, R.sup.6 and R.sup.7, which may be identical or
different, in each case denote a hydrogen atom, a C.sub.1-3-alkyl
or dialkylamino group or also, if Y.sup.1 does not denote a
nitrogen atom, the fluorine atom and R.sup.8 and R.sup.9, which may
be identical or different, each denote a hydrogen atom or a
C.sub.1-3-alkyl group, while, unless otherwise stated, all the
above-mentioned alkyl and alkoxy groups as well as the alkyl groups
present within the other groups specified comprise 1 to 7 carbon
atoms and may be straight-chain or branched, while each methylene
group may be substituted by up to 2 fluorine atoms and each methyl
group may be substituted by up to 3 fluorine atoms, all the
above-mentioned cycloalkyl groups as well as the cycloalkyl groups
present within the other groups specified, unless otherwise stated,
may comprise 3 to 10 carbon atoms, while each methylene group may
be substituted by up to 2 fluorine atoms, and all the
above-mentioned aromatic and heteroaromatic groups may additionally
be mono- di- or trisubstituted by fluorine, chlorine or bromine
atoms, by cyano or hydroxy groups and the substituents may be
identical or different, or a tautomer or salt thereof.
2. A compound of the formula (I) according to claim 1, wherein A,
X, Y, Z, R.sup.2 and R.sup.3 are defined as in claim 1 and R.sup.1
denotes a mono- or diunsaturated 5- to 7-membered aza, diaza,
triaza or thiaza heterocyclic group, in which the above-mentioned
heterocycles are linked via a carbon or nitrogen atom, contain one
or two carbonyl groups adjacent to a nitrogen atom, may be
substituted at a carbon atom by a phenyl, pyridinyl, diazinyl,
thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or
1-methylpyrazolyl group and an olefinic double bond of one of the
above-mentioned unsaturated heterocycles may be fused to a phenyl,
naphthyl, pyridine, diazine, thienyl or quinoline ring or to a
1H-quinolin-2-one ring optionally substituted at the nitrogen atom
by a methyl group, while the phenyl, pyridinyl, diazinyl, thienyl,
pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl
groups contained in R.sup.1 as well as the benzo-, pyrido- and
diazino-fused heterocycles in the carbon skeleton may additionally
be mono-, di- or trisubstituted by fluorine, chlorine, bromine or
iodine atoms, by alkyl, alkoxy, nitro, difluoromethyl,
trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino,
acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy
groups, while the substituents may be identical or different, while
the above-mentioned alkyl groups or the alkyl groups contained in
the above-mentioned groups, unless otherwise stated, contain 1 to 7
carbon atoms and may be branched or unbranched, while each
methylene group may be substituted by up to 2 fluorine atoms and
each methyl group may be substituted by up to 3 fluorine atoms, and
the above-mentioned aromatic and heteroaromatic groups may
additionally be mono- di- or trisubstituted by fluorine, chlorine
or bromine atoms or by cyano or hydroxy groups and the substituents
may be identical or different, or a tautomer or salt thereof.
3. A compound of the formula (I) according to claim 1, wherein A,
X, Y, Z, R.sup.2 and R.sup.3 are defined as in claim 1 and R.sup.1
denotes a monounsaturated 5- to 7-membered diaza or triaza
heterocyclic group, while the above-mentioned heterocycles are
linked via a nitrogen atom, contain a carbonyl group adjacent to a
nitrogen atom, may additionally be substituted at a carbon atom by
a phenyl group and an olefinic double bond of one of the
above-mentioned unsaturated heterocycles may be fused to a phenyl,
thienyl or quinoline ring, while the phenyl groups contained in
R.sup.1 as well as benzo-fused heterocycles in the carbon skeleton
may additionally be mono-, di- or trisubstituted by fluorine,
chlorine, bromine or iodine atoms, by methyl, methoxy, nitro,
difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino,
dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or
trifluoromethoxy groups, while the substituents may be identical or
different, but are preferably unsubstituted, or monosubstituted by
a fluorine, chlorine or bromine atom or by a methyl or methoxy
group, while, unless otherwise stated, all the above-mentioned
alkyl groups as well as the alkyl groups present within the other
groups comprise 1 to 7 carbon atoms and may be straight-chain or
branched and the above-mentioned aromatic and heteroaromatic groups
may additionally be mono- di- or trisubstituted by fluorine,
chlorine or bromine atoms or by cyano or hydroxy groups and the
substituents may be identical or different, or a tautomer or salt
thereof.
4. A compound of the formula (I) according to claim 1, wherein A,
X, Y, Z, R.sup.2 and R.sup.3 are defined as in claim 1 and R.sup.1
denotes a
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl,
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1--
yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-
-1-yl or
4-(2-oxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl)-piperidin-1--
yl group, while the above-mentioned mono- and bicyclic heterocycles
in the carbon skeleton may additionally be monosubstituted by a
methoxy group, while the above-mentioned aromatic and
heteroaromatic groups by fluorine, chlorine or bromine atoms, by
cyano or hydroxy groups may additionally be mono- di- or
trisubstituted and the substituents may be identical or different,
or a tautomer or salt thereof.
5. A compound of the formula (I) according to claim 1, wherein A,
X, Y, Z and R.sup.1 are defined as in claim 1 and R.sup.2 denotes
the hydrogen atom or a phenylmethyl group or a C.sub.2-7-alkyl
group which may be substituted in the .omega. position by a phenyl,
pyridinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy,
alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, acetylamino,
1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl,
[bis-(2-hydroxyethyl)]amino group while the above-mentioned
heterocyclic groups and phenyl groups may additionally be mono-,
di- or trisubstituted in the carbon skeleton by fluorine, chlorine,
bromine or iodine atoms, by methyl, alkoxy, difluoromethyl,
trifluoromethyl, hydroxy, amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, acetylamino, aminocarbonyl, cyano,
difluoromethoxy, trifluoromethoxy, amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.- 1-3-alkyl groups and the
substituents may be identical or different, R.sup.3 denotes the
hydrogen atom or a C.sub.1-3-alkyl group, while the C.sub.1-3-alkyl
group may be linked to an alkyl group present in R.sup.2 or a
phenyl or pyridyl ring present in R.sup.2 and the nitrogen atom to
which they are bound, forming a 5- to 7-membered ring, or R.sup.2
and R.sup.3 together with the enclosed nitrogen atom denote a group
of general formula 279wherein Y.sup.1 denotes the carbon atom or,
if R.sup.5 denotes a pair of free electrons, it may also denote the
nitrogen atom, q and r, if Y.sup.1 denotes the carbon atom,
represent the numbers 0 or 1 or, q and r, if Y.sup.1 denotes the
nitrogen atom, represent the numbers 1 or 2, R.sup.4 denotes the
hydrogen atom, an amino, alkylamino or dialkylamino group, or, if
Y.sup.1 does not denote the nitrogen atom, a dialkylaminomethyl
group, a phenyl, pyridinyl or diazinyl group which may be
substituted in each case by a fluorine, chlorine or bromine atom or
by a trifluoromethylcarbonyl, methyl or methoxy group, a 4- to
7-membered azacycloalkyl group, a 6- to 7-membered oxaza or
diazacycloalkyl group or a 7- to 9-membered azabicycloalkyl group,
while the above-mentioned mono- and bicyclic heterocycles are bound
via a nitrogen or carbon atom, in the above-mentioned mono- and
bicyclic heterocycles any methylene group not directly bound to a
nitrogen, oxygen or sulphur atom may be substituted by one or two
fluorine atoms and the above-mentioned mono- and bicyclic
heterocycles may be substituted by a C.sub.1-3-alkyl group, by a
benzyl, C.sub.3-6-cycloalkylalkyl, C.sub.1-4-alkanoyl,
di-(C.sub.1-3-alkyl)-amino or C.sub.1-3-alkylsulphony- l, by an
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy or carboxyalkyl group,
R.sup.5 denotes a hydrogen atom, a C.sub.1-3-alkyl group or, if
Y.sup.1 denotes a nitrogen atom, it may also denote a pair of free
electrons, R.sup.6 and R.sup.7, which may be identical or
different, in each case denote a hydrogen atom or a C.sub.1-3-alkyl
or di-(C.sub.1-3-alkyl)-amino group and R.sup.8 and R.sup.9, which
may be identical or different, in each case denote a hydrogen atom
or a C.sub.1-3-alkyl group, while, unless otherwise stated, all the
above-mentioned alkyl groups as well as the alkyl groups present
within the other groups comprise 1 to 7 carbon atoms and may be
straight-chain or branched and the above-mentioned aromatic and
heteroaromatic groups may additionally be mono-, di- or
trisubstituted by fluorine, chlorine or bromine atoms or by cyano
or hydroxy groups and the substituents may be identical or
different, or a tautomer or salt thereof.
6. A compounds of the formula (I) according to claim 1, wherein A,
X, Y, Z and R.sup.1 are defined as in claim 1 and R.sup.2 denotes a
phenylmethyl group or a C.sub.2-7-alkyl group which may be
substituted in the .omega. position by a phenyl, amino, alkylamino
or dialkylamino group, while the above-mentioned phenyl group may
be substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl group, or R.sup.3
denotes the hydrogen atom or a C.sub.1-3-alkyl group, R.sup.2 and
R.sup.3 together with the nitrogen atom to which they are bound
denote a 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl
group or R.sup.2 and R.sup.3 together with the enclosed nitrogen
atom denote a group of general formula 280wherein Y.sup.1 denotes
the carbon atom or, if R.sup.5 denotes a pair of free electrons, it
may also denote the nitrogen atom, q and r, if Y.sup.1 denotes the
carbon atom, represent the numbers 0 or 1 or q and r, if Y.sup.1
denotes the nitrogen atom, represent the numbers 1 or 2, R.sup.4
denotes the hydrogen atom, a phenyl or pyridinyl group which may be
substituted in each case by a fluorine, chlorine or bromine atom,
by a trifluoromethylcarbonyl, methyl or methoxy group, a
dimethylamino, diethylamino, perhydro-azepin-1-yl,
4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-piperidin-4-yl,
1-ethylpiperidin-4-yl, piperazin-1-yl, 4-acetyl-piperazin-1-yl,
4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl,
4-ethylpiperazin-1-yl, 4-isopropyl-piperazin-1-yl, piperidin-1-yl,
piperidin-4-yl, morpholin-4-yl, 4,4-difluoro-piperidin-1-yl,
8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl, pyridin-4-yl,
3-dimethylamino-piperidin-1-yl, 1-ethyl-piperidin-4-yl,
4-amino-piperidin-1-yl, 4-(dimethylamino)-piperidin-1-yl,
4-(diethylaminomethyl)-piperidin-1-yl,
p-trifluoromethylcarbonyl-phenyl, 1-benzyl-piperidin-4-yl,
4-benzyl-piperazin-1-yl, azetidin-1-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl,
1-(ethoxycarbonylmethyl)-piperi- din-4-yl,
4-(ethoxycarbonylmethyl)-piperazin-1-yl, 1-carboxymethyl-piperid-
in-4-yl, 4-carboxymethyl-piperazin-1-yl,
4-methylsulphonyl-piperazin-1-yl or 4-methyl-piperazin-1-yl group,
R.sup.5 denotes a hydrogen atom or, if Y.sup.1 denotes a nitrogen
atom, it may also denote a pair of free electrons, R.sup.6 and
R.sup.7 in each case denote a hydrogen atom or a dimethylamino
group and R.sup.8 and R.sup.9 in each case denote the hydrogen
atom, while, unless otherwise stated, all the above-mentioned alkyl
groups as well as the alkyl groups present within the other groups
comprise 1 to 7 carbon atoms and may be straight-chain or branched
and the above-mentioned aromatic and heteroaromatic groups may
additionally be mono-, di- or trisubstituted by fluorine, chlorine
or bromine atoms, by cyano or hydroxy groups and the substituents
may be identical or different, or a tautomer or salt thereof.
7. A compound of the formula (I) according to claim 1, wherein A
denotes an oxygen atom, a cyanoimino or phenylsulphonylimino group,
X denotes an oxygen or sulphur atom, an imino group optionally
substituted by a C.sub.1-6-alkyl group or a methylene group
optionally substituted by a C.sub.1-6-alkyl group, Y and Z
independently of one another each denote a straight-chain or
branched C.sub.1-6-alkyl group wherein each methylene group may be
substituted by up to 2 fluorine atoms and each methyl group may be
substituted by up to 3 fluorine atoms, while the above-mentioned
alkyl groups together with the carbon atoms to which they bound may
be joined to one another, forming a 4- to 8-membered ring, R.sup.1
denotes a monounsaturated 5- to 7-membered diaza or triaza
heterocyclic group, while the above-mentioned heterocycles are
linked via a nitrogen atom, contain a carbonyl group adjacent to a
nitrogen atom, may additionally be substituted at a carbon atom by
a phenyl group and an olefinic double bond of one of the
above-mentioned unsaturated heterocycles may be fused to a phenyl,
thienyl or quinoline ring, while the phenyl groups contained in
R.sup.1 as well as benzo-fused heterocycles in the carbon skeleton
may additionally be mono-, di- or trisubstituted by fluorine,
chlorine, bromine or iodine atoms, by methyl, methoxy, nitro,
difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino,
dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or
trifluoromethoxy groups, while the substituents may be identical or
different, but are preferably unsubstituted or are monosubstituted
by a fluorine, chlorine or bromine atom or by a methyl or methoxy
group, R.sup.2 denotes the hydrogen atom or a phenylmethyl group or
a C.sub.2-7-alkyl group which may be substituted in the .omega.
position by a phenyl, pyridinyl, hydroxy, amino, alkylamino,
dialkylamino, alkoxycarbonyl, carboxy, aminocarbonyl,
aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl,
4-morpholinyl or [bis-(2-hydroxyethyl)]amino group, while the
above-mentioned heterocyclic groups and phenyl groups may
additionally be mono-, di- or trisubstituted in the carbon skeleton
by fluorine, chlorine, bromine or iodine atoms, by methyl, alkoxy,
difluoromethyl, trifluoromethyl, hydroxy, amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino, acetylamino,
aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy,
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.- 1-3-alkyl groups and the
substituents may be identical or different, R.sup.3 denotes the
hydrogen atom or a C.sub.1-3-alkyl group, while the C.sub.1-3-alkyl
group may be linked to an alkyl group present in R.sup.2 or a
phenyl or pyridyl ring present in R.sup.2 and to the nitrogen atom
to which they are bound, forming a 5- to 7-membered ring, or
R.sup.2 and R.sup.3 together with the enclosed nitrogen atom denote
a group of general formula 281wherein Y.sup.1 denotes the carbon
atom or, if R.sup.5 denotes a pair of free electrons, it may also
denote the nitrogen atom, q and r, if Y.sup.1 denotes the carbon
atom, represent the numbers 0 or 1 or q and r, if Y.sup.1 denotes
the nitrogen atom, represent the numbers 1 or 2, R.sup.4 denotes
the hydrogen atom, an amino, alkylamino or dialkylamino group, or,
if Y.sup.1 does not denote the nitrogen atom, it denotes a
dialkylaminomethyl group, a phenyl, pyridinyl or diazinyl group
which may be substituted in each case by a fluorine, chlorine or
bromine atom, by a trifluoromethylcarbonyl, methyl or methoxy
group, a 4- to 7-membered azacycloalkyl group, a 6- to 7-membered
oxaza or diazacycloalkyl group or a 7- to 9-membered
azabicycloalkyl group, while the above-mentioned mono- and bicyclic
heterocycles are bound via a nitrogen or carbon atom, in the
above-mentioned mono- and bicyclic heterocycles any methylene group
not directly bound to a nitrogen, oxygen or sulphur atom may be
substituted by one or two fluorine atoms, the above-mentioned mono-
and bicyclic heterocycles may be substituted by a C.sub.1-3-alkyl
group, by a benzyl, C.sub.3-6-cycloalkylalkyl, C.sub.1-4-alkanoyl,
di-(C.sub.1-3-alkyl)-amino or C.sub.1-3-alkylsulphony- l, by an
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy or carboxyalkyl group,
R.sup.5 denotes a hydrogen atom, a C.sub.1-3-alkyl group or, if
Y.sup.1 denotes a nitrogen atom, it may also denote a pair of free
electrons, R.sup.6 and R.sup.7, which may be identical or
different, in each case denote the hydrogen atom or a
C.sub.1-3-alkyl or di-(C.sub.1-3-alkyl)-amino group and R.sup.8 and
R.sup.9, which may be identical or different, in each case denote
the hydrogen atom or a C.sub.1-3-alkyl group, while, unless
otherwise stated, the above-mentioned alkyl groups or the alkyl
groups contained in the above-mentioned groups contain 1 to 7
carbon atoms and may be branched or unbranched and the
above-mentioned aromatic and heteroaromatic groups may additionally
be mono-, di- or trisubstituted by fluorine, chlorine or bromine
atoms, by cyano or hydroxy groups and the substituents may be
identical or different, or a tautomer or salt thereof.
8. A compound of the formula (I) according to claim 1, wherein A
denotes an oxygen atom, a cyanoimino or phenylsulphonylimino group,
X denotes an oxygen atom, an imino or methylene group and Y and Z
independently of one another each denote a straight-chain or
branched C.sub.1-4-alkyl group wherein each methylene group may be
substituted by up to 2 fluorine atoms and each methyl group may be
substituted by up to 3 fluorine atoms, while the above-mentioned
alkyl groups together with the carbon atoms to which they are bound
may be joined to one another, forming a 5- to 7-membered ring,
R.sup.1 denotes a 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzod-
iazepin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-pip- eridin-1-yl,
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1- -yl,
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1--
yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-
-1-yl or 4-(2-oxo-1,4-dihydro-2H-thieno
[2,3-d]pyrimidin-3-yl)-piperidin-1- -yl group, while the
above-mentioned mono- and bicyclic heterocycles in the carbon
skeleton may additionally be monosubstituted by a methoxy group,
R.sup.2 denotes a phenylmethyl group or a C.sub.2-7-alkyl group
which may be substituted in the .omega. position by a phenyl,
amino, alkylamino or dialkylamino group, while the above-mentioned
phenyl group may be substituted by an amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.su- b.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl group, or R.sup.3
denotes the hydrogen atom or a C.sub.1-3-alkyl group, R.sup.2 and
R.sup.3 together with the nitrogen atom to which they are bound
denote a 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl
group or R.sup.2 and R.sup.3 together with the enclosed nitrogen
atom denote a group of general formula 282wherein Y.sup.1
represents the carbon atom or, if R.sup.5 denotes a pair of free
electrons, it may also denote the nitrogen atom, q and r, if
Y.sup.1 denotes the carbon atom, represent the numbers 0 or 1 or q
and r, if Y.sup.1 denotes the nitrogen atom, represent the numbers
1 or 2, R.sup.4 denotes the hydrogen atom, a phenyl or pyridinyl
group which may be substituted in each case by a fluorine, chlorine
or bromine atom, by a trifluoromethylcarbonyl, methyl or methoxy
group, a dimethylamino, diethylamino, perhydro-azepin-1-yl,
4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-piperidin-4-yl,
1-ethylpiperidin-4-yl, piperazin-1-yl, 4-acetyl-piperazin-1-yl,
4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl,
4-ethylpiperazin-1-yl, 4-isopropyl-piperazin-1-yl, piperidin-1-yl,
piperidin-4-yl, morpholin-4-yl, 4,4-difluoro-piperidin-1-yl,
8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl, pyridin-4-yl,
3-dimethylamino-piperidin-1-yl, 1-ethyl-piperidin-4-yl,
4-amino-piperidin-1-yl, 4-(dimethylamino)-piperidin-1-yl,
4-(diethylaminomethyl)-piperidin-1-yl,
p-trifluoromethylcarbonyl-phenyl, 1-benzyl-piperidin-4-yl,
4-benzyl-piperazin-1-yl, azetidin-1-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl,
1-(ethoxycarbonylmethyl)-piperi- din-4-yl,
4-(ethoxycarbonylmethyl)-piperazin-1-yl, 1-carboxymethyl-piperid-
in-4-yl, 4-carboxymethyl-piperazin-1-yl,
4-methylsulphonyl-piperazin-1-yl or 4-methyl-piperazin-1-yl group,
R.sup.5 denotes a hydrogen atom or, if Y.sup.1 denotes a nitrogen
atom, it may also denote a pair of free electrons, R.sup.6 and
R.sup.7 in each case denote a hydrogen atom or a dimethylamino
group and R.sup.8 and R.sup.9 in each case denote the hydrogen
atom, while, unless otherwise stated, all the above-mentioned alkyl
groups as well as the alkyl groups present within the other groups
comprise 1 to 7 carbon atoms and may be straight-chain or branched
and the above-mentioned aromatic and heteroaromatic groups may
additionally be mono-, di- or trisubstituted by fluorine, chlorine
or bromine atoms or by cyano or hydroxy groups and the substituents
may be identical or different, or a salt thereof.
9. A compound of the formula (I) according to claim 1, wherein A
denotes an oxygen atom or a cyanoimino group, X denotes an oxygen
atom, an imino or methylene group and Y and Z independently of one
another each denote a methyl or ethyl group wherein each methylene
group may be substituted by up to 2 fluorine atoms and the methyl
group may be substituted by up to 3 fluorine atoms, while the
above-mentioned methyl and ethyl groups together with the carbon
atoms to which they are bound may be joined to one another, forming
a 5- to 6-membered ring, R.sup.1 denotes a
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl,
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1--
yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-
-1-yl or
4-(2-oxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl)-piperidin-1--
yl group, while the above-mentioned mono- and bicyclic heterocycles
may additionally be monosubstituted in the carbon skeleton by a
methoxy group, R.sup.2 denotes a phenylmethyl group or a
C.sub.2-7-alkyl group which may be substituted in the .omega.
position by a phenyl, amino, alkylamino or dialkylamino group,
while the above-mentioned phenyl group may be substituted by an
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.su- b.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl group, or R.sup.3
denotes the hydrogen atom or a C.sub.1-3-alkyl group, R.sup.2 and
R.sup.3 together with the nitrogen atom to which they are bound
denote a 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl
group or R.sup.2 and R.sup.3 together with the enclosed nitrogen
atom denote a group of general formula 283wherein Y.sup.1
represents the carbon atom or, if R.sup.5 denotes a pair of free
electrons, it may also denote the nitrogen atom, q and r, if
Y.sup.1 denotes the carbon atom, represent the numbers 0 or 1 or q
and r, if Y.sup.1 denotes the nitrogen atom, represent the numbers
1 or 2, R.sup.4 denotes the hydrogen atom, a phenyl or pyridinyl
group which may be substituted in each case by a fluorine, chlorine
or bromine atom, by a trifluoromethylcarbonyl, methyl or methoxy
group, a dimethylamino, diethylamino, perhydro-azepin-1-yl,
4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-piperidin-4-yl,
1-ethyl-piperidin-4-yl, piperazin-1-yl, 4-acetyl-piperazin-1-yl,
4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl,
4-ethyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, piperidin-1-yl,
piperidin-4-yl, 4-morpholin-4-yl, 4,4-difluoro-1-piperidin-1-yl,
8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl, pyridin-4-yl,
3-dimethylamino-piperidin-1-yl, 1-ethyl-piperidin-4-yl,
4-amino-piperidin-1-yl, 4-(dimethylamino)-piperidin-1-yl,
4-(diethylaminomethyl)-piperidin-1-yl,
p-trifluoromethylcarbonyl-phenyl, 1-benzyl-piperidin-4-yl,
4-benzyl-piperazin-1-yl, azetidin-1-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl,
1-(ethoxycarbonyl-methyl)-piper- idin-4-yl,
4-(ethoxycarbonylmethyl)-piperazin-1-yl,
1-carboxymethyl-piperidin-4-yl, 4-carboxymethyl-piperazin-1-yl,
4-methylsulphonyl-piperazin-1-yl or 4-methyl-piperazin-1-yl group,
R.sup.5 denotes a hydrogen atom or, if Y.sup.1 denotes a nitrogen
atom, it may also denote a pair of free electrons, R.sup.6 and
R.sup.7 in each case denote a hydrogen atom or a dimethylamino
group and R.sup.8 and R.sup.9 in each case denote the hydrogen
atom, while, unless otherwise stated, all the above-mentioned alkyl
groups as well as the alkyl groups present within the other groups
comprise 1 to 7 carbon atoms and may be straight-chain or branched
and the above-mentioned aromatic and heteroaromatic groups may
additionally be mono-, di- or trisubstituted by fluorine, chlorine
or bromine atoms or by cyano or hydroxy groups and the substituents
may be identical or different, or a salt thereof.
10. A compound selected from the group consisting of: (1)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperaz-
in-1-yl]-2-oxo-ethyl}-amide, (2)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaz-
epin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(-
4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (3)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-2-ox-
o-ethyl]-amide, (4)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pi-
peridine-1-carboxylic
acid-[1-(3,4-diethyl-benzyl)-2-oxo-2-(3,4,5,6-tetrah-
ydro-2H-4,4'-bipyridinyl-1-yl)-ethyl]-amide, (5)
4-(2-oxo-1,2,4,5-tetrahyd-
ro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[2-1,4'-bipiperidi-
nyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo-ethyl]-amide, (6)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-et-
hyl]-amide, (7)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carb- oxylic
acid-{1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperid-
in-1-yl]-2-oxo-ethyl}-amide, (8)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-- piperidine-1-carboxylic
acid-{1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperi-
din-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (9)
4-(2-oxo-1,2,4,5-tetrahy-
dro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-
-ethyl]-amide, (10)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pi-
peridine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-perhydro-
-azepin-1-yl-piperidin-1-yl)-ethyl]-amide, (11)
4-(2-oxo-1,2,4,5-tetrahydr-
o-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-
-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo--
ethyl}-amide, (12)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pip-
eridine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bi-
piperidinyl-1-yl)-2-oxo-ethyl]-amide, (13)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-
-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benz-
yl)-2-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-eth-
yl}-amide, (14)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperi-
dine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-piperazin-1--
yl-piperidin-1-yl)-ethyl]-amide, (15)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benz-
odiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-[4-(4-acetyl-piperazin-
-1-yl)-piperidin-1-yl]-1-(3,4-diethyl-benzyl)-2-oxo-ethyl]-amide,
(16)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(3-dimethylamino-piperidin-1-yl)-2-o-
xo-ethyl]-amide, (17)
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-pi-
peridine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-pipe-
ridin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (18)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-
-1-yl]-2-oxo-ethyl}-amide, (19)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinoli-
n-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-m-
ethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (20)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(-
3,4-diethyl-benzyl)-2-oxo-ethyl]-amide, (21)
4-(2-oxo-1,2-dihydro-4H-thien-
o[3,4-d]pyrimidin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-b-
enzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,
(22)
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-p-
iperazin-1-yl]-2-oxo-ethyl}-amide, (23)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-be-
nzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-
-2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-amide, (24)
4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-p-
iperazin-1-yl]-2-oxo-ethyl}-amide, (25)
4-(2-oxo-1,2,4,5-tetrahydro-thieno-
[3,2-d]-1,3-diazepin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethy-
l-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-ox
o-ethyl}-amide, (26)
4-(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazep-
in-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1--
methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (27)
4-(2-oxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl)-piperidine-1-carboxy-
lic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pipera-
zin-1-yl]-2-oxo-ethyl}-amide, (28)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
azepin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-
-(4-ethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (29)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-isopropyl-piperazin-1-yl)-pipe-
ridin-1-yl]-2-oxo-ethyl}-amide, (30)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzo-
diazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-y-
l-1-(3,4-diethyl-benzyl)-2-oxo-ethyl]-amide, (31)
4-(2-oxo-1,2,4,5-tetrahy-
dro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)--
ethyl]-amide, (32)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pip-
eridine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3,4,5,6-tet-
rahydro-2H-4,4'-bipyridinyl-1-yl)-ethyl]-amide, (33)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4,4-difluoro-1,4'-bipiperidinyl-1'--
yl)-2-oxo-ethyl]-amide, (34)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-
-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-morph-
olin-4-yl-piperidin-1-yl)-2-oxo-ethyl]-amide, (35)
4-(2-oxo-1,2,4,5-tetrah-
ydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-ethyl-piperidin-4-yl)-piperazin--
1-yl]-2-oxo-ethyl}-amide, (36)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazep-
in-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-(4-diethylaminomethyl-piperid-
in-1-yl)-1-(3,4-diethyl-benzyl)-2-oxo-ethyl]-amide, (37)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-[1,4]di-
azepan-1-yl]-2-oxo-ethyl}-amide, (38)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benz-
odiazepin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-
-[3-(4-methyl-piperazin-1-yl)-azetidin-1-yl]-2-oxo-ethyl}-amide,
(39)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3-piperidin-1-yl-azetidin-1-y-
l)-ethyl]-amide, (40)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)--
piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3-pyrrol-
idin-1-yl-azetidin-1-yl)-ethyl]-amide, (41)
4-(2-oxo-1,2,4,5-tetrahydro-1,-
3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-(3-diethylamino--
azetidin-1-yl)-1-(3,4-diethyl-benzyl)-2-oxo-ethyl]-amide, (42)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-((R)-1-(3,4-diethyl-benzyl)-2-oxo-2-{4-[4-(2,2,2-trifluoro-acetyl)-
-phenyl]-piperazin-1-yl}-ethyl)-amide, (43)
4-(2-oxo-1,2,4,5-tetrahydro-1,-
3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-ben-
zyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl]-amide, (44)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-1-(3-aminomethyl-benzylcarbamoyl)-2-(3,4-diethyl-phenyl)-ethy-
l]-amide, (45)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperid-
ine-1-carboxylic
acid-[(R)-1-(5-amino-pentylcarbamoyl)-2-(3,4-diethyl-phen-
yl)-ethyl]-amide, (46)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
-piperidine-1-carboxylic
acid-[(R)-1-(4-amino-butylcarbamoyl)-2-(3,4-dieth-
yl-phenyl)-ethyl]-amide, (47)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepi-
n-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-(3,4-diethyl-phenyl)-1-(5-meth-
ylamino-pentylcarbamoyl)-ethyl]-amide, (48)
4-(2-oxo-1,2,4,5-tetrahydro-1,-
3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-[4-(4-methyl-pip-
erazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylme-
thyl)-ethyl]-amide, (49)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y-
l)-piperidine-1-carboxylic
acid-[(R)-2-[4-(1-methyl-piperidin-4-yl)-pipera-
zin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
(50)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-car-
boxylic
acid-[(R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(-
5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (51)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7-
,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (52)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-1-(5,6,7,8-tetrahyd-
ro-naphthalen-2-ylmethyl)-ethyl]-amide, (53)
4-(2-oxo-1,2,4,5-tetrahydro-1-
,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-oxo-2-(4-pipera-
zin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethy-
l]-amide, (54)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-
e-1-carboxylic
acid-[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2--
oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (55)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7,8-
-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (56)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetrahydro-
-naphthalen-2-ylmethyl)-ethyl]-amide, (57)
4-(5-oxo-3-phenyl-4,5-dihydro-[-
1,2,4]triazol-1-yl)-piperidine-1-carboxylic
acid-[(R)-2-[4-(1-methyl-piper-
idin-4-yl)-piperazin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmeth-
yl)-ethyl]-amide, (58)
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)--
piperidine-1-carboxylic
acid-[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-
-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
(59)
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carb-
oxylic
acid-[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetr-
ahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (60)
(R)-1-(3,4-diethyl-benzyl-
)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ate, (61)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-
-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(7-dimethylaminomethyl-1,2,-
4,5-tetrahydro-3-benzazepin-3-yl)-2-oxo-ethyl]-amide, (62)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-(4-azetidin-1-yl-piperidin-1-yl)-1-(3,4-diethyl-benzyl)-2-o-
xo-ethyl]-amide, (63)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)--
piperidine-1-carboxylic
acid-[(R)-2-(3-azepan-1-yl-azetidin-1-yl)-1-(3,4-d-
iethyl-benzyl)-2-oxo-ethyl]-amide, (64) ethyl
[1'-((R)-3-(3,4-diethyl-phen-
yl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-c-
arbonyl]-amino}-propionyl)-[4,4']bipiperidinyl-1-yl]-acetate, (65)
ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-ben-
zodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]--
piperazin-1-yl}-acetate, (66)
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-
-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}--
propionyl)-[4,4']bipiperidinyl-1-yl]-acetic acid, (67)
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-ben-
zodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]--
piperazin-1-yl}-acetic acid, (68) ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)--
2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carbony-
l]-amino}-propionyl)-piperidin-4-yl]-piperazin-1-yl}-acetate, (69)
ethyl
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]qu-
inolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']bipiperidinyl--
1-yl]-acetate, (70)
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dih-
ydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-
-piperidin-4-yl]-piperazin-1-yl}-acetic acid, (71)
[1'-((R)-3-(3,4-diethyl-
-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine--
1-carbonyl]-amino}-propionyl)-[4,4']bipiperidinyl-1-yl]-acetic
acid, (72)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-
-1-yl]-2-oxo-ethyl}-amide, (73)
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-m-
ethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,-
5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cya-
namide, (74)
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-y-
l)-piperidin-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-be-
nzodiazepin-3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cyanamide, (75)
N-[1-[(R)-2-[1,4']bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo-ethyla-
mino]-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-y-
l]-meth-(Z)-ylidene]-cyanamide, (76)
1-[1,4']bipiperidinyl-1'-yl-2-(3,4-di-
methyl-benzyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-
-butan-1,4-dione, (77)
2-(3,4-dimethyl-benzyl)-1-(1'-methyl-[4,4']bipiperi-
dinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-bu-
tan-1,4-dione, (78)
2-(3,4-dimethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-
-piperazin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-y-
l]-butan-1,4-dione, (79)
2-(3,4-dimethyl-benzyl)-1-[4-(4-methyl-piperazin--
1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidi-
n-1-yl]-butan-1,4-dione, (80)
2-(3,4-dimethyl-benzyl)-1-[4-(4-ethyl-pipera-
zin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-pipe-
ridin-1-yl]-butan-1,4-dione, (81)
2-(3,4-dimethyl-benzyl)-1-[4-(4-isopropy-
l-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3--
yl)-piperidin-1-yl]-butan-1,4-dione, (82)
2-(3,4-dimethyl-benzyl)-1-[4-(4--
methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2-
H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione, (83)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{1-(3,4-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1--
yl]-2-oxo-ethyl}-amide, (84)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-pipe- ridine-1-carboxylic
acid-{1-(3,4-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-
-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (85)
4-(2-oxo-1,4-dihydro-2H-qu- inazolin-3-yl)-piperidine-1-carboxylic
acid-[1-(3,4-dimethyl-benzyl)-2-(1'-
-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl]-amide, (86)
2-(3,4-diethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[-
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione,
(87)
2-(3,4-diethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl-
]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-di-
one, (88) methyl
{1'-[4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-pi-
peridin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butyryl]-[4,4']-
bipiperidinyl-1-yl}-acetate, (89)
{1'-[4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-qu-
inazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl-
)-butyryl]-[4,4']bipiperidinyl-1-yl}-acetic acid, (90) methyl
(1'-{2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-
-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate, (91)
((1'-{2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl-
)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid,
(92)
1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-
-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmet-
hyl)-butan-1,4-dione, (93)
1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2--
oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro--
naphthalen-2-ylmethyl)-butan-1,4-dione, (94)
2-indan-5-ylmethyl-1-[4-(4-me-
thyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-
-3-yl)-piperidin-1-yl]-butan-1,4-dione, (95)
2-indan-5-ylmethyl-1-(1'-meth-
yl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-p-
iperidin-1-yl]-butan-1,4-dione, (96)
1-(1'-methyl-[4,4']bipiperidinyl-1-yl-
)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,5,8,8-t-
etramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butan-1,4-dione,
(97)
1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-
-quinazolin-3-yl)-piperidin-1-yl]-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydr-
o-naphthalen-2-ylmethyl)-butan-1,4-dione, (98)
1-[1,4']bipiperidinyl-1'-yl-
-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,5,8,8-te-
tramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butan-1,4-dione,
(99)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3,4-bis-pentafluorethyl-benzyl)-2-[4-(4-methyl-piperazin-1-
-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (100)
4-(2-oxo-1,2,4,5-tetrahydro-
-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic acid
{(R)-1-(3-ethyl-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-
-1-yl]-2-oxo-ethyl}-amide, (101)
(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pip-
erazin-1-yl-piperidin-1-yl)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodia-
zepin-3-yl)-piperidine-1-carboxylate, (102)
(R)-1-(3,4-diethyl-benzyl)-2-[-
4-(1-ethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ate, (103)
(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetrah-
ydro-naphthalen-2-ylmethyl)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodia-
zepin-3-yl)-piperidine-1-carboxylate, (104)
(S)-2-(3,4-diethyl-benzyl)-4-[-
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-1-(4-p-
iperazin-1-yl-piperidin-1-yl)-butan-1,4-dione, (105)
(S)-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazep-
in-3-yl)-piperidin-1-yl]-1-(4-piperidin-4-yl-piperazin-1-yl)-butan-1,4-dio-
ne, (106)
(S)-2-(3,4-diethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-pipera-
zin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-
-1-yl]-butan-1,4-dione, (107)
(S)-2-(3,4-diethyl-benzyl)-1-[4-(4-methyl-pi-
perazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaz-
epin-3-yl)-piperidin-1-yl]-butan-1,4-dione, (108)
(S)-1-[1,4']bipiperidiny-
l-1'-yl-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodia-
zepin-3-yl)-piperidin-1-yl]-butan-1,4-dione, (109)
4-(2-oxo-1,2,4,5-tetrah-
ydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-y-
l)-piperidin-1-yl]-2-oxo-ethyl}-amide, (110)
(S)-2-(3,4-bis-trifluoromethy-
l-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4-
,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butan-1,4-dione,
(111)
(R)-1-(3,4-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-y-
l)-piperidin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazep-
in-3-yl)-piperidine-1-carboxylate, (112)
(S)-2-(3,4-diethyl-benzyl)-1-(4-d-
imethylamino-piperidin-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidin-1-yl]-butan-1,4-dione, (113)
(R)-1-(3,4-diethyl-benzyl-
)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahyd-
ro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, (114)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-(4-amino-piperidin-1-yl)-1-(3,4-diethyl-benzyl)-2-oxo-ethyl-
]-amide, (115)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbo- xylic
acid-[2-[1,4']bipiperidinyl-1'-yl-1-(3,4-dimethyl-benzyl)-2-oxo-ethy-
l]-amide, (116)
(S)-2-(3,4-diethyl-benzyl)-1-(1'-methyl-4,4'-bipiperidinyl-
-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1--
yl]-butan-1,4-dione, (117)
(S)-1-4,4'-bipiperidinyl-1-yl-2-(3,4-diethyl-be-
nzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-y-
l]-butan-1,4-dione, (118)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3--
yl)-piperidine-1-carboxylic
acid-{(R)-1-(4-ethyl-3-trifluoromethyl-benzyl)-
-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,
(119)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(4-ethyl-3-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-
-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (120)
4-(2-oxo-1,2,4,5-tetrahyd-
ro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(4-ethyl-3--
trifluoromethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl]-
-amide, (121)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidi-
ne-1-carboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(4-ethyl-3-trifluor-
omethyl-benzyl)-2-oxo-ethyl]-amide, (122)
4-(2-oxo-1,2,4,5-tetrahydro-1,3--
benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-(4-dimethylamino-p-
iperidin-1-yl)-1-(4-ethyl-3-trifluoromethyl-benzyl)-2-oxo-ethyl]-amide,
(123)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3-ethyl-4-trifluoromethyl-benzyl)-2-[4-(4-methyl-pip-
erazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (124)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3-ethyl-4-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-
-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (125)
4-(2-oxo-1,2,4,5-tetrahyd-
ro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3-ethyl-4--
trifluoromethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl]-
-amide, (126)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidi-
ne-1-carboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(3-ethyl-4-trifluor-
omethyl-benzyl)-2-oxo-ethyl]-amide, and (127)
4-(2-oxo-1,2,4,5-tetrahydro--
1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-(4-dimethylami-
no-piperidin-1-yl)-1-(3-ethyl-4-trifluoromethyl-benzyl)-2-oxo-ethyl]-amide-
, or a salt thereof.
11. A compound selected from the group consisting of: (1)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperaz-
in-1-yl]-2-oxo-ethyl}-amide, (2)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaz-
epin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(-
4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (3)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-2-ox-
o-ethyl]-amide, (4)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pi-
peridine-1-carboxylic
acid-[2-1,4'-bipiperidinyl-1'-yl-1-(3,4-diethyl-benz-
yl)-2-oxo-ethyl]-amide, (5)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin--
3-yl)-piperidine-1-carboxylic
acid-[1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyri-
dine-4-yl-piperazin-1-yl)-ethyl]-amide, (6)
4-(2-oxo-1,4-dihydro-2H-quinaz- olin-3-yl)-piperidine-1-carboxylic
acid-{1-(3,4-diethyl-benzyl)-2-[4-(4-me-
thyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (7)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-y-
l]-2-oxo-ethyl}-amide, (8)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-dimethy-
lamino-piperidin-1-yl)-2-oxo-ethyl]-amide, (9)
4-(2-oxo-1,2,4,5-tetrahydro-
-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl--
benzyl)-2-oxo-2-(4-perhydro-azepin-1-yl-piperidin-1-yl)-ethyl]-amide,
(10)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-
-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (11)
4-(2-oxo-1,2,4,5-tetrahydro--
1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-b-
enzyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl]-amide,
(12)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-
-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (13)
4-(2-oxo-1,2,4,5-tetrahydr-
o-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-
-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl]-amide,
(14)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-[4-(4-acetyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-diethyl-
-benzyl)-2-oxo-ethyl]-amide, (15)
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-tria-
zol-1-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-
-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (16)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-
-1-yl]-2-oxo-ethyl}-amide, (17)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinoli-
n-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-m-
ethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (18)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(-
3,4-diethyl-benzyl)-2-oxo-ethyl]-amide, (19)
4-(2-oxo-1,2-dihydro-4H-thien-
o[3,4-d]pyrimidin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-b-
enzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,
(20)
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-p-
iperazin-1-yl]-2-oxo-ethyl}-amide, (21)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-be-
nzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-
-2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-amide, (22)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-ethyl-piperazin-1-yl)-piperidi-
n-1-yl]-2-oxo-ethyl}-amide, (23)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaz-
epin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(-
4-isopropyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,
(24)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo-ethyl-
]-amide, (25)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidi-
ne-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyridine-4-yl--
piperazin-1-yl)-ethyl]-amide, (26)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-
azepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-ox-
o-2-(3,4,5,6-tetrahydro-2H-4,4'-bipyridinyl-1-yl)-ethyl]-amide,
(27)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2--
oxo-ethyl]-amide, (28)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-
-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-ethyl-pi-
peridin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (29)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-(4-diethylaminomethyl-piperidin-1-yl)-1-(3,4-diethyl-benzyl-
)-2-oxo-ethyl]-amide, (30)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-
-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-meth-
yl-piperidin-4-yl)-[1,4]diazepan-1-yl]-2-oxo-ethyl}-amide, (31)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[3-(4-methyl-piperazin-1-yl)-azetidi-
n-1-yl]-2-oxo-ethyl}-amide, (32)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaz-
epin-3-yl)-piperidine-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo--
2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl]-amide, (33)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7-
,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (34)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(5,6,7-
,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (35)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ic
acid-[(R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-1-(5,6,7,8-tetrahyd-
ro-naphthalen-2-ylmethyl)-ethyl]-amide, (36)
4-(2-oxo-1,2,4,5-tetrahydro-1-
,3-benzodiazepin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-oxo-2-(4-pipera-
zin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethy-
l]-amide, (37)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-
e-1-carboxylic
acid-[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2--
oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (38)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7,8-
-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (39)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylic
acid-[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetrahydro-
-naphthalen-2-ylmethyl)-ethyl]-amide, (40)
4-(5-oxo-3-phenyl-4,5-dihydro-[-
1,2,4]triazol-1-yl)-piperidine-1-carboxylic
acid-[(R)-2-[4-(1-methyl-piper-
idin-4-yl)-piperazin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmeth-
yl)-ethyl]-amide, (41)
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)--
piperidine-1-carboxylic
acid-[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl-
)-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide, (42)
(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-
-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-
e-1-carboxylate, (43)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)--
piperidine-1-carboxylic
acid-[(R)-2-(4-azetidin-1-yl-piperidin-1-yl)-1-(3,-
4-diethyl-benzyl)-2-oxo-ethyl]-amide, (44)
{4-[1-((R)-3-(3,4-diethyl-pheny-
l)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-pin-3-yl)-piperidine-1-c-
arbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazin-1-yl}-acetic
acid, (45) ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imi-
dazo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperid-
in-4-yl]-piperazin-1-yl}-acetate, (46) ethyl
[1'-((R)-3-(3,4-diethyl-pheny-
l)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
onyl]-amino-}propionyl)-[4,4']bipiperidinyl-1-yl]-acetate, (47)
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]-
quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-pi-
perazin-1-yl}-acetic acid, (48)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinoli-
n-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-m-
ethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (49)
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-
-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin--
3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cyanamide, (50)
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-
-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin--
3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cyanamide, (51)
N-[1-[(R)-2-[1,4']bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo-ethyla-
mino]-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-y-
l]-meth-(Z)-ylidene]-cyanamide, (52)
2-(3,4-dimethyl-benzyl)-1-[4-(1-methy-
l-piperidin-4-yl)-piperazin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3--
yl)-piperidin-1-yl]-butan-1,4-dione, (53)
2-(3,4-dimethyl-benzyl)-1-[4-(4--
methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazol-
in-3-yl)-piperidin-1-yl]-butan-1,4-dione, (54)
2-(3,4-dimethyl-benzyl)-1-[-
4-(4-ethyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quin-
azolin-3-yl)-piperidin-1-yl]-butan-1,4-dione, (55)
4-(2-oxo-1,4-dihydro-2H- -quinazolin-3-yl)-piperidine-1-carboxylic
acid-{1-(3,4-dimethyl-benzyl)-2--
[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,
(56)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{1-(3,4-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1--
yl]-2-oxo-ethyl}-amide, (57)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-pipe- ridine-1-carboxylic
acid-[1-(3,4-dimethyl-benzyl)-2-(1'-methyl-[4,4']bipip-
eridinyl-1-yl)-2-oxo-ethyl]-amide, (58)
2-(3,4-diethyl-benzyl)-1-[4-(4-met-
hyl-piperazin-1-yl)-piperidin-1-y]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-
-yl)-piperidin-1-yl]-butan-1,4-dione, and (59)
2-(3,4-diethyl-benzyl)-1-[4-
-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quin-
azolin-3-yl)-piperidin-1-yl]-butan-1,4-dione, or a salt
thereof.
12. A physiologically acceptable salt of a compound according to
claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, formed with inorganic or
organic acid or base.
13. A pharmaceutical composition containing a compound according to
claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, or a physiologically
acceptable salt thereof, together with one or more inert carriers
and/or diluents.
14. A method for the acute or prophylactic treatment of headache,
including migraine or cluster headaches, which comprises
administering to a host prone to or currently suffering from the
same a therapeutically effective amount of a compound according to
claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, or a physiologically
acceptable salt thereof.
15. A method for treating non-insulin-dependent diabetes mellitus
(NIDDM) which comprises administering to a host suffering from the
same a therapeutically effective amount of a compound according to
claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, or a physiologically
acceptable salt thereof.
16. A method for treating cardiovascular diseases, morphine
tolerance, diarrhoea caused by clostridium toxin, skin diseases,
particularly thermal and radiation-induced skin damage including
sunburn, inflammatory diseases, e.g. particularly inflammatory
diseases of the joints such as arthritis, neurogenic inflammation
of the oral mucosa, inflammatory lung diseases, allergic rhinitis,
asthma, diseases accompanied by excessive vasodilatation and
resultant reduced circulation of the blood, e.g. particularly shock
and sepsis, for alleviating pain in general or for preventive or
acute therapeutic treatment of the symptoms of hot flushes caused
by vasodilatation and increased blood flow in menopausal
oestrogen-deficient women and hormone-treated patients with
prostate carcinoma which comprises administering to a host
suffering from the same a therapeutic amount of a compound
according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, or a
physiologically acceptable salt thereof.
Description
RELATED APPLICATIONS
[0001] Benefit of U.S. Provisional Application Serial No.
60/426,167, filed on Nov. 14, 2002, is hereby claimed.
FIELD OF THE INVENTION
[0002] The present invention relates to CGRP antagonists of general
formula 2
[0003] the tautomers, diastereomers, enantiomers, hydrates,
mixtures thereof and the salts thereof as well as the hydrates of
the salts, particularly the physiologically acceptable salts
thereof with inorganic or organic acids, pharmaceutical
compositions containing these compounds, the use thereof and
processes for the preparation thereof.
[0004] In the above general formula (I) in a first embodiment
[0005] A denotes an oxygen or sulphur atom, a phenylsulphonylimino
or cyanoimino group,
[0006] X denotes an oxygen or sulphur atom, an imino group
optionally substituted by a C.sub.1-6-alkyl group or a methylene
group optionally substituted by a C.sub.1-6-alkyl group,
[0007] Y and Z independently of one another each denote a
straight-chain or branched C.sub.1-6-alkyl group wherein each
methylene group may be substituted by up to 2 fluorine atoms and
each methyl group may be substituted by up to 3 fluorine atoms,
[0008] while the above-mentioned alkyl groups together with the
carbon atom to which they are bound, may be joined to one another,
forming a 4- to 8-membered ring,
[0009] R.sup.1 denotes a saturated, mono- or diunsaturated 5- to
7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or
S,S-dioxido-thiadiaza heterocyclic group,
[0010] in which the above-mentioned heterocycles are linked via a
carbon or nitrogen atom,
[0011] contain one or two carbonyl or thiocarbonyl groups adjacent
to a nitrogen atom,
[0012] may be substituted at one of the nitrogen atoms by an alkyl
group,
[0013] may be substituted at one or at two carbon atoms by an alkyl
group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl,
diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl,
isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or
1-methylimidazolyl group, while the substituents may be identical
or different, and
[0014] while an olefinic double bond of one of the above-mentioned
unsaturated heterocycles may be fused to a phenyl, naphthyl,
pyridine, diazine, 1,3-oxazole, thienyl, furan, thiazole, pyrrole,
N-methylpyrrole or quinoline ring, to a 1H-quinolin-2-one ring
optionally substituted at the nitrogen atom by an alkyl group or to
an imidazole or N-methylimidazole ring or also two olefinic double
bonds of one of the above-mentioned unsaturated heterocycles may
each be fused to a phenyl ring,
[0015] 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.sup.1 as well as benzo-, thieno-, pyrido- and
diazino-fused heterocycles 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, difluoromethyl,
trifluoromethyl, alkoxycarbonyl, carboxy, hydroxy, amino,
alkylamino, dialkylamino, acetyl, 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, difluoromethoxy,
trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or
trifluoromethylsulphonyl groups, while the substituents may be
identical or different,
[0016] R.sup.2 denotes the hydrogen atom,
[0017] a phenylmethyl group or a C.sub.2-7-alkyl group which may be
substituted in the .omega. position by a cyclohexyl, phenyl,
pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino,
carboxy, alkoxycarbonyl, aminocarbonyl, aminocarbonylamino,
acetylamino, 1-pyrrolidinyl, 1-piperidinyl,
4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl,
hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino,
4-alkyl-1-piperazinyl or
4-(.omega.-hydroxy-C.sub.2-7-alkyl)-1-piperaziny- l group,
[0018] a phenyl or pyridinyl group,
[0019] while the above-mentioned heterocyclic groups and phenyl
groups may additionally be mono- di- or trisubstituted in the
carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by
methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino, acetylamino,
aminocarbonyl, cyano, methylsulphonyloxy, difluoromethoxy,
trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl,
trifluoromethylsulphonyl, amino-C.sub.1-3-alkyl,
C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl groups and the
substituents may be identical or different,
[0020] R.sup.3 denotes the hydrogen atom or a C.sub.1-3-alkyl group
optionally substituted by a phenyl or pyridinyl group,
[0021] while the C.sub.1-3-alkyl group may be linked to an alkyl
group present in R.sup.2 or a phenyl or pyridyl ring present in
R.sup.2 and the nitrogen atom to which they are bound, forming a
ring, or
[0022] R.sup.2 and R.sup.3 together with the enclosed nitrogen atom
denote a group of general formula 3
[0023] wherein
[0024] Y.sup.1 denotes the carbon atom or, if R.sup.5 is a pair of
free electrons, it may also denote the nitrogen atom,
[0025] q and r, if Y.sup.1 denotes the carbon atom, represent the
numbers 0, 1 or 2, or
[0026] q and r, if Y.sup.1 denotes the nitrogen atom, represent the
numbers 1 or 2, R.sup.4 denotes the hydrogen atom, an amino,
alkylamino, dialkylamino, alkyl, cycloalkyl, amino-C.sub.2-7-alkyl,
alkylamino-C.sub.2-7-alkyl, dialkylamino-C.sub.2-7-alkyl,
aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino,
cycloalkylamino-carbonylamino, phenylaminocarbonylamino,
aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl or carboxyalkyl group, or, if Y.sup.1 does not
denote the nitrogen atom, the carboxy, aminomethyl,
alkylaminomethyl or dialkylaminomethyl group,
[0027] a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl,
pyridinylcarbonyl or phenylcarbonyl group which may each be mono-,
di- or trisubstituted in the carbon skeleton by fluorine, chlorine,
bromine or iodine atoms, by alkyl, alkoxy, methylsulphonyloxy,
difluoromethyl, trifluoromethyl, hydroxy, amino, acetylamino,
aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano,
carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl,
alkanoyl, .omega.-(dialkylamino)alkanoyl,
.omega.-(dialkylamino)alkyl, .omega.-(dialkylamino)hydroxyalkyl,
.omega.-(carboxy)alkanoyl, difluoromethoxy, trifluoromethoxy,
trifluoromethylthio, trifluoromethylsulphinyl or
trifluoromethylsulphonyl groups, while the substituents may be
identical or different,
[0028] a 4- to 10-membered azacycloalkyl group, a 6- to 10-membered
oxaza, thiaza or diazacycloalkyl group, a 6- to 10-membered
azabicycloalkyl group, a 1-alkyl-4-piperidinylcarbonyl or
4-alkyl-1-piperazinylcarbonyl group,
[0029] while the above-mentioned mono- and bicyclic heterocycles
are bound via a nitrogen or carbon atom,
[0030] in the above-mentioned mono- and bicyclic heterocycles any
methylene group not directly bound to a nitrogen, oxygen or sulphur
atom may be substituted by one or two fluorine atoms,
[0031] the above-mentioned mono- and bicyclic heterocycles as well
as the 1-alkyl-4-piperidinylcarbonyl- and
4-alkyl-1-piperazinylcarbonyl group in the ring may be mono- or
polysubstituted by a C.sub.1-7-alkyl group, monosubstituted by a
phenyl-C.sub.1-3-alkyl, alkanoyl, dialkylamino, phenylcarbonyl,
pyridinylcarbonyl, carboxy, carboxyalkanoyl, carboxyalkyl,
alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl,
alkylaminocarbonyl, alkylsulphonyl, cycloalkyl or cycloalkylalkyl
group, or substituted by a cycloalkylcarbonyl,
azacycloalkylcarbonyl, diazacycloalkylcarbonyl or
oxazacycloalkylcarbonyl group optionally alkyl-substituted in the
ring,
[0032] while the alicyclic moieties contained in these substituents
each comprise 3 to 10 ring members and the heteroalicyclic moieties
each comprise 4 to 10 ring members and
[0033] the phenyl and pyridinyl groups contained in the
above-mentioned groups may in turn be mono-, di- or trisubstituted
by fluorine, chlorine, bromine or iodine atoms, by alkyl, alkoxy,
methylsulphonyloxy, difluoromethyl, trifluoromethyl, hydroxy,
amino, acetylamino, aminocarbonyl, aminocarbonylamino,
aminocarbonylaminomethyl, cyano, carboxy, alkoxycarbonyl,
carboxyalkyl, alkoxycarbonylalkyl, alkanoyl,
.omega.-(dialkylamino)alkanoyl, .omega.-(carboxy)alkanoyl,
difluoromethoxy, trifluoromethoxy, trifluoromethylthio,
trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, while
the substituents may be identical or different,
[0034] R.sup.5 denotes a hydrogen atom,
[0035] a C.sub.1-4-alkyl group, while an unbranched alkyl group may
be substituted in the o) position by a phenyl, pyridinyl, diazinyl,
amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl,
4-methyl-1-piperazinyl, 4-morpholinyl or hexahydro-1H-1-azepinyl
group,
[0036] an alkoxycarbonyl, the cyano or aminocarbonyl group or also,
if Y.sup.1 denotes a nitrogen atom, a pair of free electrons,
[0037] or, if Y.sup.1 does not denote a nitrogen atom, also the
fluorine atom, or
[0038] R.sup.4 together with R.sup.5 and Y.sup.1 denote a 4- to
7-membered cycloaliphatic ring, in which a methylene group may be
replaced by a --NH or --N(alkyl)-group
[0039] while a hydrogen atom bound to a nitrogen atom within the
above-mentioned group R.sup.4 may be replaced by a protecting
group,
[0040] R.sup.6 and R.sup.7, which may be identical or different, in
each case denote a hydrogen atom, a C.sub.1-3-alkyl or dialkylamino
group or also, if Y.sup.1 does not denote a nitrogen atom, the
fluorine atom and
[0041] R.sup.8 and R.sup.9, which may be identical or different, in
each case denote a hydrogen atom or a C.sub.1-3-alkyl group,
[0042] while, unless otherwise stated, all the above-mentioned
alkyl and alkoxy groups as well as the alkyl groups present within
the other groups specified comprise 1 to 7 carbon atoms and may be
straight-chain or branched, while each methylene group may be
substituted by up to 2 fluorine atoms and each methyl group may be
substituted by up to 3 fluorine atoms,
[0043] all the above-mentioned cycloalkyl groups as well as the
cycloalkyl groups present within the other groups specified, unless
otherwise stated, may comprise 3 to 10 carbon atoms, while each
methylene group may be substituted by up to 2 fluorine atoms,
[0044] all the above-mentioned aromatic and heteroaromatic groups
may additionally be mono- di- or trisubstituted by fluorine,
chlorine or bromine atoms, by cyano or hydroxy groups and the
substituents may be identical or different and
[0045] by the protective groups mentioned in the foregoing and
subsequent definitions are meant the protective groups familiar
from peptide chemistry, particularly a phenylalkoxycarbonyl group
with 1 to 3 carbon atoms in the alkoxy moiety optionally
substituted in the phenyl nucleus by a halogen atom, by a nitro or
phenyl group or by one or two methoxy groups,
[0046] for example the benzyloxycarbonyl,
2-nitro-benzyloxycarbonyl, 4-nitro-benzyloxycarbonyl,
4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl,
3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl,
4-biphenylyl-.alpha.,.alpha.-dimethyl-benzylo- xycarbonyl or
3,5-dimethoxy-.alpha.,.alpha.-dimethyl-benzyloxycarbonyl group,
[0047] an alkoxycarbonyl group with a total of 1 to 5 carbon atoms
in the alkyl moiety,
[0048] for example the methoxycarbonyl, ethoxycarbonyl,
n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,
1-methylpropoxycarbonyl, 2-methylpropoxy-carbonyl or
tert.butyloxycarbonyl group,
[0049] the allyloxycarbonyl,
2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or
9-fluorenylmethoxycarbonyl group or
[0050] the formyl, acetyl or trifluoroacetyl group.
[0051] A second embodiment of the present invention comprises the
compounds of the above general formula (I), wherein
[0052] A, X, Y, Z, R.sup.2 and R.sup.3 are defined as mentioned in
the first embodiment hereinbefore and
[0053] R.sup.1 denotes a mono- or diunsaturated 5- to 7-membered
aza, diaza, triaza or thiaza heterocyclic group,
[0054] in which the above-mentioned heterocycles are linked via a
carbon or nitrogen atom,
[0055] contain one or two carbonyl groups adjacent to a nitrogen
atom,
[0056] may be substituted at a carbon atom by a phenyl, pyridinyl,
diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl
or 1-methylpyrazolyl group and
[0057] an olefinic double bond of one of the above-mentioned
unsaturated heterocycles may be fused to a phenyl, naphthyl,
pyridine, diazine, thienyl or quinoline ring or to a
1H-quinolin-2-one ring optionally substituted at the nitrogen atom
by a methyl group,
[0058] while the phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl,
1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl groups
contained in R.sup.1 as well as the benzo-, pyrido- and
diazino-fused heterocycles in the carbon skeleton may additionally
be mono-, di- or trisubstituted by fluorine, chlorine, bromine or
iodine atoms, by alkyl, alkoxy, nitro, difluoromethyl,
trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino,
acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy
groups, while the substituents may be identical or different,
[0059] while the above-mentioned alkyl groups or the alkyl groups
contained in the above-mentioned groups, unless otherwise stated,
contain 1 to 7 carbon atoms and may be branched or unbranched,
while each methylene group may be substituted by up to 2 fluorine
atoms and each methyl group may be substituted by up to 3 fluorine
atoms, and
[0060] the above-mentioned aromatic and heteroaromatic groups may
additionally be mono- di- or trisubstituted by fluorine, chlorine
or bromine atoms or by cyano or hydroxy groups and the substituents
may be identical or different.
[0061] A third embodiment of the present invention comprises the
compounds of the above general formula (I), wherein
[0062] A, X, Y, Z, R.sup.2 and R.sup.3 are defined as hereinbefore
in the first embodiment and
[0063] R.sup.1 denotes a monounsaturated 5- to 7-membered diaza or
triaza heterocyclic group,
[0064] while the above-mentioned heterocycles are linked via a
nitrogen atom,
[0065] contain a carbonyl group adjacent to a nitrogen atom,
[0066] may additionally be substituted at a carbon atom by a phenyl
group and
[0067] an olefinic double bond of one of the above-mentioned
unsaturated heterocycles may be fused to a phenyl, thienyl or
quinoline ring,
[0068] while the phenyl groups contained in R.sup.1 as well as
benzo-fused heterocycles in the carbon skeleton may additionally be
mono-, di- or trisubstituted by fluorine, chlorine, bromine or
iodine atoms, by methyl, methoxy, nitro, difluoromethyl,
trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino,
acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy
groups, while the substituents may be identical or different, but
are preferably unsubstituted, or monosubstituted by a fluorine,
chlorine or bromine atom or by a methyl or methoxy group,
[0069] while, unless otherwise stated, all the above-mentioned
alkyl groups as well as the alkyl groups present within the other
groups comprise 1 to 7 carbon atoms and may be straight-chain or
branched and the above-mentioned aromatic and heteroaromatic groups
may additionally be mono- di- or trisubstituted by fluorine,
chlorine or bromine atoms or by cyano or hydroxy groups and the
substituents may be identical or different.
[0070] A fourth embodiment of the present invention comprises the
compounds of the above general formula (I), wherein
[0071] A, X, Y, Z, R.sup.2 and R.sup.3 are defined as hereinbefore
in the first embodiment and
[0072] R.sup.1 denotes a
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y-
l)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl- ,
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1--
yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-
-1-yl or
4-(2-oxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl)-piperidin-1--
yl group,
[0073] while the above-mentioned mono- and bicyclic heterocycles in
the carbon skeleton may additionally be monosubstituted by a
methoxy group,
[0074] while the above-mentioned aromatic and heteroaromatic groups
by fluorine, chlorine or bromine atoms, by cyano or hydroxy groups
may additionally be mono- di- or trisubstituted and the
substituents may be identical or different.
[0075] A fifth embodiment of the present invention comprises the
compounds of the above general formula (I), wherein
[0076] A, X, Y, Z and R.sup.1 are defined as hereinbefore in the
first embodiment and
[0077] R.sup.2 denotes the hydrogen atom or
[0078] a phenylmethyl group or a C.sub.2-7-alkyl group which may be
substituted in the .omega. position by a phenyl, pyridinyl,
hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl,
aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl,
1-piperidinyl, 4-morpholinyl, [bis-(2-hydroxyethyl)]amino group
[0079] while the above-mentioned heterocyclic groups and phenyl
groups may additionally be mono-, di- or trisubstituted in the
carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by
methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino, acetylamino,
aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy,
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.- 1-3-alkyl groups and the
substituents may be identical or different,
[0080] R.sup.3 denotes the hydrogen atom or a C.sub.1-3-alkyl
group,
[0081] while the C.sub.1-3-alkyl group may be linked to an alkyl
group present in R.sup.2 or a phenyl or pyridyl ring present in
R.sup.2 and the nitrogen atom to which they are bound, forming a 5-
to 7-membered ring, or
[0082] R.sup.2 and R.sup.3 together with the enclosed nitrogen atom
denote a group of general formula 4
[0083] wherein
[0084] Y.sup.1 denotes the carbon atom or, if R.sup.5 denotes a
pair of free electrons, it may also denote the nitrogen atom,
[0085] q and r, if Y.sup.1 denotes the carbon atom, represent the
numbers 0 or 1 or,
[0086] q and r, if Y.sup.1 denotes the nitrogen atom, represent the
numbers 1 or 2,
[0087] R.sup.4 denotes the hydrogen atom, an amino, alkylamino or
dialkylamino group,
[0088] or, if Y.sup.1 does not denote the nitrogen atom, a
dialkylaminomethyl group,
[0089] a phenyl, pyridinyl or diazinyl group which may be
substituted in each case by a fluorine, chlorine or bromine atom or
by a trifluoromethylcarbonyl, methyl or methoxy group,
[0090] a 4- to 7-membered azacycloalkyl group, a 6- to 7-membered
oxaza or diazacycloalkyl group or a 7- to 9-membered
azabicycloalkyl group,
[0091] while the above-mentioned mono- and bicyclic heterocycles
are bound via a nitrogen or carbon atom,
[0092] in the above-mentioned mono- and bicyclic heterocycles any
methylene group not directly bound to a nitrogen, oxygen or sulphur
atom may be substituted by one or two fluorine atoms and
[0093] the above-mentioned mono- and bicyclic heterocycles may be
substituted by a C.sub.1-3-alkyl group, by a benzyl,
C.sub.3-6-cycloalkylalkyl, C.sub.1-4-alkanoyl,
di-(C.sub.1-3-alkyl)-amino or C.sub.1-3-alkylsulphonyl, by an
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy or carboxyalkyl
group,
[0094] R.sup.5 denotes a hydrogen atom, a C.sub.1-3-alkyl group
or,
[0095] if Y.sup.1 denotes a nitrogen atom, it may also denote a
pair of free electrons,
[0096] R.sup.6 and R.sup.7, which may be identical or different, in
each case denote a hydrogen atom or a C.sub.1-3-alkyl group or
di-(C.sub.1-3-alkyl)-amino group and
[0097] R.sup.8 and R.sup.9, which may be identical or different, in
each case denote a hydrogen atom or a C.sub.1-3-alkyl group,
[0098] while, unless otherwise stated, all the above-mentioned
alkyl groups as well as the alkyl groups present within the other
groups comprise 1 to 7 carbon atoms and may be straight-chain or
branched and the above-mentioned aromatic and heteroaromatic groups
may additionally be mono-, di- or trisubstituted by fluorine,
chlorine or bromine atoms or by cyano or hydroxy groups and the
substituents may be identical or different.
[0099] A sixth embodiment of the present invention comprises the
compounds of the above general formula (I), wherein
[0100] A, X, Y, Z and R.sup.1 are defined as hereinbefore in the
first embodiment and
[0101] R.sup.2 denotes a phenylmethyl group or a C.sub.2-7-alkyl
group which may be substituted in the .omega. position by a phenyl,
amino, alkylamino or dialkylamino group,
[0102] while the above-mentioned phenyl group may be substituted by
an amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl group, or
[0103] R.sup.3 denotes the hydrogen atom or a C.sub.1-3-alkyl
group,
[0104] R.sup.2 and R.sup.3 together with the nitrogen atom to which
they are bound denote a
7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-- 3-yl group
or
[0105] R.sup.2 and R.sup.3 together with the enclosed nitrogen atom
denote a group of general formula 5
[0106] wherein
[0107] Y.sup.1 denotes the carbon atom or, if R.sup.5 denotes a
pair of free electrons, it may also denote the nitrogen atom,
[0108] q and r, if Y.sup.1 denotes the carbon atom, represent the
numbers 0 or 1 or
[0109] q and r, if Y.sup.1 denotes the nitrogen atom, represent the
numbers 1 or 2,
[0110] R.sup.4 denotes the hydrogen atom,
[0111] a phenyl or pyridinyl group which may be substituted in each
case by a fluorine, chlorine or bromine atom, by a
trifluoromethylcarbonyl, methyl or methoxy group,
[0112] a dimethylamino, diethylamino, perhydro-azepin-1-yl,
4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-piperidin-4-yl,
1-ethylpiperidin-4-yl, piperazin-1-yl, 4-acetyl-piperazin-1-yl,
4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl,
4-ethyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, piperidin-1-yl,
piperidin-4-yl, morpholin-4-yl, 4,4-difluoro-piperidin-1-yl,
8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl, pyridin-4-yl,
3-dimethylamino-piperidin-1-yl, 1-ethyl-piperidin-4-yl,
4-amino-piperidin-1-yl, 4-(dimethylamino)-piperidin-1-yl,
4-(diethylaminomethyl)-piperidin-1-yl,
p-trifluoromethylcarbonyl-phenyl, 1-benzyl-piperidin-4-yl,
4-benzyl-piperazin-1-yl, azetidin-1-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl,
1-(ethoxycarbonylmethyl)-piperi- din-4-yl,
4-(ethoxycarbonylmethyl)-piperazin-1-yl, 1-carboxymethyl-piperid-
in-4-yl, 4-carboxymethyl-piperazin-1-yl,
4-methylsulphonyl-piperazin-1-yl or 4-methyl-piperazin-1-yl
group,
[0113] R.sup.5 denotes a hydrogen atom or, if Y.sup.1 denotes a
nitrogen atom, it may also denote a pair of free electrons,
[0114] R.sup.6 and R.sup.7 in each case denote a hydrogen atom or a
dimethylamino group and
[0115] R.sup.8 and R.sup.9 in each case denote the hydrogen
atom,
[0116] while, unless otherwise stated, all the above-mentioned
alkyl groups as well as the alkyl groups present within the other
groups comprise 1 to 7 carbon atoms and may be straight-chain or
branched and the above-mentioned aromatic and heteroaromatic groups
may additionally be mono-, di- or trisubstituted by fluorine,
chlorine or bromine atoms, by cyano or hydroxy groups and the
substituents may be identical or different,
[0117] while in all the embodiments mentioned above those compounds
wherein
[0118] (i) A denotes an oxygen atom, a cyanoimino or
phenylsulphonylimino group,
[0119] X denotes an oxygen atom, an imino or methylene group
and
[0120] Y and Z independently of one another each denote a
straight-chain or branched C.sub.1-4-alkyl group wherein each
methylene group may be substituted by up to 2 fluorine atoms and
each methyl group may be substituted by up to 3 fluorine atoms,
[0121] while the above-mentioned alkyl groups together with the
carbon atoms to which they are bound may be joined to one another,
forming a 5- to 7-membered ring,
[0122] are of exceptional importance and
[0123] those compounds wherein
[0124] (ii) A denotes an oxygen atom or a cyanoimino group,
[0125] X denotes an oxygen atom, an imino or methylene group
and
[0126] Y and Z independently of one another each denote a methyl or
ethyl group
[0127] wherein each methylene group may be substituted by up to 2
fluorine atoms and the methyl group may be substituted by up to 3
fluorine atoms,
[0128] while the above-mentioned methyl and ethyl groups together
with the carbon atoms to which they are bound may be joined to one
another, forming a 5- to 6-membered ring,
[0129] are of particularly outstanding importance.
[0130] A seventh embodiment of the present invention comprises the
compounds of the above general formula (I) wherein
[0131] A denotes an oxygen atom, a cyanoimino or
phenylsulphonylimino group,
[0132] X denotes an oxygen or sulphur atom, an imino group
optionally substituted by a C.sub.1-6-alkyl group or a methylene
group optionally substituted by a C.sub.1-6-alkyl group,
[0133] Y and Z independently of one another each denote a
straight-chain or branched C.sub.1-6-alkyl group wherein each
methylene group may be substituted by up to 2 fluorine atoms and
each methyl group may be substituted by up to 3 fluorine atoms,
[0134] while the above-mentioned alkyl groups together with the
carbon atoms to which they are bound may be joined to one another,
forming a 4- to 8-membered ring,
[0135] R.sup.1 denotes a monounsaturated 5- to 7-membered diaza or
triaza heterocyclic group,
[0136] while the above-mentioned heterocycles are linked via a
nitrogen atom,
[0137] contain a carbonyl group adjacent to a nitrogen atom,
[0138] may additionally be substituted at a carbon atom by a phenyl
group and an olefinic double bond of one of the above-mentioned
unsaturated heterocycles may be fused to a phenyl, thienyl or
quinoline ring,
[0139] while the phenyl groups contained in R.sup.1 as well as
benzo-fused heterocycles in the carbon skeleton may additionally be
mono-, di- or trisubstituted by fluorine, chlorine, bromine or
iodine atoms, by methyl, methoxy, nitro, difluoromethyl,
trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino,
acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy
groups, while the substituents may be identical or different, but
are preferably unsubstituted or are monosubstituted by a fluorine,
chlorine or bromine atom or by a methyl or methoxy group,
[0140] R.sup.2 denotes the hydrogen atom or
[0141] a phenylmethyl group or a C.sub.2-7-alkyl group which may be
substituted in the .omega. position by a phenyl, pyridinyl,
hydroxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, carboxy,
aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl,
1-piperidinyl, 4-morpholinyl or [bis-(2-hydroxyethyl)]amino
group,
[0142] while the above-mentioned heterocyclic groups and phenyl
groups may additionally be mono-, di- or trisubstituted in the
carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by
methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino, acetylamino,
aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy,
amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.- 1-3-alkyl groups and the
substituents may be identical or different,
[0143] R.sup.3 denotes the hydrogen atom or a C.sub.1-3-alkyl
group,
[0144] while the C.sub.1-3-alkyl group may be linked to an alkyl
group present in R.sup.2 or a phenyl or pyridyl ring present in
R.sup.2 and the nitrogen atom to which they are bound, forming a 5-
to 7-membered ring, or
[0145] R.sup.2 and R.sup.3 together with the enclosed nitrogen atom
denote a group of general formula 6
[0146] wherein
[0147] Y.sup.1 denotes the carbon atom or, if R.sup.5 denotes a
pair of free electrons, it may also denote the nitrogen atom,
[0148] q and r, if Y.sup.1 denotes the carbon atom, represent the
numbers 0, 1 or
[0149] q and r, if Y.sup.1 denotes the nitrogen atom, represent the
numbers 1 or 2,
[0150] R.sup.4 denotes the hydrogen atom, an amino, alkylamino or
dialkylamino group,
[0151] or, if Y.sup.1 does not denote the nitrogen atom, it denotes
a dialkylaminomethyl group,
[0152] a phenyl, pyridinyl or diazinyl group which may be
substituted in each case by a fluorine, chlorine or bromine atom,
by a trifluoromethylcarbonyl, methyl or methoxy group,
[0153] a 4- to 7-membered azacycloalkyl group, a 6- to 7-membered
oxaza or diazacycloalkyl group or a 7- to 9-membered
azabicycloalkyl group,
[0154] while the above-mentioned mono- and bicyclic heterocycles
are bound via a nitrogen or carbon atom,
[0155] in the above-mentioned mono- and bicyclic heterocycles any
methylene group not directly bound to a nitrogen, oxygen or sulphur
atom may be substituted by one or two fluorine atoms,
[0156] the above-mentioned mono- and bicyclic heterocycles may be
substituted by a C.sub.1-3-alkyl group, by a benzyl,
C.sub.3-6-cycloalkylalkyl, C.sub.1-4-alkanoyl,
di-(C.sub.1-3-alkyl)-amino or C.sub.1-3-alkylsulphonyl, by an
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy or carboxyalkyl
group,
[0157] R.sup.5 denotes a hydrogen atom, a C.sub.1-3-alkyl group
or,
[0158] if Y.sup.1 denotes a nitrogen atom, it may also denote a
pair of free electrons,
[0159] R.sup.6 and R.sup.7, which may be identical or different, in
each case denote the hydrogen atom or a C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino group and
[0160] R.sup.8 and R.sup.9, which may be identical or different, in
each case denote the hydrogen atom or a C.sub.1-3-alkyl group,
[0161] while, unless otherwise stated, the above-mentioned alkyl
groups or the alkyl groups contained in the above-mentioned groups
contain 1 to 7 carbon atoms and may be branched or unbranched and
the above-mentioned aromatic and heteroaromatic groups may
additionally be mono-, di- or trisubstituted by fluorine, chlorine
or bromine atoms, by cyano or hydroxy groups and the substituents
may be identical or different.
[0162] An eighth embodiment of the present invention comprises the
compounds of the above general formula (I), wherein
[0163] A denotes an oxygen atom, a cyanoimino or
phenylsulphonylimino group,
[0164] X denotes an oxygen atom, an imino or methylene group,
[0165] Y and Z independently of one another each denote a
straight-chain or branched C.sub.4-alkyl group wherein each
methylene group may be substituted by up to 2 fluorine atoms and
each methyl group may be substituted by up to 3 fluorine atoms,
[0166] while the above-mentioned alkyl groups together with the
carbon atoms to which they are bound may be joined to one another,
forming a 5- to 7-membered ring,
[0167] R.sup.1 denotes a
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y-
l)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl- ,
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1--
yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-
-1-yl or
4-(2-oxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl)-piperidin-1--
yl group,
[0168] while the above-mentioned mono- and bicyclic heterocycles in
the carbon skeleton may additionally be monosubstituted by a
methoxy group,
[0169] R.sup.2 denotes a phenylmethyl group or a C.sub.2-7-alkyl
group which may be substituted in the .omega. position by a phenyl,
amino, alkylamino or dialkylamino group,
[0170] while the above-mentioned phenyl group may be substituted by
an amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl group, or
[0171] R.sup.3 denotes the hydrogen atom or a C.sub.1-3-alkyl
group,
[0172] R.sup.2 and R.sup.3 together with the nitrogen atom to which
they are bound denote a
7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-- 3-yl group
or
[0173] R.sup.2 and R.sup.3 together with the enclosed nitrogen atom
denote a group of general formula 7
[0174] wherein
[0175] Y.sup.1 represents the carbon atom or, if R.sup.5 denotes a
pair of free electrons, it may also denote the nitrogen atom,
[0176] q and r, if Y.sup.1 denotes the carbon atom, represent the
numbers 0 or 1 or
[0177] q and r, if Y.sup.1 denotes the nitrogen atom, represent the
numbers 1 or 2,
[0178] R.sup.4 denotes the hydrogen atom,
[0179] a phenyl or pyridinyl group which may be substituted in each
case by a fluorine, chlorine or bromine atom, by a
trifluoromethylcarbonyl, methyl or methoxy group,
[0180] a dimethylamino, diethylamino, perhydro-azepin-1-yl,
4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-piperidin-4-yl,
1-ethyl-piperidin-4-yl, piperazin-1-yl, 4-acetyl-piperazin-1-yl,
4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl,
4-ethyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, piperidin-1-yl,
piperidin-4-yl, 4-morpholin-4-yl, 4,4-difluoro-1-piperidin-1-yl,
8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl, pyridin-4-yl,
3-dimethylamino-piperidin-1-yl, 1-ethyl-piperidin-4-yl,
4-amino-piperidin-1-yl, 4-(dimethylamino)-piperidin-1-yl,
4-(diethylaminomethyl)-piperidin-1-yl,
p-trifluoromethylcarbonyl-phenyl, 1-benzyl-piperidin-4-yl,
4-benzyl-piperazin-1-yl, azetidin-1-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl,
1-(ethoxycarbonylmethyl)-piperi- din-4-yl,
4-(ethoxycarbonylmethyl)-piperazin-1-yl, 1-carboxymethyl-piperid-
in-4-yl, 4-carboxymethyl-piperazin-1-yl,
4-methylsulphonyl-piperazin-1-yl or 4-methyl-piperazin-1-yl
group,
[0181] R.sup.5 denotes a hydrogen atom or, if Y.sup.1 denotes a
nitrogen atom, it may also denote a pair of free electrons,
[0182] R.sup.6 and R.sup.7 in each case denote a hydrogen atom or a
dimethylamino group and
[0183] R.sup.8 and R.sup.9 in each case denote the hydrogen
atom,
[0184] while, unless otherwise stated, all the above-mentioned
alkyl groups as well as the alkyl groups present within the other
groups comprise 1 to 7 carbon atoms and may be straight-chain or
branched and the above-mentioned aromatic and heteroaromatic groups
may additionally be mono-, di- or trisubstituted by fluorine,
chlorine or bromine atoms or by cyano or hydroxy groups and the
substituents may be identical or different.
[0185] A ninth embodiment of the present invention comprises the
compounds of the above general formula (I), wherein
[0186] A denotes an oxygen atomor a cyanoimino group,
[0187] X denotes an oxygen atom, an imino or methylene group,
[0188] Y and Z independently of one another in each case denote a
methyl or ethyl group wherein each methylene group may be
substituted by up to 2 fluorine atoms and the methyl group may be
substituted by up to 3 fluorine atoms,
[0189] while the above-mentioned methyl and ethyl groups together
with the carbon atoms to which they are bound may be joined
together, forming a 5- to 6-membered ring,
[0190] R.sup.1 denotes a
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y-
l)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl- ,
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl,
4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1--
yl,
4-(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-
-1-yl or
4-(2-oxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl)-piperidin-1--
yl group,
[0191] while the above-mentioned mono- and bicyclic heterocycles
may additionally be monosubstituted in the carbon skeleton by a
methoxy group,
[0192] R.sup.2 denotes a phenylmethyl group or a C.sub.2-7-alkyl
group which may be substituted in the .omega. position by a phenyl,
amino, alkylamino or dialkylamino group,
[0193] while the above-mentioned phenyl group may be substituted by
an amino-C.sub.1-3-alkyl, C.sub.1-3-alkylamino-C.sub.1-3-alkyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl group, or
[0194] R.sup.3 denotes the hydrogen atom or a C.sub.1-3-alkyl
group,
[0195] R.sup.2 and R.sup.3 together with the nitrogen atom to which
they are bound denote a
7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-- 3-yl group
or
[0196] R.sup.2 and R.sup.3 together with the enclosed nitrogen atom
denote a group of general formula 8
[0197] wherein
[0198] Y.sup.1 denotes the carbon atom or, if R.sup.5 denotes a
pair of free electrons, it may also denote the nitrogen atom,
[0199] q and r, if Y.sup.1 denotes the carbon atom, represent the
numbers 0 or 1 or
[0200] q and r, if Y.sup.1 denotes the nitrogen atom, represent the
numbers 1 or 2,
[0201] R.sup.4 denotes the hydrogen atom,
[0202] a phenyl or pyridinyl group which may be substituted in each
case by a fluorine, chlorine or bromine atom, by a
trifluoromethylcarbonyl, methyl or methoxy group,
[0203] a dimethylamino, diethylamino, perhydro-azepin-1-yl,
4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-piperidin-4-yl,
1-ethyl-piperidin-4-yl, piperazin-1-yl, 4-acetyl-piperazin-1-yl,
4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl,
4-ethyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, piperidin-1-yl,
piperidin-4-yl, 4-morpholin-4-yl, 4,4-difluoro-piperidin-1-yl,
8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl, pyridin-4-yl,
3-dimethylamino-piperidin-1-yl, 1-ethyl-piperidin-4-yl,
4-amino-piperidin-1-yl, 4-(dimethylamino)-piperidin-1-yl,
4-(diethylaminomethyl)-piperidin-1-yl,
p-trifluoromethylcarbonyl-phenyl, 1-benzyl-piperidin-4-yl,
4-benzyl-piperazin-1-yl, azetidin-1-yl,
1-(methoxycarbonylmethyl)-piperidin-4-yl,
1-(ethoxycarbonylmethyl)-piperi- din-4-yl,
4-(ethoxycarbonylmethyl)-piperazin-1-yl, 1-carboxymethyl-piperid-
in-4-yl, 4-carboxymethyl-piperazin-1-yl,
4-methylsulphonyl-piperazin-1-yl or 4-methyl-piperazin-1-yl
group,
[0204] R.sup.5 denotes a hydrogen atom or, if Y.sup.1 denotes a
nitrogen atom, it may also denote a pair of free electrons,
[0205] R.sup.6 and R.sup.7 in each case denote a hydrogen atom or a
dimethylamino group and
[0206] R.sup.8 and R.sup.9 in each case denote the hydrogen
atom,
[0207] while, unless otherwise stated, all the above-mentioned
alkyl groups as well as the alkyl groups present within the other
groups comprise 1 to 7 carbon atoms and may be straight-chain or
branched and the above-mentioned aromatic and heteroaromatic groups
may additionally be mono-, di- or trisubstituted by fluorine,
chlorine or bromine atoms or by cyano or hydroxy groups and the
substituents may be identical or different.
[0208] The following are mentioned as examples of most particularly
preferred compounds of the above general formula (I): 9
[0209]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-p-
iperazin-1-yl]-2-oxo-ethyl}-amide 10
[0210]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-p-
iperidin-1-yl]-2-oxo-ethyl}-amide 11
[0211]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl-
)-2-oxo-ethyl]-amide 12
[0212]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[1-(3,4-diethyl-benzyl)-2-oxo-2-(3,4,5,6-tetrahydro-2H-4,4'--
bipyridinyl-1-yl)-ethyl]-amide 13
[0213]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[2-1,4'-bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo-eth-
yl]-amide 14
[0214]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazin-1--
yl)-ethyl]-amide 15
[0215]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-y-
l]-2-oxo-ethyl}-amide 16
[0216]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-y-
l]-2-oxo-ethyl}-amide 17
[0217]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-dimethylamino-piperidin-1-y-
l)-2-oxo-ethyl]-amide 18
[0218]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-perhydro-azepin-1-yl--
piperidin-1-yl)-ethyl]-amide 19
[0219]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diaz-
epin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 20
[0220]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl--
1-yl)-2-oxo-ethyl]-amide 21
[0221]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(8-methyl-8-aza-bicyclo[3.2-
.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 22
[0222]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperi-
din-1-yl)-ethyl]-amide 23
[0223]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-[4-(4-acetyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-d-
iethyl-benzyl)-2-oxo-ethyl]-amide 24
[0224]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(3-dimethylamino-piperidin-1-y-
l)-2-oxo-ethyl]-amide 25
[0225]
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carb-
oxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pip-
erazin-1-yl]-2-oxo-ethyl}-amide 26
[0226]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-
-1-yl]-2-oxo-ethyl}-amide 27
[0227]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pip-
erazin-1-yl]-2-oxo-ethyl}-amide 28
[0228]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-y-
l]-1-(3,4-diethyl-benzyl)-2-oxo-ethyl]-amide 29
[0229]
4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidine-1-c-
arboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)--
piperazin-1-yl]-2-oxo-ethyl}-amide 30
[0230]
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-c-
arboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)--
piperazin-1-yl]-2-oxo-ethyl}-amide 31
[0231]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyrrolidin-1-yl-piper-
idin-1-yl)-ethyl]-amide 32
[0232]
4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-
e-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-
-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 33
[0233]
4-(2-oxo-1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperi-
dine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidi-
n-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 34
[0234]
4-(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperi-
dine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidi-
n-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 35
[0235]
4-(2-oxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl)-piperidine-1-c-
arboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)--
piperazin-1-yl]-2-oxo-ethyl}-amide 36
[0236]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-ethyl-piperazin-1-yl)-pi-
peridin-1-yl]-2-oxo-ethyl}-amide 37
[0237]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-isopropyl-piperazin-1-yl-
)-piperidin-1-yl]-2-oxo-ethyl}-amide 38
[0238]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo-
-ethyl]-amide 39
[0239]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazi-
n-1-yl)-ethyl]-amide 40
[0240]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3,4,5,6-tetrahydro-2H-4-
,4'-bipyridinyl-1-yl)-ethyl]-amide 41
[0241]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4,4-difluoro-1,4'-bipiperidin-
yl-1'-yl)-2-oxo-ethyl]-amide 42
[0242]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1--
yl)-2-oxo-ethyl]-amide 43
[0243]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-ethyl-piperidin-4-yl)-pi-
perazin-1-yl]-2-oxo-ethyl}-amide 44
[0244]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-(4-diethylaminomethyl-piperidin-1-yl)-1-(3,4-diethyl--
benzyl)-2-oxo-ethyl]-amide 45
[0245]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-[-
1,4]diazepan-1-yl]-2-oxo-ethyl}-amide 46
[0246]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
{(R)-1-(3,4-diethyl-benzyl)-2-[3-(4-methyl-piperazin-1-yl)-a-
zetidin-1-yl]-2-oxo-ethyl}-amide 47
[0247]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3-piperidin-1-yl-azetid-
in-1-yl)-ethyl]-amide 48
[0248]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3-pyrrolidin-1-yl-azeti-
din-1-yl)-ethyl]-amide 49
[0249]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-(3-diethylamino-azetidin-1-yl)-1-(3,4-diethyl-benzyl)-
-2-oxo-ethyl]-amide 50
[0250]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
((R)-1-(3,4-diethyl-benzyl)-2-oxo-2-{4-[4-(2,2,2-trifluoro-a-
cetyl)-phenyl]-piperazin-1-yl}-ethyl)-amide 51
[0251]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-pipera-
zin-1-yl)-ethyl]-amide 52
[0252]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-1-(3-aminomethyl-benzylcarbamoyl)-2-(3,4-diethyl-phenyl-
)-ethyl]-amide 53
[0253]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-1-(5-amino-pentylcarbamoyl)-2-(3,4-diethyl-phenyl)-ethy-
l]-amide 54
[0254]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(4-amino-butylcarbamoyl)-2-(3,4-diethyl-phenyl)-ethyl-
]-amide 55
[0255]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-(3,4-diethyl-phenyl)-1-(5-methylamino-pentylcarbamoyl-
)-ethyl]-amide 56
[0256]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1--
(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 57
[0257]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1--
(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 58
[0258]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1--
(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 59
[0259]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1--
(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 60
[0260]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-1-(5,6,7,8-te-
trahydro-naphthalen-2-ylmethyl)-ethyl]-amide 61
[0261]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-te-
trahydro-naphthalen-2-ylmethyl)-ethyl]-amide 62
[0262]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic acid
[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(5-
,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 63
[0263]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic acid
[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5-
,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 64
[0264]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic acid
[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetr-
ahydro-naphthalen-2-ylmethyl)-ethyl]-amide 65
[0265]
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-car-
boxylic acid
[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(-
5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 66
[0266]
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-car-
boxylic
acid-[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(-
5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 67
[0267]
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-car-
boxylic
acid-[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tet-
rahydro-naphthalen-2-ylmethyl)-ethyl]-amide 68
[0268]
(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-
-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pip-
eridine-1-carboxylate 69
[0269]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(7-dimethylaminomethyl-1,2,4,5-
-tetrahydro-3-benzazepin-3-yl)-2-oxo-ethyl]-amide 70
[0270]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-(4-azetidin-1-yl-piperidin-1-yl)-1-(3,4-diethyl-benzy-
l)-2-oxo-ethyl]-amide 71
[0271]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-(3-azepan-1-yl-azetidin-1-yl)-1-(3,4-diethyl-benzyl)--
2-oxo-ethyl]-amide 72
[0272] ethyl
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahyd-
ro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']-
bipiperidinyl-1-yl]-acetate 73
[0273] ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrah-
ydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-pipe-
ridin-4-yl]-piperazin-1-yl}-acetate 74
[0274]
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-
-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']bipipe-
ridinyl-1-yl]-acetic acid 75
[0275]
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1-
,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin--
4-yl]-piperazin-1-yl}-acetic acid 76
[0276] ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-im-
idazo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperi-
din-4-yl]-piperazin-1-yl}-acetate 77
[0277] ethyl
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imid-
azo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']bi-
piperidinyl-1-yl]-acetate 78
[0278]
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imidazo[-
4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin-4--
yl]-piperazin-1-yl}-acetic acid 79
[0279]
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,-
5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']bipiperi-
dinyl-1-yl]-acetic acid 80
[0280]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic acid
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-pip-
eridin-1-yl]-2-oxo-ethyl}-amide 81
[0281]
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pip-
erazin-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodia-
zepin-3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cyanamide 82
[0282]
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-pip-
eridin-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodia-
zepin-3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cyanamide 83
[0283]
N-[1-[(R)-2-[1,4']bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo--
ethylamino]-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperid-
in-1-yl]-meth-(Z)-ylidene]-cyanamide 84
[0284]
1-[1,4']bipiperidinyl-1'-yl-2-(3,4-dimethyl-benzyl)-4-[4-(2-oxo-1,4-
-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione 85
[0285]
2-(3,4-dimethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-
-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione
86
[0286]
2-(3,4-dimethyl-benzyl)-1-[4-(1-methyl-piperdin-4-yl)-piperazin-1-y-
l]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-d-
ione 87
[0287]
2-(3,4-dimethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1--
yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4--
dione 88
[0288]
2-(3,4-dimethyl-benzyl)-1-[4-(4-ethyl-piperazin-1-yl)-piperidin-1-y-
l]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-d-
ione 89
[0289]
2-(3,4-dimethyl-benzyl)-1-[4-(4-isopropyl-piperazin-1-yl)-piperidin-
-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1-
,4-dione 90
[0290]
2-(3,4-dimethyl-benzyl)-1-[4-(4-methanesulphonyl-piperazin-1-yl)-pi-
peridin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]--
butan-1,4-dione 91
[0291]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid
{1-(3,4-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1--
yl]-2-oxo-ethyl}-amide 92
[0292]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid
{1-(3,4-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1--
yl]-2-oxo-ethyl}-amide 93
[0293]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid
[1-(3,4-dimethyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-ox-
o-ethyl]-amide 94
[0294]
2-(3,4-diethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-y-
l]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-d-
ione 95
[0295]
2-(3,4-diethyl-benzyl)-1-[4-(1'-methyl-piperidin-4-yl)-piperazin-1--
yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4--
di one 96
[0296] methyl
{1'-[4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piper-
idin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butyryl]-[4,4']bip-
iperidinyl-1-yl}-acetate 97
[0297]
{1'-[4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1--
yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butyryl]-[4,4']bipiperidi-
nyl-1-yl}-acetic acid 98
[0298] methyl
(1'-{2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-qui-
nazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate
99
[0299]
((1'-{2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoli-
n-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic
acid 100
[0300]
1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihy-
dro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-
-ylmethyl)-butan-1,4-dione 101
[0301]
1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-q-
uinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethy-
l)-butan-1,4-dione 102
[0302]
2-indan-5-ylmethyl-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-
-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione
103
[0303]
2-indan-5-ylmethyl-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-o-
xo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione
104
[0304]
1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-q-
uinazolin-3-yl)-piperidin-1-yl]-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro--
naphthalen-2-ylmethyl)-butan-1,4-dione 105
[0305]
1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihy-
dro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,5,8,8-tetramethyl-5,6,7,8-tet-
rahydro-naphthalen-2-ylmethyl)-butan-1,4-dione 106
[0306]
1-[1,4']bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-
-yl)-piperidin-1-yl]-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen--
2-ylmethyl)-butan-1,4-dione 107
[0307]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
{(R)-1-(3,4-bis-pentafluoroethyl-benzyl)-2-[4-(4-methyl-pipe-
razin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 108
[0308]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
{(R)-1-(3-ethyl-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1--
yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 109
[0309]
(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl-
)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-c-
arboxylate 110
[0310]
(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-ethyl-piperidin-4-yl)-piperazin--
1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pipe-
ridine-1-carboxylate 111
[0311]
(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetrahydro-
-naphthalen-2-ylmethyl)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepi-
n-3-yl)-piperidine-1-carboxylate 112
[0312]
(S)-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzo-
diazepin-3-yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1-yl)-butan-1-
,4-dione 113
[0313]
(S)-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzo-
diazepin-3-yl)-piperidin-1-yl]-1-(4-piperidin-4-yl-piperazin-1-yl)-butan-1-
,4-dione 114
[0314]
(S)-2-(3,4-diethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-
-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1--
yl]-butan-1,4-dione 115
[0315]
(S)-2-(3,4-diethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-
-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1--
yl]-butan-1,4-dione 116
[0316]
(S)-1-[1,4']bipiperidinyl-1'-yl-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo--
1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butan-1,4-dione
117
[0317]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
{(R)-1-(3,4-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piper-
azin-1-yl)- piperidin-1-yl]-2-oxo-ethyl}-amide 118
[0318]
(S)-2-(3,4-bis-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-y-
l)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)--
piperidin-1-yl]-butan-1,4-dione 119
[0319]
(R)-1-(3,4-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-y-
l)-piperidin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazep-
in-3-yl)-piperidine-1-carboxylate 120
[0320]
(S)-2-(3,4-diethyl-benzyl)-1-(4-dimethylamino-piperidin-1-yl)-4-[4--
(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butan-1,-
4-dione 121
[0321]
(R)-1-(3,4-diethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-
-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylate 122
[0322]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
[(R)-2-(4-amino-piperidin-1-yl)-1-(3,4-diethyl-benzyl)-2-oxo-
-ethyl]-amide 123
[0323]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid
[2-[1,4']bipiperidinyl-1'-yl-1-(3,4-dimethyl-benzyl)-2-oxo-ethyl]-am-
ide 124
[0324]
(S)-2-(3,4-diethyl-benzyl)-1-(1'-methyl-4,4'-bipiperidinyl-1-yl)-4--
[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butan-
-1,4-dione 125
[0325]
(S)-1-4,4'-bipiperidinyl-1-yl-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo-1,-
2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butan-1,4-dione
126
[0326]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(4-ethyl-3-trifluoromethyl-benzyl)-2-[4-(4-methyl-pip-
erazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 127
[0327]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(4-ethyl-3-trifluoromethyl-benzyl)-2-[4-(1-methyl-pip-
eridin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 128
[0328]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(4-ethyl-3-trifluoromethyl-benzyl)-2-(1'-methyl-4,4'--
bipiperidinyl-1-yl)-2-oxo-ethyl]-amide 129
[0329]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(4-ethyl-3-trifluoromethyl-
-benzyl)-2-oxo-ethyl]-amide 130
[0330]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4-ethyl-3-trifluo-
romethylbenzyl)-2-oxo-ethyl]-amide 131
[0331]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3-ethyl-4-trifluoromethyl-benzyl)-2-[4-(4-methyl-pip-
erazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 132
[0332]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3-ethyl-4-trifluoromethyl-benzyl)-2-[4-(1-methyl-pip-
eridin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 133
[0333]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3-ethyl-4-trifluoromethyl-benzyl)-2-(1'-methyl-4,4'--
bipiperidinyl-1-yl)-2-oxo-ethyl]-amide 134
[0334]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(3-ethyl-4-trifluoromethyl-
-benzyl)-2-oxo-ethyl]-amide 135
[0335]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-(4-dimethylamino-piperidin-1-yl)-1-(3-ethyl-4-trifluo-
romethylbenzyl)-2-oxo-ethyl]-amide,
[0336] the enantiomers, the diastereomers and the salts thereof,
while the compounds
[0337] (1)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-y-
l)-piperazin-1-yl]-2-oxo-ethyl}-amide,
[0338] (2)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-y-
l)-piperidin-1-yl]-2-oxo-ethyl}-amide,
[0339] (3)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-[1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl--
1-yl)-2-oxo-ethyl]-amide,
[0340] (4)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-[2-1,4'-bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo-
-ethyl]-amide,
[0341] (5)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-[1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazi-
n-1-yl)-ethyl]-amide,
[0342] (6)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyli- c
acid-{1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1--
yl]-2-oxo-ethyl}-amide,
[0343] (7)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyli- c
acid-{1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1--
yl]-2-oxo-ethyl}-amide,
[0344] (8)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-dimethylamino-piperidin-
-1-yl)-2-oxo-ethyl]-amide,
[0345] (9)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-perhydro-azepin-1-
-yl-piperidin-1-yl)-ethyl]-amide,
[0346] (10)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-
-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,
[0347] (11)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bipiperid-
inyl-1-yl)-2-oxo-ethyl]-amide,
[0348] (12)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(8-methyl-8-aza-bicycl-
o[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,
[0349] (13)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-p-
iperidin-1-yl)-ethyl]-amide,
[0350] (14)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-2-[4-(4-acetyl-piperazin-1-yl)-piperidin-1-yl]-1-(-
3,4-diethyl-benzyl)-2-oxo-ethyl]-amide,
[0351] (15)
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-
-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl-
)-piperazin-1-yl]-2-oxo-ethyl}-amide,
[0352] (16)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyl- ic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperaz-
in-1-yl]-2-oxo-ethyl}-amide,
[0353] (17)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-
-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl-
)-piperazin-1-yl]-2-oxo-ethyl}-amide,
[0354] (18)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidi-
n-1-yl]-1-(3,4-diethyl-benzyl)-2-oxo-ethyl]-amide,
[0355] 19)
4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidine-
-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4--
yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,
[0356] 20)
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidine-
-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4--
yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,
[0357] (21)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyrrolidin-1-yl--
piperidin-1-yl)-ethyl]-amide,
[0358] (22)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-ethyl-piperazin-1-y-
l)-piperidin-1-yl]-2-oxo-ethyl}-amide,
[0359] (23)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-isopropyl-piperazin-
-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,
[0360] (24)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)--
2-oxo-ethyl]-amide,
[0361] (25)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-pip-
erazin-1-yl)-ethyl]-amide,
[0362] (26)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3,4,5,6-tetrahydro-
-2H-4,4'-bipyridinyl-1-yl)-ethyl]-amide,
[0363] (27)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-morpholin-4-yl-piperid-
in-1-yl)-2-oxo-ethyl]-amide,
[0364] (28)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-ethyl-piperidin-4-y-
l)-piperazin-1-yl]-2-oxo-ethyl}-amide,
[0365] (29)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-2-(4-diethylaminomethyl-piperidin-1-yl)-1-(3,4-die-
thyl-benzyl)-2-oxo-ethyl]-amide,
[0366] (30)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4--
yl)-[1,4]diazepan-1-yl]-2-oxo-ethyl}-amide,
[0367] (31)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[3-(4-methyl-piperazin-1--
yl)-azetidin-1-yl]-2-oxo-ethyl}-amide,
[0368] (32)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-p-
iperazin-1-yl)-ethyl]-amide,
[0369] (33)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-o-
xo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
[0370] (34)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-o-
xo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
[0371] (35)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-1-(5,6,7-
,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
[0372] (36)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7-
,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
[0373] (37)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-
-carboxylic
acid-[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-
-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
[0374] (38)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-
-carboxylic
acid-[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-
-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
[0375] (39)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-
-carboxylic
acid-[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-
-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
[0376] (40)
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine--
1-carboxylic
acid-[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-ox-
o-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
[0377] (41)
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine--
1-carboxylic
acid-[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,-
8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide,
[0378] (42)
(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pipe-
razin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl-
)-piperidine-1-carboxylate,
[0379] (43)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-2-(4-azetidin-1-yl-piperidin-1-yl)-1-(3,4-diethyl--
benzyl)-2-oxo-ethyl]-amide,
[0380] (44)
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahy-
dro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piper-
idin-4-yl]-piperazin-1-yl}-acetic acid,
[0381] (45) ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihyd-
ro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-p-
iperidin-4-yl]-piperazin-1-yl}-acetate,
[0382] (46) ethyl
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-
-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,-
4']bipiperidinyl-1-yl]-acetate,
[0383] (47)
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imi-
dazo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperid-
in-4-yl]-piperazin-1-yl}-acetic acid,
[0384] (48)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-
-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl-
)-piperidin-1-yl]-2-oxo-ethyl}-amide,
[0385] (49)
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl-
)-piperazin-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-ben-
zodiazepin-3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cyanamide,
[0386] (50)
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl-
)-piperidin-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-ben-
zodiazepin-3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cyanamide,
[0387] (51)
N-[1-[(R)-2-[1,4']bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-
-oxo-ethylamino]-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pi-
peridin-1-yl]-meth-(Z)-ylidene]-cyanamide,
[0388] (52)
2-(3,4-dimethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperaz-
in-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-
-1,4-dione,
[0389] (53)
2-(3,4-dimethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperid-
in-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-
-1,4-dione,
[0390] (54)
2-(3,4-dimethyl-benzyl)-1-[4-(4-ethyl-piperazin-1-yl)-piperidi-
n-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan--
1,4-dione,
[0391] (55)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyl- ic
acid-{1-(3,4-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin--
1-yl]-2-oxo-ethyl}-amide,
[0392] (56)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyl- ic
acid-{1-(3,4-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin--
1-yl]-2-oxo-ethyl}-amide,
[0393] (57)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyl- ic
acid-[1-(3,4-dimethyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2--
oxo-ethyl]-amide,
[0394] (58)
2-(3,4-diethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidi-
n-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan--
1,4-dione,
[0395] (59)
2-(3,4-diethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazi-
n-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan--
1,4-dione,
[0396] the enantiomers, the diastereomers and the salts thereof are
particularly preferred.
[0397] The compounds of general formula (I) are prepared by methods
known in principle. The following methods have proved particularly
satisfactory for preparing the compounds of general formula (I)
according to the invention:
[0398] (a) In order to prepare compounds of general formula (I)
wherein X denotes an oxygen atom or the NH group and R.sup.1 to
R.sup.3 are as hereinbefore defined, with the proviso that these
groups do not contain any free carboxylic acid function:
[0399] Reacting Piperidines of General Formula 136
[0400] wherein R.sup.1 is as hereinbefore defined,
[0401] (i) with carbonic acid derivatives of general formula
137
[0402] wherein A is as hereinbefore defined and G denotes a
nucleofugic group, preferably the phenoxy, 1H-imidazol-1-yl,
H-1,2,4-triazol-1-yl, trichloromethoxy or the
2,5-dioxo-pyrrolidin-1-yloxy group, with the proviso that X denotes
the NH group, or
[0403] (ii) with carbonic acid derivatives of general formula
138
[0404] wherein A denotes the oxygen atom and G denotes a
nucleofugic group which may be identical or different, preferably
the chlorine atom or the p-nitrophenoxy or trichloro-ethoxy group,
with the proviso that X denotes the oxygen atom,
[0405] and with compounds of general formula 139
[0406] wherein X denotes an oxygen atom or an --NH group and Y, Z,
R.sup.2 and R.sup.3 are as hereinbefore defined, with the proviso
that R.sup.2 and R.sup.3 do not contain any free carboxylic acid,
any other free primary or secondary aliphatic amino function or any
other free hydroxy function.
[0407] The fundamentally two-step reactions are normally carried
out as one-pot processes, in which, preferably, in the first step,
one of the two components (III) or (V) is reacted with equimolar
amounts of the carbonic acid derivative of general formula (IV) in
a suitable solvent at lower temperature, then at least equimolar
amounts of the other component (III) or (V) are added and the
reaction is completed at a higher temperature. The reactions with
bis-(trichloromethyl)-carbonate are preferably carried out in the
presence of at least 2 equivalents (based on
bis-(trichloromethyl)-carbonate) of a tertiary base, for example
triethylamine, N-ethyldiisopropylamine, pyridine,
1,5-diaza-bicyclo-[4,3,- 0]-non-5-ene,
1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo-[5,4,0]-un-
dec-7-ene. The solvents used, which should be anhydrous, may be for
example tetrahydrofuran, dioxane, dimethylformamide,
dimethylacetamide, N-methyl-2-pyrrolidone,
1,3-dimethyl-2-imidazolidinone or acetonitrile, while if
bis-(trichloromethyl)-carbonate is used as the carbonyl component
anhydrous chlorohydrocarbons, for example dichloromethane,
1,2-dichloroethane or trichloroethylene are preferred. The reaction
temperatures for the first reaction step are between -30.degree. C.
and +25.degree. C., preferably -5.degree. C. and +10.degree. C.,
for the second reaction step between +15.degree. C. and the boiling
temperature of the solvent used, preferably between +20.degree. C.
and +70.degree. C. (cf. also: H. A. Staab and W. Rohr, "Synthesen
mit heterocyclischen Amiden (Azoliden)", Neuere Methoden der
Prparativen Organischen Chemie, Volume V, p. 53-93, Verlag Chemie,
Weinheim/Bergstr., 1967; P. Majer and R. S. Randad, J. Org. Chem.
59, p. 1937-1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara
and H. Ogura, Tetrahedron Letters 24 (42), 4569-4572 (1983)); S. R.
Sandler and W. Karo in "Organic Functional Group Preparations",
Vol. II, S. 223-245, Academic Press, New York 1971).
[0408] (b) In order to prepare compounds of general formula (I)
wherein X denotes the methylene group and R.sup.1 to R.sup.3 are as
hereinbefore defined, with the proviso that these groups do not
contain any free carboxylic acid and/or other free primary or
secondary aliphatic amino function:
[0409] Coupling a carboxylic acid of general formula 140
[0410] wherein Y, Z, R.sup.2 and R.sup.3 are as hereinbefore
defined, to a piperidine of general formula 141
[0411] wherein R.sup.1 has the meanings given hereinbefore.
[0412] The coupling is preferably carried out using methods known
from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der
Organischen Chemie, Vol. 15/2), for example using carbodiimides
such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl
carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide,
O-(1H-benzotriazol-1-yl)-N,N-- N',N'-tetramethyluronium
hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or
1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt)
or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the
reaction speed can be increased. The couplings are normally carried
out with equimolar amounts of the coupling components as well as
the coupling reagent in solvents such as dichloromethane,
tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl
acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and
at temperatures between -30 and +30.degree. C., preferably -20 and
+25.degree. C. If necessary, N-ethyl-diisopropylamine (DIEA) (Hunig
base) is preferably used as an additional auxiliary base.
[0413] The so-called anhydride process is used as a further
coupling method for synthesising compounds of general formula (I)
(cf. also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988,
p. 58-59; M. Bodanszky, "Principles of Peptide Synthesis",
Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed
anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem.
Soc. 73, 3547 (1951)), in which the mixed anhydride of the
carboxylic acid of general formula (VI) which is to be coupled and
monoisobutyl carbonate is obtained, using isobutyl chlorocarbonate
in the presence of bases such as 4-methyl-morpholine or
4-ethylmorpholine. The preparation of this mixed anhydride and the
coupling with amines are carried out in a one-pot process, using
the above-mentioned solvents and at temperatures between -20 and
+25.degree. C., preferably 0.degree. C. and +25.degree. C.
[0414] (c) In order to prepare compounds of general formula (I)
wherein X denotes the methylene group and R.sup.2 and R.sup.3 are
as hereinbefore defined, with the proviso that these groups do not
contain any free primary or secondary amine:
[0415] Coupling a compound of general formula 142
[0416] wherein Y, Z, R.sup.2 and R.sup.3 are as hereinbefore
defined, with the proviso that R.sup.2 and R.sup.3 do not contain
any free primary or secondary amine, and Nu denotes a leaving
group, for example a halogen atom, such as the chlorine, bromine or
iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms
in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy
group optionally mono-, di- or trisubstituted by chlorine or
bromine atoms or by methyl or nitro groups, while the substituents
may be identical or different, a 1H-imidazol-1-yl, a
1H-pyrazol-1-yl optionally substituted by one or two methyl groups
in the carbon skeleton, a 1H-1,2,4-triazol-1-yl,
1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl,
propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl,
pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a
dimethylaminyloxy, 2(1H)-oxopyridin-1-yl-oxy,
2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy,
1H-benzo-triazol-1-yloxy or azide group,
[0417] with a piperidine of general formula 143
[0418] wherein R.sup.1 is as hereinbefore defined.
[0419] The reaction is carried out under Schotten-Baumann or
Einhorn conditions, i.e. the components are reacted in the presence
of at least one equivalent of an auxiliary base at temperatures
between -50.degree. C. and +120.degree. C., preferably -10.degree.
C. and +30.degree. C., and optionally in the presence of solvents.
The auxiliary bases used are preferably alkali metal and alkaline
earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide
or barium hydroxide, alkali metal carbonates, e.g. sodium
carbonate, potassium carbonate or caesium carbonate, alkali metal
acetates, e.g. sodium or potassium acetate, as well as tertiary
amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline,
triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,
1,4-diazabicyclo[2,2,2]octane or
1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for
example, dichloromethane, tetrahydrofuran, 1,4-dioxane,
acetonitrile, dimethyl formamide, dimethyl acetamide,
N-methyl-pyrrolidone or mixtures thereof; if alkali metal or
alkaline earth metal hydroxides, alkali metal carbonates or
acetates are used as the auxiliary bases, water may also be added
to the reaction mixture as cosolvent.
[0420] (d) In order to prepare compounds of general formula (I)
wherein all the groups are as hereinbefore defined:
[0421] Coupling a carboxylic acid of general formula 144
[0422] wherein all the groups are as hereinbefore defined, with an
amine of general formula HNR.sup.2R.sup.3, wherein R.sup.2 and
R.sup.3 are as hereinbefore defined, with the proviso that it does
not contain any free carboxylic acid and/or other free primary or
secondary aliphatic amino function.
[0423] The coupling is preferably carried out using methods known
from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der
Organischen Chemie, Vol. 15/2), for example using carbodiimides
such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl
carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide,
O-(1H-benzotriazol-1-yl)-N,N-- N',N'-tetramethyluronium
hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or
1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt)
or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the
reaction speed can be increased. The couplings are normally carried
out with equimolar amounts of the coupling components as well as
the coupling reagent in solvents such as dichloromethane,
tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl
acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and
at temperatures between -30 and +30.degree. C., preferably -20 and
+25.degree. C. If necessary, N-ethyl-diisopropylamine (DIEA) (Hunig
base) is preferably used as an additional auxiliary base.
[0424] The so-called anhydride process is used as a further
coupling method for synthesising compounds of general formula (I)
(cf. also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988,
p. 58-59; M. Bodanszky, "Principles of Peptide Synthesis",
Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed
anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem.
Soc. 73, 3547 (1951)), in which the mixed anhydride of the
carboxylic acid of general formula (VI) which is to be coupled and
monoisobutyl carbonate is obtained, using isobutyl chlorocarbonate
in the presence of bases such as 4-methyl-morpholine or
4-ethylmorpholine. The preparation of this mixed anhydride and the
coupling with amines are carried out in a one-pot process, using
the above-mentioned solvents and at temperatures between -20 and
+25.degree. C., preferably 0.degree. C. and +25.degree. C.
[0425] (e) In order to prepare compounds of general formula (I)
wherein R.sup.1 is as hereinbefore defined, with the proviso that
no free primary or secondary amine is present:
[0426] Coupling a compound of general formula 145
[0427] wherein all the groups are as hereinbefore defined and Nu
denotes a leaving group, for example a halogen atom, such as the
chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1
to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or
naphthylsulphonyloxy group optionally mono-, di- or trisubstituted
by chlorine or bromine atoms, by methyl or nitro groups, while the
substituents may be identical or different, a 1H-imidazol-1-yl, a
1H-pyrazol-1-yl optionally substituted by one or two methyl groups
in the carbon skeleton, a 1H-1,2,4-triazol-1-yl,
1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl,
propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl,
pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a
dimethylaminyloxy, 2(1H)-oxopyridin-1-yl-oxy,
2,5-dioxopyrrolidin-1-yloxy- , phthalimidyloxy,
1H-benzo-triazol-1-yloxy or azide group, with an amine of general
formula HNR.sup.2R.sup.3, wherein R.sup.2 and R.sup.3 are as
hereinbefore defined, with the proviso that no free carboxylic acid
and/or other free primary or secondary aliphatic amino function is
present.
[0428] The reaction is carried out under Schotten-Baumann or
Einhorn conditions, i.e. the components are reacted in the presence
of at least one equivalent of an auxiliary base at temperatures
between -50.degree. C. and +120.degree. C., preferably -10.degree.
C. and +30.degree. C., and optionally in the presence of solvents.
The auxiliary bases used are preferably alkali metal and alkaline
earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide
or barium hydroxide, alkali metal carbonates, e.g. sodium
carbonate, potassium carbonate or caesium carbonate, alkali metal
acetates, e.g. sodium or potassium acetate, as well as tertiary
amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline,
triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,
1,4-diazabicyclo[2,2,2]octane or
1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for
example, dichloromethane, tetrahydrofuran, 1,4-dioxane,
acetonitrile, dimethyl formamide, dimethyl acetamide,
N-methyl-pyrrolidone or mixtures thereof; if alkali metal or
alkaline earth metal hydroxides, alkali metal carbonates or
acetates are used as the auxiliary bases, water may also be added
to the reaction mixture as cosolvent.
[0429] The new compounds of general formula (I) according to the
invention contain one or more chiral centres. If for example there
are two chiral centres the compounds may occur in the form of two
pairs of diastereomeric antipodes. The invention covers the
individual isomers as well as the mixtures thereof.
[0430] The diastereomers may be separated on the basis of their
different physico-chemical properties, e.g. by fractional
crystallisation from suitable solvents, by high pressure liquid or
column chromatography, using chiral or preferably non-chiral
stationary phases.
[0431] Racemates covered by general formula (I) may be separated
for example by HPLC on suitable chiral stationary phases (e.g.
Chiral AGP, Chiralpak AD). Racemates which contain a basic or
acidic function can also be separated via the diastereomeric,
optically active salts which are produced on reacting with an
optically active acid, for example (+) or (-)-tartaric acid, (+) or
(-)-diacetyl tartaric acid, (+) or (-)-monomethyl tartrate or
camphorsulphonic acid, or an optically active base, for example
with (R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine or
(S)-brucine.
[0432] According to a conventional method of separating isomers,
the racemate of a compound of general formula (I) is reacted with
one of the above-mentioned optically active acids or bases in
equimolar amounts in a solvent and the resulting crystalline,
diastereomeric, optically active salts thereof are separated using
their different solubilities. This reaction may be carried out in
any type of solvent provided that it is sufficiently different in
terms of the solubility of the salts. Preferably, methanol, ethanol
or mixtures thereof, for example in a ratio by volume of 50:50, are
used. Then each of the optically active salts is dissolved in
water, carefully neutralised with a base such as sodium carbonate
or potassium carbonate, or with a suitable acid, e.g. dilute
hydrochloric acid or aqueous methanesulphonic acid, and in this way
the corresponding free compound is obtained in the (+) or (-)
form.
[0433] The (R) or (S) enantiomer alone or a mixture of two
optically active diastereomeric compounds covered by general
formula I may also be obtained by performing the syntheses
described above with a suitable reaction component in the (R) or
(S) configuration.
[0434] The starting compounds of general formula (III) may be
obtained, if they are not known from the literature or even
commercially available, according to the processes described in WO
98/11128 and DE 199 52 146. The starting compounds of general
formula (IV) are commercially available. Compounds of general
formula (V) may be obtained by methods familiar to the peptide
chemist from protected phenylalanines and amines of general formula
HNR.sup.2R.sup.3.
[0435] The phenyalanine derivatives needed to prepare the optically
pure compounds of general formula (V) may be prepared from the
compounds of general formula 146
[0436] wherein Y and Z are as hereinbefore defined and R denotes an
unbranched alkyl group, preferably the methyl or ethyl group, by
racemate cleavage.
[0437] This racemate cleavage can be carried out using enzymatic
methods, while only one enantiomer of the racemate is transformed
and the mixture produced is then separated using physicochemical
methods, preferably using chromatographic methods. A suitable
enzyme system for this step consists of the enzyme Alcalase 2.4 L
FG (Novozymes A/S; DK 2880 Bagsvaerd). The compounds of general
formula (X) can then be converted into the enantiomerically pure
compounds of general formula (V) by methods familiar to the peptide
chemist.
[0438] If the group X in compounds of general formula (V) denotes
the oxygen atom, the hydroxycarboxylic acids needed for the
synthesis, of general formula 147
[0439] wherein Y and Z are as hereinbefore defined,
[0440] may be prepared from compounds of general formula (X), with
the proviso that R denotes the hydrogen atom.
[0441] The compounds of general formula (XI) may be obtained by
diazotisation of compounds of general formula (X) with a suitable
diazotising reagent, preferably sodium nitrite in an acidic medium.
If enantiomerically pure compounds are used, the corresponding
enantiomerically pure hydroxycarboxylic acid compounds are
obtained, and the configuration is retained during the
reaction.
[0442] Another method of obtaining compounds of general formula
(XI) comprises alkylating the compound 148
[0443] with correspondingly substituted benzyl chlorides, benzyl
bromides or benzyl iodides of general formula 149
[0444] wherein X denotes a chlorine, bromine or iodine atom,
analogously to methods known from the literature (Michael T.
Crimmins, Kyle A. Emmitte and Jason D. Katz, Org. Lett. 2,
2165-2167 [2000]).
[0445] The diastereomeric products obtained can then be separated
by physicochemical methods, preferably using chromatographic
methods. The hydrolytic cleaving of the chiral auxiliary, coupling
with amines of general formula HNR.sup.2R.sup.3 and cleaving the
benzyl protecting group also provides access to enantiomerically
pure hydroxycarboxylic acid compounds of general formula (V).
[0446] The starting compounds of general formula (VI) are obtained
for example by reacting amines of general formula HNR.sup.2R.sup.3
with 2-(alkoxycarbonylmethyl)-3-aryl-propanoic acids and
subsequently hydrolytically cleaving the alkyl group. The
2-(alkoxycarbonylmethyl)-3-a- ryl-propanoic acids required may be
prepared analogously to methods known from the literature (David A.
Evans, Leester D. Wu, John J. M. Wiener, Jeffrey S. Johnson, David
H. B. Ripin and Jason S. Tedrow, J. Org. Chem 64, 6411-6417 [1999];
Saul G. Cohen and Aleksander Milovanovic, J. Am. Chem. Soc. 90,
3495-3502 [1968]; Hiroyuki Kawano, Youichi Ishii, Takao Ikariya,
Masahiko Saburi, Sadao Yoshikawa, Yasuzo Uchida and Hidenori
Kumobayashi, Tetrahedron Letters 28, 1905-1908 [1987]). Carboxylic
acids of general formula (VIII) may be prepared from generally
available starting materials in accordance with the processes
described in WO 98/11128.
[0447] The compounds of general formula I obtained may, if they
contain suitable basic functions, be converted, particularly for
pharmaceutical use, into their physiologically acceptable salts
with inorganic or organic acids. Suitable acids include for example
hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,
sulphuric acid, methanesulphonic acid, ethanesulphonic acid,
benzenesulphonic acid, p-toluenesulphonic acid, acetic acid,
fumaric acid, succinic acid, lactic acid, mandelic acid, malic
acid, citric acid, tartaric acid or maleic acid.
[0448] Moreover, the new compounds of formula (I), if they contain
a carboxylic acid function, may if desired be converted into the
addition salts thereof with inorganic or organic bases,
particularly for pharmaceutical use into the physiologically
acceptable addition salts thereof. Suitable bases for this include,
for example, sodium hydroxide, potassium hydroxide, ammonia,
cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine
and triethanolamine.
[0449] The present invention relates to racemates if the compounds
of general formula (I) have only one chiral element. However, the
application also includes the individual diastereomeric pairs of
antipodes or mixtures thereof which are obtained if there is more
than one chiral element in the compounds of general formula (I), as
well as the individual optically active enantiomers of which the
above-mentioned racemates are made up.
[0450] Also included in the subject matter of this invention are
the compounds according to the invention, including the salts
thereof, in which one or more hydrogen atoms are replaced by
deuterium.
[0451] The new compounds of general formula (I) and the
physiologically acceptable salts thereof have valuable
pharmacological properties, based on their selective
CGRP-antagonistic properties. The invention further relates to
pharmaceutical compositions containing these compounds, their use
and the preparation thereof.
[0452] The new compounds of general formula I and the
physiologically acceptable salts thereof have CGRP-antagonistic
properties and exhibit good affinities in CGRP receptor binding
studies. The compounds display CGRP-antagonistic properties in the
pharmacological test systems described hereinafter.
[0453] The following experiments were carried out to demonstrate
the affinity of the above-mentioned compounds for human
CGRP-receptors and their antagonistic properties:
[0454] A. Binding Studies with SK-N-MC Cells (Expressing the Human
CGRP Receptor)
[0455] SK-N-MC cells are cultivated in "Dulbecco's modified Eagle
medium". The medium is removed from confluent cultures. The cells
are washed twice with PBS buffer (Gibco 041-04190 M), detached by
the addition of PBS buffer mixed with 0.02% EDTA, and isolated by
centrifuging. After resuspension in 20 ml of "Balanced Salts
Solution" [BSS (in mM): NaCl 120, KCl 5.4, NaHCO.sub.3 16.2,
MgSO.sub.4 0.8, NaHPO.sub.4 1.0, CaCl.sub.2 1.8, D-glucose 5.5,
HEPES 30, pH 7.40] the cells are centrifuged twice at 100.times.g
and resuspended in BSS. After the number of cells has been
determined, the cells are homogenised using an Ultra-Turrax and
centrifuged for 10 minutes at 3000.times.g. The supernatant is
discarded and the pellet is recentrifuged in Tris buffer (10 mM
Tris, 50 mM NaCl, 5 mM MgCl.sub.2, 1 mM EDTA, pH 7.40) enriched
with 1% bovine serum albumin and 0.1% bacitracin, and resuspended
(1 ml/1000000 cells). The homogenised product is frozen at
-80.degree. C. The membrane preparations are stable for more than 6
weeks under these conditions.
[0456] After thawing, the homogenised product is diluted 1:10 with
assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl.sub.2, 1 mM EDTA,
pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230
.mu.l of the homogenised product are incubated for 180 minutes at
ambient temperature with 50 pM
.sup.125I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham)
and increasing concentrations of the test substances in a total
volume of 250 .mu.l. The incubation is ended by rapid filtration
through GF/B-glass fibre filters treated with polyethyleneimine
(0.1%) using a cell harvester. The protein-bound radioactivity is
measured using a gamma counter. Non-specific binding is defined as
the bound radioactivity in the presence of 1 .mu.M human CGRP-alpha
during incubation.
[0457] The concentration binding curves are analysed using
computer-aided non-linear curve matching.
[0458] The compounds mentioned hereinbefore show IC.sub.50 values
.ltoreq.10000 nM in the test described.
[0459] B. CGRP Antagonism in SK-N-MC Cells
[0460] SK-N-MC cells (1 million cells) are washed twice with 250
.mu.l incubation buffer (Hanks' HEPES, 1 mM
3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at
37.degree. C. for 15 minutes. After the addition of CGRP (10 .mu.l)
as agonist in increasing concentrations (10.sup.-11 to 10.sup.-6
M), or additionally the substance in 3 to 4 different
concentrations, the mixture is incubated for another 15
minutes.
[0461] Intracellular cAMP is then extracted by the addition of 20
.mu.l of 1M HCl and centrifugation (2000.times.g, 4.degree. C., for
15 minutes). The supernatants are frozen in liquid nitrogen and
stored at -20.degree. C.
[0462] The cAMP contents of the samples are determined by
radioimmunoassay (Messrs. Amersham) and the pA.sub.2 values of
antagonistically acting substances are determined graphically.
[0463] The compounds of general formula I exhibit CGRP-antagonistic
properties in the in vitro test model described, in a dosage range
between 10.sup.-12 and 10.sup.-5 M.
[0464] In view of their pharmacological properties the compounds of
general formula I and the salts thereof with physiologically
acceptable acids are thus suitable for the acute and prophylactic
treatment of headaches, particularly migraine or cluster headaches.
Moreover, the compounds of general formula I also have a positive
effect on the following diseases: non-insulin-dependent diabetes
mellitus ("NIDDM"), cardiovascular diseases, morphine tolerance,
diarrhoea caused by clostridium toxin, skin diseases, particularly
thermal and radiation-induced skin damage including sunburn,
inflammatory diseases, e.g. inflammatory diseases of the joints
(arthritis), neurogenic inflammation of the oral mucosa,
inflammatory lung diseases, allergic rhinitis, asthma, diseases
accompanied by excessive vasodilatation and resultant reduced blood
supply to the tissues, e.g. shock and sepsis. In addition, the
compounds according to the invention have a general pain-relieving
effect. The symptoms of menopausal hot flushes caused by
vasodilatation and increased blood flow in oestrogen-deficient
women and hormone-treated patients with prostate carcinoma are
favourably affected by the CGRP-antagonists of the present
application in a preventive and acute-therapeutic capacity, this
therapeutic approach being distinguished from hormone replacement
by the absence of side effects.
[0465] The dosage required to achieve a corresponding effect is
conveniently 0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1
mg/kg of body weight, when administered intravenously or
subcutaneously and 0.01 to 10 mg/kg of body weight, preferably 0.1
to 10 mg/kg of body weight when administered orally, nasally or by
inhalation, 1 to 3.times.a day in each case.
[0466] If the treatment with CGRP antagonists and/or CGRP release
inhibitors is given as a supplement to conventional hormone
substitution, it is advisable to reduce the doses specified above,
in which case the dosage may be from 1/5 of the lower limits
mentioned above up to 1/1 of the upper limits specified.
[0467] The compounds prepared according to the invention may be
administered either on their own or optionally in combination with
other active substances for the treatment of migraine by
intravenous, subcutaneous, intramuscular, intrarectal, intranasal
route, by inhalation, transdermally or orally, while aerosol
formulations are particularly suitable for inhalation. The
combinations may be administered either simultaneously or
sequentially.
[0468] Categories of active substance which may be used in the
combination include e.g. antiemetics, prokinetics, neuroleptics,
antidepressants, neurokinine antagonists, anti-convulsants,
histamine-H1 receptor antagonists, antimuscarinics,
.beta.-blockers, .alpha.-agonists and .alpha.-antagonists, ergot
alkaloids, mild analgesics, non-steroidal antiinflammatories,
corticosteroids, calcium antagonists, 5-HT.sub.1B/1D agonists or
other anti-migraine agents, which may be formulated together with
one or more inert conventional carriers and/or diluents, e.g. with
corn starch, lactose, glucose, microcrystalline cellulose,
magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric
acid, water, water/ethanol, water/glycerol, water/sorbitol,
water/polyethylene glycol, propylene glycol, cetylstearyl alcohol,
carboxymethylcellulose or fatty substances such as hard fat or
suitable mixtures thereof, into conventional galenic preparations
such as plain or coated tablets, capsules, powders, suspensions,
solutions, metered dose aerosols or suppositories.
[0469] Thus other active substances which may be used for the
combinations mentioned above include for example the non-steroidal
antiinflammatories aceclofenac, acemetacin, acetylsalicylic acid,
azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen,
flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide,
lomoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam,
sulphasalazine, zomepirac or the pharmaceutically acceptable salts
thereof as well as meloxicam and other selective COX2-inhibitors,
such as for example rofecoxib and celecoxib.
[0470] It is also possible to use ergotamine, dihydroergotamine,
metoclopramide, domperidone, diphenhydramine, cyclizine,
promethazine, chlorpromazine, vigabatrin, timolol, isometheptene,
pizotifen, botox, gabapentin, topiramate, riboflavin, montelukast,
lisinopril, prochloroperazine, dexamethasone, flunarizine,
dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol,
atenolol, clonidine, indoramin, carbamazepine, phenytoin,
valproate, amitryptiline, lidocaine or diltiazem and other
5-HT.sub.1B/1D-agonists such as, for example, almotriptan,
avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan,
sumatriptan and zolmitriptan.
[0471] The dosage of these active substances is expediently 1/5 of
the lowest recommended dose to 1/1 of the normally recommended
dose, i.e. for example 20 to 100 mg of sumatriptan.
[0472] The invention further relates to the use of the compounds
according to the invention as valuable adjuvants for the production
and purification (by affinity chromatography) of antibodies as well
as in RIA and ELISA assays, after suitable radioactive labelling,
for example by tritiation of suitable precursors, for example by
catalytic hydrogenation with tritium or replacing halogen atoms
with tritium, and as a diagnostic or analytical adjuvant in
neurotransmitter research.
EXPERIMENTAL SECTION
[0473] As a rule, IR, .sup.1H-NMR and/or mass spectra have been
obtained for the compounds prepared. Unless otherwise stated,
R.sub.f values were obtained using ready-made silica gel TLC plates
60 F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber
saturation. The R.sub.f values obtained under the name Alox were
obtained using ready-made aluminium oxide 60 F254 TLC plates (E.
Merck, Darmstadt, item no. 1.05713) without chamber saturation. The
ratios given for the eluants relate to units by volume of the
solvent in question. The units by volume given for NH.sub.3 are
based on a concentrated solution of NH.sub.3 in water.
[0474] Unless otherwise stated the acid, base and saline solutions
used for working up the reaction solutions are aqueous solutions
having the concentrations specified. For chromatographic
purification, silica gel made by Millipore (MATREX.TM., 35-70
.mu.m) was used. For chromatographic purification Alox (E. Merck,
Darmstadt, standardised aluminium oxide 90, 63-200 .mu.m, Article
no. 1.01097.9050) is used.
[0475] The HPLC data provided are measured using the parameters
specified below: Analytical column: Zorbax column (Agilent
Technologies), SB (Stable Bond)--C18; 3.5 .mu.m; 4.6.times.75 mm;
column temperature: 30.degree. C.; flow: 0.8 mL/min; injection
volume: 5 .mu.L; detection at 254 nm
1 Method A: percent by volume of water percent by volume of
acetonitrile time (min) (with 0.1% formic acid) (with 0.1% formic
acid) 0 90 10 9 10 90 10 10 90 11 90 10
[0476] In preparative HPLC purifications as a rule the same
gradients are used as were used to raise the analytical HPLC
data.
[0477] The products are collected under mass control and the
fractions containing the product are combined and freeze-dried.
[0478] If no detailed information is given as to the configuration,
it is not clear whether it is a pure enantiomer or whether partial
or even complete racemisation has occurred.
[0479] The following abbreviations are used in the description of
the experiments:
2 abs. absolute Boc tert.-butoxycarbonyl CDI
N,N'-carbonyldiimidazole CDT 1,1'-carbonyldi-(1,2,4-triazole) Cyc
cyclohexane DCM dichloromethane DMF N,N-dimethylformamide EtOAc
ethyl acetate EtOH ethanol h hour semiconc. semiconcentrated HCl
hydrochloric acid HOAc acetic acid HOBt
1-hydroxybenzotriazole-hydrate i. vac. in vacuo (in a vacuum) KOH
potassium hydroxide conc. concentrated MeOH methanol NaCl sodium
chloride NaOH sodium hydroxide org. organic PE petroleum ether RT
room temperature TBTU
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-
tetrafluoroborate tert. tertiary TFA trifluoroacetic acid THF
tetrahydrofuran
Example 1
[0480]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-p-
iperazin-1-yl]-2-oxo-ethyl}-amide 150
[0481] 1a) 3,4-diethylbenzoic Acid
[0482] 152.8 mL (3.0 mol) of bromine was slowly added dropwise to
an ice-cooled solution of 394.8 g (9.87 mol) of NaOH in 3.3 L of
water. Then at 10.degree. C. a solution of 174 g (0.99 mol) of
1-(3,4-diethyl-phenyl)-ethanone in 400 mL of 1,4-dioxane was added
dropwise to this solution. It was stirred for 2 h at RT, the
bromoform obtained was separated off, the aqueous phase was washed
twice with 400 mL of diethyl ether and adjusted to pH .about.3 with
semiconcentrated HCl. The precipitated product was suction
filtered, washed with water and recrystallised from PE. The desired
product was obtained in the form of a white solid.
3 Yield: 100.0 g (57% of theory) ESI-MS: (M - H).sup.- 177
[0483] 1b) 3,4-(diethyl-phenyl)-methanol
[0484] A solution of 90 g (0.51 mol) of 3,4-diethylbenzoic acid in
300 mL of THF was added dropwise at RT to the suspension of 20.8 g
(0.55 mol) of lithium aluminium hydride in 1500 mL THF. The mixture
was stirred for 30 min at RT and refluxed for 1 h. While cooling
with ice 15 mL of 20% NaOH was added dropwise and then sufficient
water until a granular precipitate was formed. The precipitate was
suction filtered, washed twice with THF and the filtrate was
evaporated down under reduced pressure. The desired product was
obtained in the form of a yellow oil.
4 Yield: 75.0 g (90% of theory) ESI-MS: (M -
H).sup..quadrature.163
[0485] 1c) 4-bromomethyl-1,2-diethyl-benzene
[0486] 16.1 mL (0.17 mol) of phosphorus tribromide was added
dropwise to the solution of 81.0 g (0.49 mol) of
3,4-(diethyl-phenyl)-methanol in 500 mL of diethyl ether while
cooling with ice. The reaction mixture was stirred for 30 min at
30.degree. C., carefully poured onto ice, neutralised by the
addition of NaHCO.sub.3 solution and exhaustively extracted with
diethyl ether. The combined diethyl ether extracts were dried and
evaporated down under reduced pressure. 104.0 g (92%) of an oil
were obtained, which was further reacted without any further
purification.
5 EI-MS: M.sup.+ 226/228 (Br)
[0487] 1d)
(R)-2-amino-3-(3,4-diethyl-phenyl)-N-((1S,2S)-2-hydroxy-1-methy-
l-2-phenylethyl)-N-methyl-propionamide
[0488] In a three-necked flask 250 mL of a 1 molar solution of
lithium-bis-(trimethylsilyl)-amide (250 mmol) and 15.4 g (64.1
mmol) of (1S,2S)-pseudoephedrine-glycinamide hydrate were added to
500 mL of THF under a nitrogen atmosphere and while cooling with
ice. The mixture was stirred for 1.5 h at 0.degree. C., slowly
combined with 15.4 g (67.1 mmol) of
4-bromomethyl-1,2-diethyl-benzene, dissolved in 10 mL of THF, and
stirred for 2 h at 0.degree. C. While cooling with ice 10 mL of
water and 6 mL semiconcentrated HCl were added dropwise, stirred
for a further 20 min and made alkaline with concentrated ammonia
solution. The reaction mixture was exhaustively extracted with
EtOAc, the combined organic phases were dried and evaporated down
under reduced pressure. The residue remaining was purified through
silica gel. The desired product was obtained in the form of a
solid.
6 Yield: 7.4 g (31% of theory) ESI-MS: (M + H).sup.+ 369
[0489] 1e) (R)-2-amino-3-(3,4-diethyl-phenyl)-propionic Acid
[0490] A mixture of 7.8 g (21.2 mmol) of
(R)-2-amino-3-(3,4-diethyl-phenyl-
)-N-((1S,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide,
50 mL of water and 50 mL of 1,4-dioxane was refluxed for 7 days.
The reaction mixture was evaporated down under reduced pressure,
the residue remaining was stirred with EtOH and suction filtered.
The desired product was obtained in the form of a white solid.
7 Yield: 4.0 g (85% of theory) ESI-MS: (M + H).sup.+ 222; (M -
H).sup.- 220 R.sub.f: 0.25 (silica gel, DCM/MeOH/cyc/NH.sub.3
70:15:15:2)
[0491] 1f)
(R)-2-tert-butoxycarbonylamino-3-(3,4-diethyl-phenyl)-propionic
Acid
[0492] A mixture of 4.0 g (18.1 mmol) of
(R)-2-amino-3-(3,4-diethyl-phenyl- )-propionic acid, 4.2 g (39.2
mmol) of Na.sub.2CO.sub.3, 100 mL of water and 25 mL of THF was
combined with 5.0 g (22.2 mmol) of di-tert.-butyldicarbonate,
dissolved in 25 mL of THF, while cooling with ice. It was stirred
for 30 min while cooling with ice and for 3 h at RT. The organic
phase was separated off and the aqueous phase was repeatedly
extracted with diethyl ether. The combined organic phases were
extracted with 15% K.sub.2CO.sub.3 solution, the combined aqueous
phases were acidified with 1 M KHSO.sub.4 solution and exhaustively
extracted with EtOAc. The combined organic extracts were dried over
MgSO.sub.4 and evaporated down under reduced pressure. The desired
product was obtained in the form of a colourless oil.
8 Yield: 4.9 g (84% of theory) ESI-MS: (M + H).sup.+ 320 R.sub.f:
0.33 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0493] 1g) tert. butyl
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidi-
n-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbaminate
[0494] A mixture of 4.9 g (15.25 mmol) of
(R)-2-tert.-butoxycarbonylamino-- 3-(3,4-diethyl-phenyl)-propionic
acid, 5.3 g (16.5 mmol) of TBTU, 2.1 g (15.23 mmol) of HOBt, 17 mL
N-ethyldiisopropylamine, 15 mL of DMF and 150 mL of THF was stirred
for 30 min at RT, combined with 6.2 g (19.9 mmol) of
1-(1-methyl-piperidin-4-yl)-piperazine and stirred for a further 4
h. The reaction mixture was evaporated down under reduced pressure,
the residue remaining was combined with 15% K.sub.2CO.sub.3
solution and extracted three times with DCM. The combined organic
extracts were dried over MgSO.sub.4, evaporated down and the
residue remaining was purified through silica gel. The desired
product was obtained in the form of a pale yellow oil.
9 Yield: 5.0 g (67% of theory) EI-MS: M.sup.+ 486 R.sub.f: 0.56
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0495] 1h)
(R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(1-methyl-piperidin-4-y-
l)-piperazin-1-yl]-propan-1-one
[0496] A mixture of 5.0 g (10.27 mmol) of tert. butyl
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl-
]-2-oxo-ethyl}-carbaminate, 100 mL of DCM and 20 mL of TFA was
stirred for 1.5 h at RT. The reaction mixture was then evaporated
down under reduced pressure, the residue combined with 15%
K.sub.2CO.sub.3 solution and extracted exhaustively with DCM. The
combined organic extracts were dried and evaporated down under
reduced pressure. The desired product was obtained in the form of a
bright yellow oil.
10 Yield: 3.6 g (91% of theory) ESI-MS: (M + H).sup.+ 387 R.sub.f:
0.22 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0497] 1i)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-y-
l)-piperazin-1-yl]-2-oxo-ethyl}-amide
[0498] 1.70 g (4.39 mmol) of
(R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(1-me-
thyl-piperidin-4-yl)-piperazin-1-yl]-propan-1-one, dissolved in 25
mL of THF, was slowly added dropwise to the ice-cooled mixture of
75 mL of THF and 0.80 g (4.63 mmol) of CDT. Then the mixture was
stirred for 30 min in the ice bath and for a further 45 min at RT
before the solution of 1.1 g (4.48 mmol) of
3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on- e in 20
mL of DMF was added and refluxed for 4 h. The reaction mixture was
evaporated down under reduced pressure, the residue was combined
with 50 mL of 15% K.sub.2CO.sub.3 solution and exhaustively
extracted with DCM. The combined organic extracts were washed with
water, dried over MgSO.sub.4, evaporated down and purified through
silica gel. The crystallisation was from acetone. The desired
product was obtained in the form of a crystalline solid.
11 Yield: 1.2 g (42% of theory) ESI-MS: (M + H).sup.+ 658 R.sub.f:
0.28 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0499]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-p-
iperazin-1-yl]-2-oxo-ethyl}-amide-dimaleinate
[0500] 0.5 g (0.76 mmol)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y-
l)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-
-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide and 0.176 g
(1.52 mmol) maleic acid were suspended in 20 mL acetone and after
the addition of 5 mL methanol the mixture was refluxed for. The
precipitate formed after cooling to ambient temperature was
filtered off, washed with acetone and dried.
12 Yield: 0.5 g (74% of theory) melting point: 165.degree. C.
(decomp.)
[0501]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-p-
iperazin-1-yl]-2-oxo-ethyl}-amide-benzenesulphonate
[0502] 1.0 g (1.52 mmol) of
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin--
3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-met-
hyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide and 0.24 g
(1.52 mmol) benzenesulphonic acid were refluxed in 20 mL
isopropanol. Then the solution was continuously cooled over three
days from 50.degree. C. to 25.degree. C., during which time a
crystalline precipitate was formed. The solid formed was filtered
off, washed with isopropanol and dried.
13 Yield: 0.58 g (47% of theory) melting point: 192.degree. C.
(decomp.)
Example 2
[0503]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-p-
iperidin-1-yl]-2-oxo-ethyl}-amide 151
[0504] 2a) tert. butyl
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazi-
n-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-carbaminate
[0505] 4.2 mL ethyldiisopropylamine were added to a mixture of 3.7
g (11.52 mmol) of
(R)-2-tert.-butoxycarbonylamino-3-(3,4-diethyl-phenyl)-pr- opionic
acid, 3.9 g (12 mmol) of TBTU, 1.7 g (12 mmol) of HOBt and 2.2 g
(11.6 mmol) of 1-methyl-4-piperidin-4-yl-piperazine in 100 mL of
THF and the reaction mixture was stirred overnight at RT. The
reaction mixture was evaporated down under reduced pressure, the
residue remaining was combined with Na.sub.2CO.sub.3 solution and
extracted with EtOAc. The combined organic extracts were dried over
Na.sub.2SO.sub.4 and evaporated down. The desired product was
obtained in the form of a pale yellow oil.
14 Yield: 5.5 g (97% of theory) R.sub.f = 0.5 (Alox, DCM/MeOH =
30/1)
[0506] 2b)
(R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(4-methyl-piperazin-1-y-
l)-piperidin-1-yl]-propan-1-one
[0507] A mixture of 5.4 g (11.1 mmol) of tert. butyl
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl-
]-2-oxo-ethyl}-carbaminate, 100 mL of DCM and 20 mL of TFA was
stirred for 4 h at RT. The reaction mixture was added dropwise to a
Na.sub.2CO.sub.3 solution, stirred for 10 min, the organic phase
was then separated off and dried over Na.sub.2SO.sub.4. The solvent
was removed in vacuo. The desired product was obtained in the form
of a bright yellow oil.
15 Yield: 4.2 g (98% of theory) R.sub.f = 0.54 (Alox, DCM/MeOH =
19/1)
[0508] 2c)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic acid-20
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin--
1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide
[0509] 4.1 g (10.61 mmol) of
(R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(4-me-
thyl-piperazin-1-yl)-piperidin-1-yl]-propan-1-one, dissolved in 50
mL of THF, were slowly added dropwise to the ice-cooled mixture of
150 mL of THF and 1.9 g (11.2 mmol) of CDT.
[0510] Then the mixture was stirred for 30 min in the ice bath and
for a further 45 min at RT before the solution of 2.7 g (11.0 mmol)
of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in
20 mL of DMF was added and the mixture was refluxed for 4 h. The
reaction mixture was evaporated down under reduced pressure, the
residue was combined with Na.sub.2CO.sub.3 solution and
exhaustively extracted with EtOAc. The combined organic extracts
were washed with water, dried over Na.sub.2SO.sub.4, evaporated
down and purified over aluminium oxide. The product was obtained as
a solid.
16 Yield: 4.2 g (60% of theory) R.sub.f = 0.32 (Alox, DCM/MeOH =
30/1)
Example 3
[0511]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl-
)-2-oxo-ethyl]-amide 152
[0512] 3a) diethyl
2-acetylamino-2-(3,4-diethyl-benzyl)-malonate
[0513] Under a nitrogen atmosphere 8.14 g (354 mmol) of sodium were
added batchwise to 200 mL of absolute EtOH and stirred until
completely dissolved. 76.9 g (354 mmol) of diethyl
2-acetylaminomalonate were added to this solution, whereupon the
sodium salt formed was precipitated. After the addition of 150 mL
of 1,4-dioxane a solution of 80 g (352 mmol) of
4-bromomethyl-1,2-diethyl-benzene in 500 mL of 1,4-dioxane was
added dropwise to this suspension. The reaction solution was kept
for 2 h at 50.degree. C. and then stirred overnight at RT. The
solvent was distilled off in vacuo, the oily residue was combined
with water, whereupon the product was obtained in the form of white
crystals. These were suction filtered, washed with water and
reacted without any further purification.
17 R.sub.f = 0.35 (silica gel, PE/EtOAc = 2/1)
[0514] 3b) (R,S)-2-amino-3-(3,4-diethyl-phenyl)-propionic Acid
[0515] The crude product described in Example 3a) was dissolved in
250 mL of AcOH and combined with 250 mL of concentrated HCl and 150
mL of water. The reaction solution was refluxed for 3 h, the
solvents were concentrated by evaporation in vacuo, the residue was
taken up in EtOH, the precipitate formed was suction filtered and
washed with diethyl ether.
18 Yield: 45 g (57% of theory) ESI-MS: (M + H).sup.+ 222 R.sub.f =
0.35 (silica gel, EtOAc/MeOH/AcOH = 90:10:3)
[0516] 3c) methyl 2-amino-3-(3,4-diethyl-phenyl)-propionate
[0517] 41 g (159 mmol) of
(R,S)-2-amino-3-(3,4-diethyl-phenyl)-propionic acid were combined
with 300 mL of HCl-saturated MeOH and left to stand overnight at
RT, during which time the desired hydrochloride precipitated out.
It was heated to 50.degree. C., whereupon HCl was given off and the
product went back into solution. The solution was evaporated down
to 1/3 of its original volume in vacuo, the precipitated product
was stirred with diethyl ether, suction filtered and washed twice
with diethyl ether. The crude product was reacted without any
further purification.
19 Yield: 42 g (97% of theory) ESI-MS: (M + H).sup.+ 236 R.sub.f =
0.7 (silica gel, MeOH)
[0518] 3d) methyl
3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1-
,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionate
[0519] 7.4 g (45 mmol) of CDT were added to a solution of 10.5 g
(44.6 mmol) of methyl 2-amino-3-(3,4-diethyl-phenyl)-propionate in
250 mL of THF cooled to 0.degree. C. and stirred for a further 30
min at this temperature. Then 10.9 g (44.6 mmol) of
3-piperidin-4-yl-1,3,4,5-tetrahyd- ro-1,3-benzodiazepin-2-one was
added and the reaction solution was kept for a further 20 min at
this temperature before being refluxed for 30 min. The solvent was
removed in vacuo, the residue was taken up in saturated NaHCO.sub.3
solution, exhaustively extracted with diethyl ether/EtOAc (1:1) and
dried over MgSO.sub.4. After elimination of the desiccant and
solvent the crude product was reacted without any further
purification.
20 Yield: quantitative R.sub.f = 0.6 (silica gel: EtOAc/petroleum
ether = 6:4)
[0520] 3e)
3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benz-
odiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic Acid
[0521] 26 g of the crude product described in 3d) were dissolved in
200 mL EtOH, combined with 2.3 g (55 mmol) of lithium hydroxide
hydrate and stirred overnight at RT. The reaction solution was
concentrated by evaporation in vacuo, the residue was taken up with
water, extracted with diethyl ether, acidified with citric acid
solution and exhaustively extracted with EtOAc. The combined
organic phases were dried over MgSO.sub.4 and evaporated down in
vacuo.
21 Yield: 19 g (75% of theory) R.sub.f: 0.1 (silica gel,
EtOAc/petroleum ether 6:4)
[0522] 3f)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-[1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl--
1-yl)-2-oxo-ethyl]-amide
[0523] 0.3 mL of triethylamine, 323 mg (1.01 mmol) of TBTU, 155 mg
(1.01 mmol) of HOBt and 184 mg (1.01 mmol) of
methyl-[4,4']bipiperidinyl were added to a solution of 500 mg (1.02
mmol) of 3-(3,4-diethyl-phenyl)-2-{[4-
-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]--
amino}-propionic acid in 50 mL of THF and stirred for 4 h at RT and
2 h at 40.degree. C. The reaction mixture was evaporated down, the
residue was stirred with 40 mL of saturated NaHCO.sub.3 solution,
the precipitated product was suction filtered, washed twice with
water and triturated with EtOH. The white substance precipitated
was suction filtered and washed twice with diethyl ether.
22 Yield: 420 mg (63% of theory) ESI-MS: (M + H).sup.+ 657 R.sub.f
= 0.45 (silica gel, MeOH)
Example 4
[0524]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[1-(3,4-diethyl-benzyl)-2-oxo-2-(3,4,5,6-tetrahydro-2H-4,4'--
bipyridinyl-1-yl)-ethyl]-amide 153
[0525] Prepared analogously to Example 3f) from
3-(3,4-diethyl-phenyl)-2-{-
[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl-
]-amino}-propionic acid and
1,2,3,4,5,6-hexahydro-[4,4']bipyridinyl.
23 Yield: 270 mg (42% of theory) ESI-MS: (M + H).sup.+ 637 R.sub.f
= 0.55 (silica gel, MeOH)
Example 5
[0526]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[2-1,4'-bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo-eth-
yl]-amide 154
[0527] Prepared analogously to Example 3f) from
3-(3,4-diethyl-phenyl)-2-{-
[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl-
]-amino}-propionic acid and [1,4']-bipiperidinyl.
24 Yield: 37% of theory ESI-MS: (M + H).sup.+ 643 R.sub.f: 0.55
(silica gel, MeOH)
Example 6
[0528]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazin-1--
yl)-ethyl]-amide 155
[0529] Prepared analogously to Example 3f) from
3-(3,4-diethyl-phenyl)-2-{-
[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl-
]-amino}-propionic acid and 1-pyridin-4-yl-piperazine.
25 Yield: 57% of theory ESI-MS: (M + H).sup.+ 638 R.sub.f: 0.45
(silica gel, MeOH)
Example 7
[0530]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-y-
l]-2-oxo-ethyl}-amide 156
[0531] 7a) methyl
3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quina-
zolin-3-yl)-piperidine-1-carbonyl]-amino}-propionate
[0532] 3.3 mL ethyldiisopropyl-amine and 2.06 g (12.6 mmol) of CDT
were added to an ice-cooled solution of 2.95 g (12.54 mmol) of
methyl 2-amino-3-(3,4-diethyl-phenyl)-propionate in 200 mL of THF
and stirred for a further 90 min at 0-101C. Then 20 mL of DMF were
added, the mixture was stirred for a further 30 min, 2.91 g (12.6
mmol) of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one were
added and the suspension was refluxed for 10 h. The reaction
mixture was evaporated down in vacuo, combined with semisaturated
NaHCO.sub.3 solution, exhaustively extracted with EtOAc and dried
over MgSO.sub.4. After elimination of the desiccant and solvent the
crude product was reacted without any further purification.
26 Yield: 6.0 g (97% of theory) R.sub.f: 0.8 (silica gel,
EtOAc/MeOH/AcOH 30:10:1)
[0533] 7b)
3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-
-yl)-piperidine-1-carbonyl]-amino}-propionic Acid
[0534] The crude product (6 g, 11.84 mmol) described in 7a) was
placed in 120 mL MeOH, combined with 40 mL 1M NaOH (40 mmol) and
refluxed for 5 h. The reaction mixture was concentrated by
evaporation in vacuo, the residue was combined with 150 mL of water
and 40 mL 1M HCl, exhaustively extracted with DCM and the combined
organic phases were dried over MgSO.sub.4. After elimination of the
desiccant and solvent the residue was triturated with
diisopropylether and suction filtered.
27 Yield: 3.5 g (62% of theory) ESI-MS: (M + H).sup.+ 479 R.sub.f:
0.5 (silica gel, PE/EtOAc/AcOH 70:30:3)
[0535] 7c)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyli- c
acid-{1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1--
yl]-2-oxo-ethyl}-amide
[0536] 336 mg (1.05 mmol) of TBTU, 161 mg (1.05 mmol) of HOBt, 0.75
mL of triethylamine and 192 mg (1.05 mmol) of
1-methyl-4-piperidin-4-yl-piperaz- ine were added to a solution of
500 mg (1.05 mmol) of
3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piper-
idine-1-carbonyl]-amino}-propionic acid in 100 mL of THF, and
stirred for 4 h at RT and 2 h at 40.degree. C. The solvent was
removed in vacuo, the residue taken up in 40 mL of saturated
NaHCO.sub.3 solution, exhaustively extracted with EtOAc and dried
over MgSO.sub.4. After elimination of the desiccant and solvent the
crude product was purified by chromatography (silica gel,
MeOH/NH.sub.3 100:3).
28 Yield: 350 mg (52% of theory) ESI-MS: (M + H).sup.+ 644 R.sub.f:
0.3 (silica gel, MeOH/NH.sub.3 100:3)
Example 8
[0537]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-y-
l]-2-oxo-ethyl}-amide 157
[0538] 336 mg (1.05 mmol) of TBTU, 161 mg (1.05 mmol) of HOBt, 1.02
mL triethylamine and 326 mg (1.05 mmol) of
1-(1-methyl-piperidin-4-yl)-piper- azine (used as the
tris-hydrochloride) were added to a solution of 500 mg (1.05 mmol)
of 3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazo-
lin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid in 100 mL of
THF, stirred for 4 h at RT and 2 h at 40.degree. C. The solvent was
removed in vacuo, the residue was stirred with 40 mL of saturated
NaHCO.sub.3 solution, the precipitated product was suction
filtered, taken up in MeOH and purified by chromatography over
silica gel (MeOH). The product fractions were evaporated down, the
residue triturated with diethyl ether, suction filtered, washed
twice with diethyl ether and dried.
29 Yield: 120 mg (18% of theory) ESI-MS: (M + H).sup.+ 644 R.sub.f:
0.35 (silica gel, MeOH/NH.sub.3 100:3)
Example 9
[0539]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-dimethylamino-piperidin-1-y-
l)-2-oxo-ethyl]-amide 158
[0540] 9a) diethyl
2-acetylamino-2-(3,4-diethyl-benzyl)-malonate
[0541] 6.7 g (0.29 mol) sodium were added to 300 mL EtOH under an
argon atmosphere. 60.0 g (0.27 mol) ethyl acetamidomalonate were
added to the resulting solution, stirred for 1.5 h and then 62.0 g
(0.27 mol) 4-bromomethyl-1,2-diethyl-benzene were slowly added
dropwise. The reaction mixture was stirred overnight at RT, poured
onto 1 L of water and vigorously stirred for 1 h at RT. The
precipitate formed was suction filtered, suspended twice with a
little water, suction filtered and dried.
30 Yield: 93.5 g (95% of theory) ESI-MS: (M + H).sup.+ 364 R.sub.f:
0.72 (silica gel, DCM/MeOH 19:1)
[0542] 9b) monoethyl
2-acetylamino-2-(3,4-diethyl-benzyl)-malonate
[0543] A solution of 50 g (138 mmol) diethyl
2-acetylamino-2-(3,4-diethyl-- benzyl)-malonate in 300 mL EtOH was
combined with 5.8 g (138.2 mmol) lithium hydroxide hydrate
dissolved in 46 mL water and the reaction mixture was stirred for
19 h at RT. The solvent was evaporated down under reduced pressure,
the residue was combined with 100 mL water and washed twice with
tert-butylmethylether. The aqueous phase was then acidified by the
addition of 2 M HCl while being cooled, the precipitate was suction
filtered, washed with water and dried.
31 Yield: 37.2 g (81% of theory) ESI-MS: (M + H).sup.+ 336 R.sub.f:
0.10 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0544] 9c) ethyl
2-acetylamino-3-(3,4-diethyl-phenyl)-propionate
[0545] A mixture of 35.2 g (104.9 mmol) monoethyl
2-acetylamino-2-(3,4-die- thyl-benzyl)-malonate and 400 mL toluene
was refluxed for 15 h. The reaction mixture was evaporated down
under reduced pressure, the residue was taken up in DCM and the
organic phase was washed with saturated NaHCO.sub.3 solution. The
organic phase was then dried and evaporated down under reduced
pressure.
32 Yield: 29.7 g (97% of theory) ESI-MS: (M + H).sup.+ 290 R.sub.f:
0.70 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0546] 9d) ethyl
(R)-2-acetylamino-3-(3,4-diethyl-phenyl)-propionate
[0547] 27 mL Alcalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd)
were added to a solution of 38.0 g (213.5 mmol) disodium hydrogen
phosphate dihydrate in 500 mL water at a temperature of 37.degree.
C. and the pH was adjusted to 7.5 by the addition of sodium
dihydrogen phosphate dihydrate. Then at 37.degree. C. with stirring
29.7 g (101.9 mmol) ethyl
2-acetylamino-3-(3,4-diethyl-phenyl)-propionate dissolved in 150 mL
acetone was added dropwise. The pH value of the reaction mixture
was kept constantly kept in the range from pH 7.4 to pH 7.6 by the
addition of 1 M NaOH. After the addition had ended the mixture was
stirred for 4 h at 37.degree. C. The reaction mixture was extracted
three times with tert-butylmethylether, the combined organic
extracts were washed with 15% K.sub.2CO.sub.3 solution, dried and
evaporated down under reduced pressure.
33 Yield: 13.8 g (47% of theory) ESI-MS: (M + H).sup.+ 292 R.sub.f:
0.77 (silica gel, EtOAc) ee value: >99% [HPLC: Chiralpak AD, 10
.mu.m, 4,6 .times. 250 mm; eluant: EtOH/hexane 15:85 + 0.1%
diethylamine]
[0548] 9e) (R)-2-amino-3-(3,4-diethyl-phenyl)-propionic acid
[0549] A mixture of 13.8 g (47.4 mmol) ethyl
(R)-2-acetylamino-3-(3,4-diet- hyl-phenyl)-propionate and 160 mL 6
M HCl was refluxed in the oil bath for 3 h. The reaction mixture
was cooled in the ice bath and the precipitate formed was suction
filtered.
34 Yield: 10.6 g (87% of theory) ESI-MS: (M + H).sup.+ 222
[0550] 9f) methyl (R)-2-amino-3-(3,4-diethyl-phenyl)-propionate
[0551] 44 mL (607 mmol) thionyl chloride were added dropwise to 600
mL methanol within 1.5 h while cooling with ice. Then while cooling
with ice 40.2 g (156 mmol)
(R)-2-amino-3-(3,4-diethyl-phenyl)-propionic acid was added, and
the mixture was stirred overnight at RT. The reaction mixture was
evaporated down under reduced pressure, stirred twice with
tert-butylmethylether, suction filtered and dried.
35 Yield: 41.7 g (98% of theory)
[0552] 9g) methyl
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahyd-
ro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionate
[0553] The mixture of 41.7 g (0.153 mol) methyl
(R)-2-amino-3-(3,4-diethyl- -phenyl)-propionate, 800 mL THF and 28
mL (0.161 mol) ethyldiisopropylamine was combined with 25.4 g
(0.157 mol) CDT and then 38.0 g (0.155 mol)
3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-- 2-one while
cooling with an ice bath and refluxed for 3 h with stirring. The
reaction mixture was then extracted with 300 mL 10% citric acid
solution, three times with 100 mL aliquots of water and 200 mL
saturated NaCl solution, dried and evaporated down under reduced
pressure.
36 Yield: 74.4 g (96% of theory)
[0554] 9h)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3--
benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic
Acid
[0555] 74.4 g (0.147 mol) methyl
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1-
,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-pr-
opionate dissolved in 600 mL THF was combined with 5.4 g (0.221
mol) lithium hydroxide hydrate in 300 mL water while cooling with
an ice bath and stirred overnight at RT. The reaction mixture was
evaporated down under reduced pressure, 300 mL water was added and
the mixture was extracted three times with 200 mL EtOAc. The
aqueous phase was freed from the organic solvent under reduced
pressure and combined with 500 mL 2 M HCl with stirring and cooling
with the ice bath. The precipitate formed was suction filtered,
washed with water and dried.
37 Yield: 67.8 g (94% of theory)
[0556] 9i)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine--
1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-dimethylamino-piperidin-
-1-yl)-2-oxo-ethyl]-amide
[0557] A mixture of 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-
-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-ami-
no}-propionic acid, 280 mg (0.87 mmol) TBTU, 0.17 mL (0.97 mmol)
ethyldiisopropylamine and 45 mL THF was stirred for 1 h at RT, then
combined with 130 mg (1.01 mmol) dimethyl-piperidin-4-yl-amine and
5 mL DMF and stirred overnight. The reaction mixture was diluted by
the addition of 30 mL EtOAc, extracted with 30 mL of a 15%
K.sub.2CO.sub.3 solution and the organic phase was dried. The
product fractions were evaporated down under reduced pressure, the
residue was triturated with diisopropylether, suction filtered and
dried.
38 Yield: 490 mg (41% of theory) ESI-MS: (M + H).sup.+ 603 R.sub.f:
0.61 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 10
[0558]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-perhydro-azepin-1-yl--
piperidin-1-yl)-ethyl]-amide 159
[0559] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-20 amino}-propionic acid and 180
mg (0.99 mmol) 1-piperidin-4-yl-azepan.
39 Yield: 200 mg (38% of theory) ESI-MS: (M + H).sup.+ 657 R.sub.f:
0.66 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 11
[0560]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diaz-
epin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 160
[0561] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 200 mg
(1.01 mmol) 1-methyl-4-piperidin-4-yl-[1,4]diazepan.
40 Yield: 12 mg (2% of theory) ESI-MS: (M + H).sup.+ 672 R.sub.f:
0.54 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 12
[0562]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl--
1-yl)-2-oxo-ethyl]-amide 161
[0563] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 260 mg
(1.02 mmol) 1-methyl-[4,4']bipiperidinyl.
41 Yield: 200 mg (38% of theory) ESI-MS: (M + H).sup.+ 657 R.sub.f:
0.60 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 13
[0564]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(8-methyl-8-aza-bicyclo[3.2-
.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 162
[0565] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 320 mg
(1.00 mmol) 8-methyl-3-piperazin-1-yl-8-aza-bicyclo[3.2.1]octane
trihydrochloride.
42 Yield: 160 mg (29% of theory) ESI-MS: (M + H).sup.+ 684 R.sub.f:
0.60 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 14
[0566]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperi-
din-1-yl)-ethyl]-amide 163
[0567] A mixture of 500 mg (1.02 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-
-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-ami-
no}-propionic acid, 320 mg (1.09 mmol) TBTU, 0.22 mL (0.97 mmol)
ethyldiisopropylamine and 45 mL THF was stirred for 1 h at RT, then
combined with 310 mg (1.20 mmol)
1-benzyl-4-piperidin-4-yl-piperazine and 5 mL DMF and stirred
overnight. The reaction mixture was diluted by the addition of 30
mL EtOAc, extracted with 30 mL of a 15% K.sub.2CO.sub.3 solution
and the organic phase was dried. The organic phase was evaporated
down under reduced pressure and the residue purified by
chromatography on silica gel. The intermediate product fractions
were evaporated down under reduced pressure, the residue remaining
(260 mg) was dissolved in 20 mL MeOH and hydrogenated in the
autoclave in the presence of 50 mg Pd/C (10%) at 50.degree. C. and
3 bar hydrogen pressure until the calculated volume of hydrogen had
been taken up. The catalyst was filtered off, the solvent
eliminated under reduced pressure and the residue purified by
chromatography on silica gel. The product fractions were evaporated
down under reduced pressure, the residue was triturated with
diisopropylether, suction filtered and dried.
43 Yield: 110 mg (17% of theory) ESI-MS: (M + H).sup.+ 644 R.sub.f:
0.50 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 15
[0568]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-[4-(4-acetyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-d-
iethyl-benzyl)-2-oxo-ethyl]-amide 164
[0569] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-20 amino}-propionic acid and 230
mg (1.09 mmol) 1-(4-piperidin-4-yl-piperazin-1-yl)-ethanone.
44 Yield: 280 mg (50% of theory) ESI-MS: (M + H).sup.+ 686 R.sub.f:
0.57 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 16
[0570]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(3-dimethylamino-piperidin-1-y-
l)-2-oxo-ethyl]-amide 165
[0571] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 130 mg
(1.01 mmol) dimethyl-piperidin-3-yl-amine.
45 Yield: 160 mg (33% of theory) ESI-MS: (M + H).sup.+ 603 R.sub.f:
0.59 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 17
[0572]
4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carb-
oxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pip-
erazin-1-yl]-2-oxo-ethyl}-amide 166
[0573] A mixture of 400 mg (1.04 mmol)
(R)-2-amino-3-(3,4-diethyl-phenyl)--
1-[4-(1-methylpiperidin-4-yl)-piperazin-1-yl]-propan-1-one, 205 mg
(1.25 mmol) CDT, 0.2 mL (1.15 mmol) ethyldiisopropylamine and 50 mL
THF was stirred for 1 h while cooling with an ice bath and stirred
for 1 h at RT, then combined with 270 mg (1.11 mmol)
5-phenyl-2-piperidin-4-yl-2,4-dihyd- ro-[1,2,4]triazol-3-one and
refluxed for 4 h. The reaction mixture was evaporated down under
reduced pressure, the residue was combined with saturated
NaHCO.sub.3 solution and exhaustively extracted with DCM. The
combined organic phases were dried, evaporated down under reduced
pressure and the residue was purified by chromatography on silica
gel. The product fractions were evaporated down under reduced
pressure, the residue was triturated with diisopropylether, suction
filtered and dried.
46 Yield: 180 mg (27% of theory) ESI-MS: (M + H).sup.+ 657 R.sub.f:
0.37 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0574] The Following Were Obtained Accordingly:
Example 18
[0575]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-
-1-yl]-2-oxo-ethyl}-amide
47 167 Yield: (50% of theory) ESI-MS: (M + H).sup.+ 644 R.sub.f:
0.29 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 19
[0576]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pip-
erazin-1-yl]-2-oxo-ethyl}-amide
48 168 Yield: (45% of theory) ESI-MS: (M + H).sup.+ 681 R.sub.f:
0.20 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 20
[0577]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-y-
l]-1-(3,4-diethyl-benzyl)-2-oxo-ethyl]-amide 169
[0578] 20a) tert-butyl
4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidine-1-
-carboxylate
[0579] 1.26 g (20.0 mmol) sodium cyanoborohydride was added
batchwise at RT to a stirred mixture of 1.71 g (5.0 mmol)
tert-butyl 4-piperazin-1-yl-piperidine-1-carboxylate
dihydrochloride, 0.75 mL (10.0 mmol) cyclopropanecarbaldehyde, 30
mL EtOH and 20 mL MeOH and stirred overnight at RT. The reaction
mixture was evaporated down under reduced pressure, the residue was
taken up in saturated NaHCO.sub.3 solution and extracted
erschopfend with EtOAc. The combined organic phases were dried over
Na.sub.2SO.sub.4, suction filtered, evaporated down under reduced
pressure and purified by column chromatography over silica gel.
49 Yield: 1.36 g (84% of theory) EI-MS: (M).sup.+ 323
[0580] 20b) 1-cyclopropylmethyl-4-piperidin-4-yl-piperazine
tris-trifluoroacetate
[0581] 5.0 mL TFA was added dropwise to the solution of 1.36 g
(4.20 mmol) tert-butyl
4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidine-1-carboxylat- e
in 30 mL DCM while cooling with an ice bath and the reaction
mixture was stirred for 4 h at RT. The solvent was eliminated under
reduced pressure, the residue stirred with diethyl ether, suction
filtered and dried.
50 Yield: 1.86 g (78% of theory) EI-MS: (M).sup.+ 223
[0582] 20c)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic acid
[(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidi-
n-1-yl]-1-(3,4-diethyl-benzyl)-2-oxo-ethyl]-amide
[0583] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 350 mg
(0.62 mmol) 1-cyclopropylmethyl-4-piperidin-4-yl-piperazine
tris-trifluoroacetate.
51 Yield: 100 mg (18% of theory) ESI-MS: (M + H).sup.+ 698 R.sub.f:
0.73 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 21
[0584] 4-(2-oxo-1,2-dihydro-4H-thieno
[3,4-d]pyrimidin-3-yl)-piperidine-1-- carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-
-piperazin-1-yl]-2-oxo-ethyl}-amide 170
Example 22
[0585]
4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-c-
arboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)--
piperazin-1-yl]-2-oxo-ethyl}-amide 171
Example 23
[0586]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyrrolidin-1-yl-piper-
idin-1-yl)-ethyl]-amide 172
[0587] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 160 mg
(0.99 mmol) 4-pyrrolidin-1-yl-piperidine.
52 Yield: 170 mg (33% of theory) ESI-MS: (M + H).sup.+ 629 R.sub.f:
0.59 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 24
[0588]
4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-
e-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-
-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 173
Example 25
[0589]
4-(2-oxo-1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperi-
dine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidi-
n-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 174
Example 26
[0590]
4-(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperi-
dine-1-carboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidi-
n-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 175
Example 27
[0591]
4-(2-oxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl)-piperidine-1-c-
arboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)--
piperazin-1-yl]-2-oxo-ethyl}-amide 176
Example 28
[0592]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-ethyl-piperazin-1-yl)-pi-
peridin-1-yl]-2-oxo-ethyl}-amide 177
[0593] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 550 mg
(1.02 mmol)
1-ethyl-4-piperidin-4-yl-piperazine-tris-trifluoroacetate.
53 Yield: 250 mg (46% of theory) ESI-MS: (M + H).sup.+ 672 R.sub.f:
0.59 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 29
[0594]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-isopropyl-piperazin-1-yl-
)-piperidin-1-yl]-2-oxo-ethyl}-amide 178
[0595] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 210 mg
(0.99 mmol) 1-isopropyl-4-piperidin-4-yl-piperazine.
54 Yield: 80 mg (14% of theory) ESI-MS: (M + H).sup.+ 686 R.sub.f:
0.59 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 30
[0596]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo-
-ethyl]-amide 179
[0597] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg
(1.01 mmol) [1,4']bipiperidinyl.
55 Yield: 230 mg (44% of theory) ESI-MS: (M + H).sup.+ 643 R.sub.f:
0.59 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 31
[0598]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazi-
n-1-yl)-ethyl]-amide 180
[0599] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg
(1.04 mmol) 1-pyridin-4-yl-piperazine.
56 Yield: 150 mg (29% of theory) ESI-MS: (M + H).sup.+ 638 R.sub.f:
0.56 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 32
[0600]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3,4,5,6-tetrahydro-2H-4-
,4'-bipyridinyl-1-yl)-ethyl]-amide 181
[0601] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg
(1.04 mmol) 1,2,3,4,5,6-hexahydro-[4,4']bipyridinyl.
57 Yield: 280 mg (54% of theory) ESI-MS: (M + H).sup.+ 637 R.sub.f:
0.62 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 33
[0602]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4,4-difluoro-1,4'-bipiperidin-
yl-1'-yl)-2-oxo-ethyl]-amide 182
[0603] 33a) 1'-benzyl-4,4-difluoro-[1,4']bipiperidinyl
[0604] Under a nitrogen atmosphere a mixture of 6.8 g (25.0 mmol)
1'-benzyl-[1,4']bipiperidinyl-4-one and 60 mL DCM was combined with
stirring at RT with a solution of 7.8 mL (42.4 mmol)
[bis-(2-methoxyethyl)-amino]-sulphur trifluoride in 40 mL DCM and
then with 0.3 mL EtOH. The reaction mixture was stirred overnight,
a further 15.6 mL [bis-(2-methoxyethyl)-amino]-sulphur trifluoride
and 0.6 mL EtOH were added and the mixture was stirred for 24 h.
The reaction mixture was then combined with saturated NaHCO.sub.3
solution, exhaustively extracted with DCM, dried and freed from the
organic solvent under reduced pressure. The residue was purified by
chromatography on silica gel.
58 Yield: 2.8 g (38% of theory) ESI-MS: (M + H).sup.+ 295 R.sub.f:
0.50 (silica gel, DCM/MeOH/NH.sub.3 90:10:1)
[0605] 33b) 4,4-difluoro-[1,4']bipiperidinyl
[0606] A solution of 2.8 g (9.5 mmol)
1'-benzyl-4,4-difluoro-[1,4']bipiper- idinyl in 300 mL MeOH was
hydrogenated in the presence of 1.2 g Pd/C (10%) at 50.degree. C.
and 50 psi hydrogen pressure with the addition of a few drops of 1
M HCl until the calculated volume of hydrogen had been taken up.
The catalyst was filtered off and the filtrate was evaporated down
under reduced pressure. The residue was triturated with
diisopropylether, suction filtered and dried.
59 Yield: 0.56 g (29% of theory) ESI-MS: (M + H).sup.+ 204 R.sub.f:
0.10 (silica gel, DCM/MeOH/NH.sub.3 90:10:1)
[0607] 33c)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4,4-difluoro-1,4'-bipipe-
ridinyl-1'-yl)-2-oxo-ethyl]-amide
[0608] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 200 mg
(0.98 mmol) 4,4-difluoro-[1,4']bipiperidinyl.
60 Yield: 270 mg (49% of theory) ESI-MS: (M + H).sup.+ 679 R.sub.f:
0.65 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 34
[0609]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3,4-diethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1--
yl)-2-oxo-ethyl]-amide 183
[0610] Prepared analogously to Example 9i) from 400 mg (0.81 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg
(1.00 mmol) 4-piperidin-4-yl-morpholine.
61 Yield: 330 mg (63% of theory) ESI-MS: (M + H).sup.+ 645 R.sub.f:
0.62 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0611] The following were obtained accordingly:
Example 35
[0612]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-ethyl-piperidin-4-yl)-pi-
perazin-1-yl]-2-oxo-ethyl}-amide
62 184 Yield: 7% of theory ESI-MS: (M + H).sup.+ 672 R.sub.f: 0.60
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 36
[0613]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-2-(4-diethylaminomethyl-piperidin-1-yl)-1-(3,4-diethyl--
benzyl)-2-oxo-ethyl]-amide
63 185 Yield: 15% of theory ESI-MS: (M + H).sup.+ 645 R.sub.f: 0.60
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 37
[0614]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-[-
1,4]diazepan-1-yl]-2-oxo-ethyl}-amide
64 186 Yield: 59% of theory ESI-MS: (M + H).sup.+ 672 R.sub.f: 0.45
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 38
[0615]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
{(R)-1-(3,4-diethyl-benzyl)-2-[3-(4-methyl-piperazin-1-yl)-a-
zetidin-1-yl]-2-oxo-ethyl}-amide
65 187 Yield: 33% of theory ESI-MS: (M + H).sup.+ 630 R.sub.f: 0.53
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 39
[0616]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3-piperidin-1-yl-azetid-
in-1-yl)-ethyl]-amide
66 188 Yield: 42% of theory ESI-MS: (M + H).sup.+ 630 R.sub.f: 0.70
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 40
[0617]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(3-pyrrolidin-1-yl-azeti-
din-1-yl)-ethyl]-amide
67 189 Yield: 49% of theory ESI-MS: (M + H).sup.+ 601 R.sub.f: 0.70
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 41
[0618]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-2-(3-diethylamino-azetidin-1-yl)-1-(3,4-diethyl-benzyl)-
-2-oxo-ethyl]-amide
68 190 Yield: 29% of theory ESI-MS: (M + H).sup.+ 603 R.sub.f: 0.79
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 42
[0619]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic acid
((R)-1-(3,4-diethyl-benzyl)-2-oxo-2-{4-[4-(2,2,2-trifluoro-a-
cetyl)-phenyl]-piperazin-1-yl}-ethyl)-amide
69 191 Yield: 78% of theory ESI-MS: (M + H).sup.+ 733 R.sub.f: 0.20
(silica gel, EtOAc)
Example 43
[0620]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-pipera-
zin-1-yl)-ethyl]-amide 192
[0621] Prepared analogously to Example 14) from 500 mg (1.02 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaze-
pin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 720 mg
(1.20 mmol)
1-(1-benzyl-piperidin-4-yl)-piperazine-tris-trifluoroacetate.
70 Yield: 160 mg (25% of theory) ESI-MS: (M + H).sup.+ 644 R.sub.f:
0.36 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 44
[0622]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-1-(3-aminomethyl-benzylcarbamoyl)-2-(3,4-diethyl-phenyl-
)-ethyl]-amide 193
[0623] A mixture of 500 mg (1.02 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-
-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-ami-
no}-propionic acid, 350 mg (1.09 mmol) TBTU, 0.5 mL (2.8 mmol)
ethyldiisopropylamine and 45 mL THF was stirred for 1 h at RT, then
combined with 290 mg (1.23 mmol) tert-butyl
(3-aminomethyl-benzyl)-carbam- inate and 5 mL DMF and stirred
overnight. The reaction mixture was diluted by the addition of 30
mL EtOAc and extracted with 30 mL 15% K.sub.2CO.sub.3 solution. The
organic phase was dried, evaporated down under reduced pressure and
the residue purified by chromatography on silica gel. The
intermediate product fractions were evaporated down, the residue
remaining (600 mg) was combined with 20 mL DCM and 1.5 mL (19.6
mmol) TFA and stirred overnight. Then the reaction mixture was
poured onto 60 mL 15% K.sub.2CO.sub.3 solution, the organic phase
was separated off, dried and evaporated down under reduced
pressure. The residue remaining was purified by chromatography on
silica gel. The product fractions were evaporated down under
reduced pressure, the residue was triturated with diisopropylether,
suction filtered and dried.
71 Yield: 90 mg (15% of theory) ESI-MS: (M + H).sup.+ 611 R.sub.f:
0.55 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0624] The Following Compounds Were Prepared Analogously:
Example 45
[0625]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-1-(5-amino-pentylcarbamoyl)-2-(3,4-diethyl-phenyl)-ethy-
l]-amide
72 194 Yield: 48% of theory ESI-MS: (M + H).sup.+ 577 R.sub.f: 0.33
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0626] The Following Compounds May be Prepared Analogously:
Example 46
[0627]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(4-amino-butylcarbamoyl)-2-(3,4-diethyl-phenyl)-ethyl-
]-amide 195
Example 47
[0628]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-(3,4-diethyl-phenyl)-1-(5-methylamino-pentylcarbamoyl-
)-ethyl]-amide 196
Example 48
[0629]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1--
(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 197
[0630] 48a) monoethyl
2-acetylamino-2-(5,6,7,8-tetrahydro-naphthalen-2-ylm-
ethyl)-malonate
[0631] 19 mL 6 M NaOH (114 mmol) were added dropwise to a stirred
solution of 38.5 g (106.5 mmol) diethyl
2-acetylamino-2-(5,6,7,8-tetrahydro-naphth-
alen-2-ylmethyl)-malonate in 250 mL EtOH. The reaction mixture was
stirred overnight at RT, the solvent was eliminated under reduced
pressure and the residue was taken up in 250 mL water. With
stirring and cooling with the ice bath 120 mL 1 M HCl were added,
the precipitate was suction filtered, suspended twice with 100 mL
aliquots of water, suction filtered and dried.
73 Yield: 30.1 g (85% of theory) ESI-MS: (M + H).sup.+ 334 R.sub.f:
0.08 (silica gel, DCM/MeOH/NH.sub.3 90:10:1)
[0632] 48b) ethyl
2-acetylamino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-pro-
pionate
[0633] A mixture of 29.2 g (87.6 mmol) monoethyl
2-acetylamino-2-(5,6,7,8--
tetrahydro-naphthalen-2-ylmethyl)-malonate and 400 mL toluene was
refluxed for 5 h. The reaction mixture was then washed with 1 M
NaOH and water, dried and evaporated down under reduced
pressure.
74 Yield: 22.1 g (87% of theory) ESI-MS: (M + H).sup.+ 290 R.sub.f:
0.40 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0634] 48c) ethyl
(R)-2-acetylamino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-
-propionate
[0635] 20 mL Alcalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd)
were added to a solution of 28.3 g (159 mmol) disodium hydrogen
phosphate dihydrate in 500 mL water at a temperature of 37.degree.
C. and by the addition of sodium dihydrogen phosphate the pH was
adjusted to 7.5. Then 22.0 g (76.0 mmol) ethyl
2-acetylamino-3-(5,6,7,8-tetrahydro-naphthalen-2- -yl)-propionate
dissolved in 130 mL acetone was added dropwise at 37.degree. C.
with stirring. The pH value of the reaction mixture was kept in the
range from pH 7.4 to pH 7.6 by the addition of 1 M NaOH. After the
addition had ended the mixture was stirred for 3 h at 37.degree. C.
and overnight at RT. The reaction mixture was extracted three times
with tert-butylmethylether, the combined organic extracts were
washed with 15% K.sub.2CO.sub.3 solution, dried and evaporated down
under reduced pressure.
75 Yield: 10.3 g (47% of theory) ESI-MS: (M + H).sup.+ 290 R.sub.f:
0.75 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2) ee value: 99.8%
[HPLC (Chiralpak AD, 10 .mu.m, 4,6 .times. 250 mm; eluant:
n-hexane/EtOH 90:10)]
[0636] 48d)
(R)-2-amino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionic
Acid
[0637] A mixture of 10.0 g (34.6 mmol) ethyl
(R)-2-acetylamino-3-(5,6,7,8--
tetrahydro-naphthalen-2-yl)-propionate and 120 mL 6 M HCl was
refluxed for 3 h. The reaction mixture was cooled in the ice bath,
the precipitate was suction filtered, washed with water and
diisopropylether and dried.
76 Yield: 8.4 g (95% of theory) ESI-MS: (M + H).sup.+ 220 R.sub.f:
0.10 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0638] 48e) ethyl
(R)-2-amino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propi- onate
[0639] A mixture of 3.7 g (14.5 mmol)
(R)-2-amino-3-(5,6,7,8-tetrahydro-na- phthalen-2-yl)-propionic acid
and 150 mL EtOH was combined with 50 mL ethanolic HCl with
stirring. The reaction mixture was stirred for 2 h, evaporated down
under reduced pressure and the residue was taken up in DCM. The
organic solution was washed with 15% K.sub.2CO.sub.3 solution,
dried and evaporated down under reduced pressure.
77 Yield: 3.3 g (92% of theory) ESI-MS: (M + H).sup.+ 248 R.sub.f:
0.05 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0640] 48f) ethyl
(R)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3--
yl)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-p-
ropionate
[0641] A mixture of 20 mL THF, 1.65 g (6.7 mmol) ethyl
(R)-2-amino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate and
1.25 g (7.6 mmol) CDT was stirred for 1 h in the ice bath and for 1
h at RT. Then 1.70 g (6.9 mmol)
3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiaze- pin-2-one was
added and the mixture was refluxed for 3 h. The reaction mixture
was evaporated down under reduced pressure, the residue combined
with 15% K.sub.2CO.sub.3 solution, the precipitate was suction
filtered and dried.
78 Yield: 3.4 g (98% of theory) ESI-MS: (M + H).sup.+ 519 R.sub.f:
0.47 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0642] 48g)
(R)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pi-
peridine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propion-
ic Acid
[0643] A mixture of 20 mL THF and 3.4 g (6.5 mmol) ethyl
(R)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1--
carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate
was combined with a solution of 0.58 g (13.5 mmol) lithium
hydroxide hydrate in 5 mL water and stirred overnight. The reaction
mixture was evaporated down under reduced pressure, the residue was
taken up in water and acidified by the addition of 1 M HCl. The
precipitate was suction filtered and dried.
79 Yield: 2.9 g (90% of theory) ESI-MS: (M + H).sup.+ 491 R.sub.f:
0.47 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0644] 48h)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic acid
[(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-o-
xo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide
[0645] A mixture of 500 mg (1.02 mmol)
(R)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-
-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahyd-
ro-naphthalen-2-yl)-propionic acid, 350 mg (1.09 mmol) TBTU, 0.19
mL (1.08 mmol) 10 ethyldiisopropylamine and 30 mL THF was stirred
for 30 min at RT, then combined with 195 mg (1.06 mmol)
1-methyl-4-piperidin-4-yl-piper- azin and stirred overnight. The
reaction mixture was poured onto 100 mL of a 15% K.sub.2CO.sub.3
solution and extracted twice with DCM. The combined organic
extracts were dried, evaporated down under reduced pressure and the
residue was purified by chromatography on silica gel. The product
fractions were evaporated down under reduced pressure, the residue
was triturated with diisopropylether, suction filtered and
dried.
80 Yield: 430 mg (64% of theory) ESI-MS: (M + H).sup.+ 656 R.sub.f:
0.49 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0646] The Following Were Obtained Accordingly:
Example 49
[0647]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1--
(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide
81 198 Yield: 52% of theory ESI-MS: (M + H).sup.+ 656 R.sub.f: 0.42
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 50
[0648]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1--
(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide
82 199 Yield: 16% of theory ESI-MS: (M + H).sup.+ 732 R.sub.f: 0.55
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 51
[0649]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1--
(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide
83 200 Yield 42% of theory ESI-MS: (M + H).sup.+ 732 R.sub.f: 0.57
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 52
[0650]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-1-(5,6,7,8-te-
trahydro-naphthalen-2-ylmethyl)-ethyl]-amide 201
[0651] A solution of 100 mg (0.14 mmol)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-be-
nzodiazepin-3-yl)-piperidine-1-carboxylic acid
[(R)-2-[4-(1-benzyl-piperid-
in-4-yl)-piperazin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl-
)-ethyl]-amide (Example 50) in 10 mL MeOH was hydrogenated in the
presence of 20 mg Pd/C (10%) at 50.degree. C. and 3 bar hydrogen
pressure until the calculated volume of hydrogen had been taken up.
The catalyst was filtered off, the solvent eliminated under reduced
pressure and the residue purified by chromatography on silica gel.
The product fractions were evaporated down under reduced pressure
and dried.
84 Yield: 22 mg (25% of theory) ESI-MS: (M + H).sup.+ 642
[0652] The Following Was Obtained Accordingly:
Example 53
[0653]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-te-
trahydro-naphthalen-2-ylmethyl)-ethyl]-amide
85 202 Yield: 10% of theory) ESI-MS: (M + H).sup.+ 642
Example 54
[0654]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic Acid
[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(5-
,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 203
[0655] 54a)
(R)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-pipe-
ridine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionat-
e ethyl A mixture of 15 mL THF, 0.825 g (3.3 mmol) ethyl
(R)-2-amino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate and
0.63 g (3.8 mmol) CDT was stirred for 1 h in the ice bath and for 1
h at RT. Then 0.95 g (3.5 mmol)
3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-c]quinoli- n-2-one was
added and refluxed for 3 h. The reaction mixture was evaporated
down under reduced pressure, the residue combined with 15%
K.sub.2CO.sub.3 solution, the precipitate was suction filtered and
dried.
86 Yield: 1.65 g (91% of theory) MS: (M - H) 540 R.sub.f: 0.30
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0656] 54b)
(R)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-pipe-
ridine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionic
Acid
[0657] A mixture of 15 mL THF and 1.65 g (3.0 mmol) ethyl
(R)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-ca-
rbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate
was combined with a solution of 0.40 g (6.3 mmol) lithium hydroxide
hydrate in 5 mL water and stirred overnight. The reaction mixture
was evaporated down under reduced pressure, the residue was taken
up in water and acidified by the addition of 1 M HCl. The
precipitate was suction filtered and dried.
87 Yield: 1.1 g (70% of theory) ESI-MS: (M + H).sup.+ 514 R.sub.f:
0.14 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0658] 54c)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-
-carboxylic acid
[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-
-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide
[0659] A mixture of 500 mg (0.97 mmol)
(R)-2-{[4-(2-oxo-1,2-dihydro-imidaz-
o[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-
-naphthalen-2-yl)-propionic acid, 350 mg (1.09 mmol) TBTU, 0.19 mL
(1.08 mmol) ethyldiisopropylamine and 30 mL THF was stirred for 30
min at RT, then combined with 195 mg (1.06 mmol)
1-(1-methyl-piperidin-4-yl)-piperaz- ine and stirred overnight. The
reaction mixture was poured onto 100 mL of a 15% K.sub.2CO.sub.3
solution and extracted twice with DCM. The combined organic
extracts were dried, evaporated down under reduced pressure and the
residue was purified by chromatography on silica gel. The product
fractions were evaporated down under reduced pressure, the residue
was triturated with diisopropylether, suction filtered and
dried.
88 Yield: 345 mg (52% of theory) ESI-MS: (M + H).sup.+ 677 R.sub.f:
0.38 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0660] The Following was Obtained Accordingly:
Example 55
[0661]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic Acid
[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5-
,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide
89 204 Yield: 50% of theory ESI-MS: (M + H).sup.+ 753 R.sub.f: 0.49
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 56
[0662]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic Acid
[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetr-
ahydro-naphthalen-2-ylmethyl)-ethyl]-amide 205
[0663] A solution of 300 mg (0.40 mmol)
4-(2-oxo-1,2-dihydro-imidazo[4,5-c-
]quinolin-3-yl)-piperidine-1-carboxylic acid
[(R)-2-[4-(4-benzyl-piperazin-
-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)--
ethyl]-amide in 10 mL MeOH was hydrogenated in the presence of 30
mg Pd/C (10%) at 50.degree. C. and 3 bar hydrogen pressure until
the calculated volume of hydrogen had been taken up. The catalyst
was filtered off, the solvent eliminated under reduced pressure and
the residue purified by chromatography on silica gel. The product
fractions were evaporated down under reduced pressure and
dried.
90 Yield: 80 mg (30% of theory) ESI-MS: (M + H).sup.+ 665
Example 57
[0664]
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-car-
boxylic Acid
[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(-
5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide 206
[0665] 57a) ethyl
(R)-2-{[4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-y-
l)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-pr-
opionate
[0666] A mixture of 15 mL THF, 0.830 g (3.4 mmol) ethyl
(R)-2-amino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate and
0.63 g (3.8 mmol) CDT was stirred for 1 h in the ice bath and for 1
h at RT. Then 0.83 g (3.4 mmol)
5-phenyl-2-piperidin-4-yl-2,4-dihydro-[1,2,4]triaz- ol-3-one was
added and the mixture was refluxed for 3 h. The reaction mixture
was evaporated down under reduced pressure, the residue was
combined with 15% K.sub.2CO.sub.3 solution, the precipitate was
suction filtered and dried.
91 Yield: 1.50 g (86% of theory) ESI-MS: (M - H).sup.- 516 R.sub.f:
0.34 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0667] 57b)
(R)-2-{[4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-pip-
eridine
1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propioni-
c Acid
[0668] Prepared analogously to Example 54b) from 1.50 g (2.9 mmol)
ethyl
(R)-2-{[4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-c-
arbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate.
92 Yield: 0.80 g (56% of theory) ESI-MS: (M + H).sup.+ 490 R.sub.f:
0.15 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0669] 57c)
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine--
1-carboxylic
acid-[(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-ox-
o-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide
[0670] Prepared analogously to Example 54c) from 300 mg (0.61 mmol)
(R)-2-{[4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-c-
arbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionic
acid and 120 mg (0.66 mmol)
1-(1-methylpiperidin-4-yl)-piperazine.
93 Yield: 150 mg (37% of theory) ESI-MS: (M + H).sup.+ 653 Rf: 0.41
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0671] The Following was Obtained Accordingly:
Example 58
[0672]
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-car-
boxylic
acid-[(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(-
5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide
94 207 Yield: 25% of theory ESI-MS: (M + H).sup.+ 729 R.sub.f: 0.54
((silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 59
[0673]
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-car-
boxylic
acid-[(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tet-
rahydro-naphthalen-2-ylmethyl)-ethyl]-amide 208
[0674] A solution of 80 mg (0.11 mmol)
4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,-
4]triazol-1-yl)-piperidine-1-carboxylic acid
[(R)-2-[4-(4-benzyl-piperazin-
-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)--
ethyl]-amide in 10 mL MeOH was hydrogenated in the presence of 10
mg Pd/C (10%) at 50.degree. C. and 3 bar hydrogen pressure until
the calculated volume of hydrogen had been taken up. The catalyst
was filtered off, the solvent eliminated under reduced pressure and
the residue purified by chromatography on silica gel. The product
fractions were evaporated down under reduced pressure and
dried.
95 Yield: 15 mg (22% of theory) ESI-MS: (M + H).sup.+ 641
Example 60
[0675]
(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-
-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pip-
eridine-1-carboxylate 209
[0676] 60a) (R)-3-(3,4-diethyl-phenyl)-2-hydroxy-propionic Acid
[0677] A solution of 3.2 g (47 mmol) sodium nitrite in 20 mL water
was slowly added dropwise with stirring to an ice-cooled mixture of
2.0 g (7.8 mmol) (R)-2-amino-3-(3,4-diethyl-phenyl)-propionic acid
in 60 mL 0.5 M H.sub.2SO.sub.4. The reaction mixture was stirred
for 3 h while cooling with ice and for 3 days at RT, combined with
80 mL diethyl ether, vigorously stirred and the organic phase is
separated off. The aqueous phase was again extracted with 80 mL
diethyl ether, the combined organic phases were dried and
evaporated down under reduced pressure. The residue was purified by
chromatography on silica gel and the product fractions were
evaporated down under reduced pressure.
96 Yield: 0.64 g (37% of theory) ESI-MS: (M - H).sup.- 221
[0678] 60b) benzyl
(R)-2-amino-3-(3,4-diethyl-phenyl)-propionate
[0679] 0.64 g (2.9 mmol)
(R)-3-(3,4-diethyl-phenyl)-2-hydroxy-propionic acid was dissolved
in 10 mL MeOH and 1 mL water and adjusted to a pH of 7.0 by the
addition of 20% Cs.sub.2CO.sub.3 solution. The reaction mixture was
evaporated down, the residue taken up in 10 mL DMF and the solution
was again evaporated down under reduced pressure. The oily residue
was taken up in 10 mL DMF and the ice-cooled solution was combined
with 0.34 mL (2.9 mmol) benzylbromide under an argon atmosphere.
The reaction mixture was stirred for 2 h while cooling with an ice
bath and for two days at RT, then combined with 10 mL water and
extracted twice with 20 mL diethyl ether. The combined organic
phases were dried, evaporated down and purified by chromatography
on silica gel.
97 Yield: 0.67 g (74% of theory) ESI-MS: (M - H).sup.- 311 R.sub.f:
0.40 (silica gel, cyc/EtOAc 8:2)
[0680] 60c)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carbonylchloride
[0681] 6 g (12.1 mmol) phosgene (20 percent by weight in toluene)
were added to a solution of 2.5 g (10.2 mmol)
3-piperidin-4-yl-1,3,4,5-tetrahy- dro-1,3-benzodiazepin-2-one and
2.6 mL (14.9 mmol) ethyldiisopropylamine in 75 mL DCM cooled to
0.degree. C. and the reaction mixture was stirred for 30 min at
this temperature. It was allowed to come up to RT, evaporated down
i.vac. to approx. 50 mL and filtered through silica gel, this was
washed with 200 mL DCM/EtOAc (1:1) and the combined filtrates were
again evaporated down i.vac. The residue was stirred with
diisopropylether, suction filtered and dried i.vac.
98 Yield: 2.42 g (77% of theory) R.sub.f = 0.43 (silica gel,
DCM/EtOAc 1:1)
[0682] 60d) (R)-1-benzyloxycarbonyl-2-(3,4-diethyl-phenyl)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ate
[0683] 87 mg (2.0 mmol) sodium hydride (55% in mineral oil) were
added to an ice-cooled mixture of 600 mg (1.9 mmol) benzyl
(R)-2-amino-3-(3,4-diet- hyl-phenyl)-propionate and 40 mL THF,
stirred for 30 min at RT, cooled in the ice bath and 660 mg (2.1
mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzod-
iazepin-3-yl)-piperidine-1-carbonylchloride in 20 mL THF were added
dropwise within 10 min. The reaction mixture was stirred for a
further 30 min while cooling with ice and for 1 h at RT and then
evaporated down under reduced pressure. The residue was taken up in
EtOAc and purified by chromatography on silica gel.
99 Yield: 0.36 g (32% of theory) ESI-MS: (M + H).sup.+ 584 R.sub.f:
0.56 (silica gel, EtOAc/cyc 2:1)
[0684] 60e) (R)-1-carboxy-2-(3,4-diethyl-phenyl)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxyl-
ate
[0685] A mixture of 350 mg (0.60 mmol)
(R)-1-benzyloxycarbonyl-2-(3,4-diet- hyl-phenyl)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pipe-
ridine-1-carboxylate and 30 mL MeOH was hydrogenated in the
presence of 50 mg Pd/C (5%) at RT and 3 bar hydrogen pressure until
the calculated volume of hydrogen had been taken up. The catalyst
was filtered off, the solvent was eliminated under reduced
pressure.
100 Yield: 0.30 g (100% of theory) ESI-MS: (M + H).sup.+ 494
retention time (HPLC): 8.97 min (method A)
[0686] 60f)
(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pipe-
razin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl-
)-piperidine-1-carboxylate
[0687] A mixture of 150 mg (0.30 mmol)
(R)-1-carboxy-2-(3,4-diethyl-phenyl- )-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-c-
arboxylate, 98 mg (0.30 mmol) TBTU, 0.2 mL (1.1 mmol)
ethyldiisopropylamine and 15 mL THF as well as 3 mL DMF was stirred
for 1 h at RT, then combined with 56 mg (0.30 mmol)
1-(1-methylpiperidin-4-yl)-- piperazin and stirred for 2 h. The
reaction mixture was combined with 30 mL of a semisaturated
NaHCO.sub.3 solution and extracted with 30 mL EtOAc. The organic
phase was dried, evaporated down under reduced pressure and the
residue was purified by chromatography on silica gel. The product
fractions were evaporated down under reduced pressure, the residue
was triturated with diisopropylether, suction filtered and
dried.
101 Yield: 39 mg (20% of theory) ESI-MS: (M + H).sup.+ 659 R.sub.f:
0.37 (silica gel, EtOAc/MeOH/NH.sub.3 80:20:2)
Example 61
[0688]
2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbo-
xylic
acid-[(R)-1-4-diethyl-benzyl)-2-(7-dimethylaminomethyl-1,2,4,5-tetra-
hydro-3-benzazepin-3-yl)-2-o-ethyl]-amide 210
[0689] 61a)
1-(7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-
-2,2,2-trifluoro-ethanone
[0690] 11.7 mL (23.4 mmol) of a 2 M dimethylamine solution in THF
were added to a solution of 4.5 g (16.59 mmol)
3-(2,2,2-trifluoro-acetyl)-2,3,-
4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde in 150 mL THF and
the solution was adjusted to pH 5 with 1 mL glacial acetic acid.
After 30 min 4.62 g (21.79 mmol) sodium triacetoxyborohydride were
added and the reaction mixture was stirred overnight at RT. The
reaction solution was carefully combined with saturated NaHCO.sub.3
solution, stirred for 30 min, exhaustively extracted with EtOAc,
the organic phase was separated off and dried over
Na.sub.2SO.sub.4. After the desiccant and solvent had been
eliminated the desired product was obtained, which was further
reacted without purification.
102 Yield: 4.5 g (90% of theory) ESI-MS: (M + H).sup.+ = 301
R.sub.f = 0.76 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0691] 61b)
dimethyl-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylmethyl)-amine
[0692] 50 mL water and 8.5 g (61.51 mmol) K.sub.2CO.sub.3 were
added to a solution of 4.5 g (14.98 mmol)
1-(7-dimethylaminomethyl-1,2,4,5-tetrahydr-
o-3-benzazepin-3-yl)-2,2,2-trifluoro-ethanone in 50 mL MeOH and the
reaction mixture was stirred for 72 h at RT. The reaction solution
was evaporated down i.vac., the residue was combined with DCM,
filtered to remove insoluble ingredients and evaporated down i.vac.
The desired product was obtained in the form of a light-brown
oil.
103 Yield: 2.9 g (95% of theory) ESI-MS: (M + H).sup.+ = 205
R.sub.f = 0.39 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0693] 61c)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic acid
[(R)-1-(3,4-diethyl-benzyl)-2-(7-dimethylaminomethyl-1,-
2,4,5-tetrahydro-3-benzazepin-3-yl)-2-oxo-ethyl]-amide
[0694] Prepared analogously to Example 34 from
(R)-3-(3,4-diethyl-phenyl)--
2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbo-
nyl]-amino}-propionic acid and
dimethyl-(2,3,4,5-tetrahydro-1H-3-benzazepi-
n-7-ylmethyl)-amine.
104 Yield: 45% of theory ESI-MS: (M + H).sup.+ 679 R.sub.f: 0.56
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 62
[0695]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-(4-azetidin-1-yl-piperidin-1-yl)-1-(3,4-diethyl-benzy-
l)-2-oxo-ethyl]-amide 211
[0696] 62a) 4-azetidin-1-yl-1-benzyl-piperidine
[0697] 1.0 mL (17.5 mmol) glacial acetic acid were added to the
stirred mixture of 3.0 mL (16.5 mmol) 1-benzyl-4-piperidone, 1.0 g
(17.5 mmol) azetidine and 100 mL DCM. Then 6.0 g (39.5 mmol) sodium
triacetoxy-borohydride was added batchwise within one hour while
cooling with an ice bath and the mixture was stirred for a further
12 h at RT. The reaction mixture was extracted with 200 mL EtOAc,
the organic phase was dried, evaporated down under reduced pressure
and the residue was purified by chromatography.
105 Yield: 3.2 g (84% of theory) ESI-MS: (M + H).sup.+ 231 R.sub.f:
0.57 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0698] 62b) 4-azetidin-1-yl-piperidine
[0699] 3.2 g (13.9 mmol) 4-azetidin-1-yl-1-benzyl-piperidine
dissolved in 50 mL MeOH were hydrogenated in the autoclave in the
presence of 0.5 g Pd/C (10%) at 50.degree. C. and 3 bar hydrogen
pressure until the calculated volume of hydrogen had been taken up.
The catalyst was filtered off and the solvent was eliminated under
reduced pressure.
106 Yield: 1.9 g (98% of theory) ESI-MS: (M + H).sup.+ 141 R.sub.f:
0.19 (silica gel, DCM/MeOH/NH.sub.3 75:25:5)
[0700] 62c)
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-
-1-carboxylic acid
[(R)-2-(4-azetidin-1-yl-piperidin-1-yl)-1-(3,4-diethyl--
benzyl)-2-oxo-ethyl]-amide
[0701] Prepared analogously to Example 34 from
(R)-3-(3,4-diethyl-phenyl)--
2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbo-
nyl]-amino}-propionic acid and 4-azetidin-1-yl-piperidine.
107 Yield: 36% of theory ESI-MS: (M + H).sup.+ 615 R.sub.f: 0.53
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 63
[0702]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
[(R)-2-(3-azepan-1-yl-azetidin-1-yl)-1-(3,4-diethyl-benzyl)--
2-oxo-ethyl]-amide 212
[0703] Prepared analogously to Example 34 from
(R)-3-(3,4-diethyl-phenyl)--
2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbo-
nyl]-amino}-propionic acid and
1-azetidin-3-yl-perhydro-azepine.
108 Yield: 37% of theory ESI-MS: (M + H).sup.+ 629 R.sub.f: 0.66
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 64
[0704] ethyl
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahyd-
ro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']-
bipiperidinyl-1-yl]-acetate 213
[0705] Prepared analogously to Example 34 from
(R)-3-(3,4-diethyl-phenyl)--
2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbo-
nyl]-amino}-propionic acid and ethyl
[4,4']bipiperidinyl-1-yl-acetate
109 Yield: 42% of theory ESI-MS: (M + H).sup.+ 729
Example 65
[0706] ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrah-
ydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-pipe-
ridin-4-yl]-piperazin-1-yl}-acetate 214
[0707] Prepared analogously to Example 34 from
(R)-3-(3,4-diethyl-phenyl)--
2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbo-
nyl]-amino}-propionic acid and ethyl
(4-piperidin-4-yl-piperazin-1-yl)-ace- tate
110 Yield: 33% of theory ESI-MS: (M + H).sup.+ 730
Example 66
[0708]
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-
-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']bipipe-
ridinyl-1-yl]-acetic Acid 215
[0709] A mixture of 150 mg (0.21 mmol) ethyl
[1'-((R)-3-(3,4-diethyl-pheny-
l)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rbonyl]-amino}-propionyl)-[4,4']bipiperidinyl-1-yl]-acetate, 20 mL
THF and 2.5 mL 0.1 M NaOH was stirred for 12 h at RT. The organic
solvent was eliminated under reduced pressure and the pH of the
reaction mixture was adjusted to exactly 7.0 by the addition of 0.1
M HCl. The precipitate was suction filtered, washed with a little
water and dried.
111 Yield: 139 mg (90% of theory) ESI-MS: (M + H).sup.+ 701
Example 67
[0710]
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1-
,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin--
4-yl]-piperazin-1-yl}-acetic Acid 216
[0711] Prepared analogously to Example 66 from ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-ben-
zodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]--
piperazin-1-yl}-acetate
112 Yield: 99% of theory ESI-MS: (M + H).sup.+ 702
Example 68
[0712] ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-im-
idazo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperi-
din-4-yl]-piperazin-1-yl}-acetate 217
[0713] Prepared analogously to Example 1i) from
3-piperidin-4-yl-1,3-dihyd- ro-imidazo[4,5-c]quinolin-2-one and
ethyl (4-{1-[(R)-2-amino-3-(3,4-diethy-
l-phenyl)-propionyl]-piperidin-4-yl}-piperazin-1-yl)-acetate
113 Yield: 64% of theory ESI-MS: (M + H).sup.+ 753
Example 69
[0714] ethyl
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imid-
azo[4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']bi-
piperidinyl-1-yl]-acetate 218
[0715] Prepared analogously to Example 1i) from
3-piperidin-4-yl-1,3-dihyd- ro-imidazo[4,5-c]quinolin-2-one and
ethyl {1'-[(R)-2-amino-3-(3,4-diethyl--
phenyl)-propionyl]-[4,4']bipiperidinyl-1-yl}-acetate
114 Yield: 49% of theory ESI-MS: (M + H).sup.+ 752
Example 70
[0716]
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imidazo[-
4,5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin-4--
yl]-piperazin-1-yl}-acetic Acid 219
[0717] Prepared analogously to Example 66 from ethyl
{4-[1-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]-
quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-pi-
perazin-1-yl}-acetate
115 Yield: 42% of theory ESI-MS: (M + H).sup.+ 725
Example 71
[0718]
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,-
5-c]quinolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']bipiperi-
dinyl-1-yl]-acetic Acid 220
[0719] Prepared analogously to Example 66 from ethyl
[1'-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]qu-
inolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4']bipiperidinyl--
1-yl]-acetate
116 Yield: 69% of theory ESI-MS: (M + H).sup.+ 724
Example 72
[0720]
4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carb-
oxylic Acid
{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-pip-
eridin-1-yl]-2-oxo-ethyl}-amide 221
[0721] Prepared analogously to Example 17) from
(R)-2-amino-3-(3,4-diethyl-
-phenyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-propan-1-one
and 3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one
117 Yield: 25% of theory) ESI-MS: (M + H).sup.+ 681
Example 73
[0722]
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-pip-
erazin-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodia-
zepin-3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cyanamide 222
[0723] A mixture of 390 mg (1.01 mmol)
(R)-2-amino-3-(3,4-diethyl-phenyl)--
1-[4-(1-methylpiperidin-4-yl)-piperazin-1-yl]-propan-1-one, 270 mg
(1.01 mmol) diphenylcyano-carbonimidate and 50 mL DCM was stirred
for 4 h at RT and then evaporated down under reduced pressure. The
residue was combined with 30 mL acetonitrile and 270 mg (1.10 mmol)
3-piperidin-4-yl-1,3,4,5-t- etrahydro-1,3-benzodiazepin-2-one and
refluxed for 14 h. The reaction mixture was evaporated down under
reduced pressure and the residue was purified by chromatography.
The product fractions were evaporated down, the residue was
triturated with PE and suction filtered.
118 Yield: 200 mg (29% of theory) ESI-MS: (M + H).sup.+ 682
R.sub.f: 0.33 (silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 74
[0724]
N-[1-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-pip-
eridin-1-yl]-2-oxo-ethylamino}-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodia-
zepin-3-yl)-piperidin-1-yl]-meth-(Z)-ylidene]-cyanamide 223
[0725] Prepared analogously to Example 73 from
3-piperidin-4-yl-1,3,4,5-te- trahydro-benzo[d][1,3]diazepin-2-one
and (R)-2-amino-3-(3,4-diethyl-phenyl-
)-1-[4-(4-methylpiperazin-1-yl)-piperidin-1-yl]-propan-1-one
119 Yield: 26% of theory ESI-MS: (M + H).sup.+ 682 R.sub.f: 0.47
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 75
[0726]
N-[1-[(R)-2-[1,4']bipiperidinyl-1'-yl-1-(3,4-diethyl-benzyl)-2-oxo--
ethylamino]-1-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperid-
in-1-yl]-meth-(Z)-ylidene]-cyanamide 224
[0727] Prepared analogously to Example 73 from
3-piperidin-4-yl-1,3,4,5-te- trahydro-benzo[d][1,3]diazepin-2-one
and (R)-2-amino-1-[1,4']bipiperidinyl-
-1'-yl-3-(3,4-diethyl-phenyl)-propan-1-one
120 Yield: 15% of theory ESI-MS: (M + H).sup.+ 667 R.sub.f: 0.49
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 76
[0728]
1-[1,4']bipiperidinyl-1'-yl-2-(3,4-dimethyl-benzyl)-4-[4-(2-oxo-1,4-
-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione
225
[0729] 76a) tert-butyl
4-(3,4-dimethyl-phenyl)-3,3-bis-ethoxycarbonyl-buta- noate
[0730] 1.56 g (35.7 mmol) sodium hydride (55% in mineral oil) was
added batchwise to the solution of 8.80 mL (34.0 mmol) 4-tert-butyl
2-ethoxycarbonyl-succinate in 140 mL THF while cooling with ice and
the mixture was stirred for 1 h. Then 6.5 g (32.6 mmol)
4-bromomethyl-1,2-dimethyl-benzene dissolved in 70 mL THF was
slowly added dropwise to the ice-cooled mixture and stirred for 1 h
at RT. The reaction mixture was evaporated down under reduced
pressure, the residue was combined with 20% citric acid solution
and extracted three times with EtOAc. The combined organic phases
were dried and evaporated down under reduced pressure.
121 Yield: 11.6 g (91% of theory) R.sub.f: 0.6 (silica gel,
PE/EtOAc/glacial acetic acid 8:2:0.5)
[0731] 76b) 4-(3,4-dimethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic
Acid
[0732] A mixture of 11.6 g (29.5 mmol) tert-butyl
4-(3,4-dimethyl-phenyl)-- 3,3-bis-ethoxycarbonyl-butanoate and 100
mL DCM was combined with 20 mL TFA, the reaction mixture was
stirred for 3 h at RT and evaporated down under reduced
pressure.
122 Yield: 10.0 g (100% of theory) Rf: 0.35 (silica gel,
PE/EtOAc/glacial acetic acid 8:2:0.5)
[0733] 76c) diethyl
2-(3,4-dimethyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihyd-
ro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate
[0734] A mixture of 10.0 g (29.7 mmol)
4-(3,4-dimethyl-phenyl)-3,3-bis-eth- oxycarbonyl-butanoic acid,
10.5 g (32.7 mmol) TBTU, 4.2 g (30.5 mmol) HOBt, 5.8 mL (32.4 mmol)
ethyldiisopropylamine, 270 mL THF and 30 mL water was stirred for
15 min at RT and then combined with 7.6 g (32.9 mmol)
3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one. The reaction
mixture was stirred for 5 h at RT and evaporated down under reduced
pressure. The residue was stirred with 150 mL saturated NaHCO.sub.3
solution, suction filtered, washed with water and dried in the
circulating air dryer.
123 Yield: 15.6 g (96% of theory) R.sub.f: 0.77 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0735] 76d)
2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quina-
zolin-3-yl)-piperidin-1-yl]-butanoic Acid
[0736] A solution of 15.5 g (28.2 mmol) diethyl
2-(3,4-dimethyl-benzyl)-2--
{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}--
malonate in 100 mL EtOH was combined with 11.2 g (169.7 mmol) KOH
dissolved in 150 mL water and the mixture was refluxed for 5 h.
After the addition of another 11.2 g (169.7 mmol) KOH dissolved in
150 mL water the mixture was refluxed again for 5 h, then combined
with 150 mL water and the precipitate was suction filtered. The
filter cake was dissolved in 500 mL water, washed twice with 100 mL
EtOAc and adjusted to pH 4 by the addition of conc. HCl. The
precipitate formed was suction filtered and dried in the
circulating air dryer.
124 Yield: 6.7 g (53% of theory) R.sub.f: 0.18 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0737] 76e)
1-[1,4']bipiperidinyl-1'-yl-2-(3,4-dimethyl-benzyl)-4-[4-(2-ox-
o-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione
[0738] A mixture of 0.9 g (2.0 mmol)
2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-
-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid,
0.71 g (2.2 mmol) TBTU, 0.28 g (2.1 mmol) HOBt, 0.39 mL (2.2 mmol)
ethyldiisopropylamine, 45 mL THF and 5 mL water was stirred for 10
min at RT, combined with 0.37 g (2.1 mmol) [1,4']bipiperidinyl and
stirred for a further 4 h. The reaction mixture was evaporated down
under reduced pressure, the residue was combined with saturated
NaHCO.sub.3 solution and extracted three times with DCM/MeOH
(95:5). The combined organic phases were dried, evaporated down
under reduced pressure and purified by chromatography over silica
gel. The product fractions were evaporated down under reduced
pressure, the residue was triturated with diisopropylether and
suction filtered.
125 Yield: 0.6 g (50% of theory) R.sub.f: 0.52 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 77
[0739]
2-(3,4-dimethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-
-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione
226
[0740] Prepared analogously to Example 76e) from
2-(3,4-dimethyl-benzyl)-4-
-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic
acid and 1-methyl-[4,4']bipiperidinyl
126 Yield: 33% of theory R.sub.f: 0.36 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 78
[0741]
2-(3,4-dimethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1--
yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4--
dione 227
[0742] Prepared analogously to Example 76e) from
2-(3,4-dimethyl-benzyl)-4-
-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic
acid and 1-(1-methyl-piperidin-4-yl)-piperazine.
127 Yield: 27% of theory R.sub.f: 0.35 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 79
[0743]
2-(3,4-dimethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1--
yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4--
dione 228
[0744] Prepared analogously to Example 76e) from
2-(3,4-dimethyl-benzyl)-4-
-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic
acid and 1-methyl-4-piperidin-4-yl-piperazine
128 Yield: 33% of theory R.sub.f: 0.53 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 80
[0745]
2-(3,4-dimethyl-benzyl)-1-[4-(4-ethyl-piperazin-1-yl)-piperidin-1-y-
l]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-d-
ione 229
[0746] Prepared analogously to Example 76e) from
2-(3,4-dimethyl-benzyl)-4-
-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic
acid and 1-ethyl-4-piperidin-4-yl-piperazine
129 Yield: 29% of theory R.sub.f: 0.61 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 81
[0747]
2-(3,4-dimethyl-benzyl)-1-[4-(4-isopropyl-piperazin-1-yl)-piperidin-
-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1-
,4-dione 230
[0748] Prepared analogously to Example 76e) from
2-(3,4-dimethyl-benzyl)-4-
-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic
acid and 1-isopropyl-4-piperidin-4-yl-piperazine
130 Yield: 18% of theory R.sub.f: 0.59 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 82
[0749]
2-(3,4-dimethyl-benzyl)-1-[4-(4-methanesulphonyl-piperazin-1-yl)-pi-
peridin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]--
butan-1,4-dione 231
[0750] Prepared analogously to Example 76e) from
2-(3,4-dimethyl-benzyl)-4-
-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic
acid and 1-methanesulphonyl-4-piperidin-4-yl-piperazine.
131 Yield: 45% of theory R.sub.f: 0.65 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 83
[0751]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
Acid
{1-(3,4-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1--
yl]-2-oxo-ethyl}-amide 232
[0752] 83a) ethyl 2-amino-3-(3,4-dimethyl-phenyl)-propionate
[0753] A mixture of 18.6 g (93.5 mmol)
4-bromomethyl-1,2-dimethyl-benzene, 25.0 g (93.5 mmol) ethyl
(diphenylmethylidene-amino)-acetate, 3.29 g (10.0 mmol)
tetrabutylammonium bromide, 41.3 g (250 mmol)
K.sub.2CO.sub.3x1.5H.sub.2O and 600 mL acetonitrile was refluxed
overnight. The reaction mixture was filtered, the filtrate was
evaporated down under reduced pressure, the residue was taken up in
500 mL diethyl ether and combined with 250 mL semiconc. HCl with
vigorous stirring. Then the organic phase was separated off, the
aqueous phase was extracted twice with diethyl ether and
neutralised by the addition of solid NaHCO.sub.3. The aqueous phase
was extracted by shaking three times with 200 mL EtOAc, the
combined organic phases were washed once with water, dried over
Na.sub.2SO.sub.4, filtered and evaporated down under reduced
pressure.
132 Yield: 11.3 g (55% of theory) R.sub.f: 0.62 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0754] 83b) ethyl
3-(3,4-dimethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quin-
azolin-3-yl)-piperidine-1-carbonyl]-amino}-propionate
[0755] 10.0 g (57.9 mmol) CDT were added to the solution of 11.0 g
(49.7 mmol) ethyl 2-amino-3-(3,4-dimethyl-phenyl)-propionate in 250
mL THF cooled in the ice bath, stirred for 1 h while cooling with
an ice bath and for 1 h at RT. Then 12.7 g (54.7 mmol)
3-piperidin-4-yl-3,4-dihydro-1- H-quinazolin-2-one was added, the
reaction mixture was refluxed for 2.5 h and evaporated down under
reduced pressure. The residue was distributed between saturated
NaHCO.sub.3 solution and EtOAc and the aqueous phase was extracted
twice more with EtOAc. The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and evaporated down under reduced
pressure.
133 Yield: 17.5 g (74% of theory) R.sub.f: 0.6 (silica gel,
DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
[0756] 83c)
3-(3,4-dimethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-
-3-yl)-piperidine-1-carbonyl]-amino}-propionic Acid
[0757] 17.5 g (36.6 mmol) ethyl
3-(3,4-dimethyl-phenyl)-2-{[4-(2-oxo-1,4-d-
ihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionate
dissolved in 100 mL MeOH was combined with 200 mL 1 M NaOH and
stirred overnight at RT. The reaction mixture was filtered, the
filtrate was washed three times with tert-butylmethylether and
combined with 200 mL 1 M HCl. The aqueous phase was extracted three
times with EtOAc, the combined organic phases were dried, filtered
and evaporated down under reduced pressure. The residue was
triturated with diisopropylether, suction filtered, stirred with
diethyl ether and dried at 50.degree. C. in the circulating air
dryer.
134 Yield: 6.0 g (36% of theory)
[0758] 83d)
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyl- ic
Acid
{1-(3,4-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin--
1-yl]-2-oxo-ethyl}-amide
[0759] 0.90 g (2.80 mmol) TBTU, 0.35 g (2.55 mol) HOBt, 0.49 mL
(2.80 mmol) ethyldiisopropylamine was added to a mixture of 1.15 g
(2.55 mol)
3-(3,4-dimethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-pipe-
ridine-1-carbonyl]-amino}-propionic acid and 100 mL THF and the
mixture was stirred for 30 min at RT. Then 20 mL DMF was added, the
mixture was stirred for 15 min and combined with 0.49 g (2.65 mmol)
1-methyl-4-piperidin-4-yl-piperazine. The reaction mixture was
stirred overnight at RT, evaporated down under reduced pressure and
the residue was combined with 70 mL saturated NaHCO.sub.3 solution.
The aqueous phase was extracted three times with DCM, the combined
organic phases were dried over Na.sub.2SO.sub.4, filtered and
evaporated down under reduced pressure. The residue was purified by
column chromatography over silica gel, the product fractions were
evaporated down under reduced pressure, triturated with diethyl
ether and suction filtered.
135 Yield: 0.45 g (29% of theory) EI-MS (M).sup.+ 615 R.sub.f: 0.49
(silica gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 84
[0760]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
Acid
{1-(3,4-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1--
yl]-2-oxo-ethyl}-amide 233
[0761] Prepared analogously to Example 83d) from
3-(3,4-dimethyl-phenyl)-2-
-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1'-carbonyl]-amino}-
-propionic acid and 1-methyl-4-piperidin-4-yl-piperazine
136 Yield: 19% of theory EI-MS (M).sup.+ 615 R.sub.f: 0.25 (silica
gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 85
[0762]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1'-carboxylic
Acid
[1-(3,4-dimethyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-ox-
o-ethyl]-amide 234
[0763] Prepared analogously to Example 83d) from
3-(3,4-dimethyl-phenyl)-2-
-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}--
propionic acid and 1-methyl-[4,4']bipiperidinyl.
137 Yield: 35% of theory EI-MS (M).sup.+ 614 R.sub.f: 0.42 (silica
gel, DCM/MeOH/cyc/NH.sub.3 70:15:15:2)
Example 86
[0764]
2-(3,4-diethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-y-
l]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-d-
ione 235
[0765] 86a) tert-butyl
4-(3,4-diethyl-phenyl)-3,3-bis-ethoxycarbonyl-butan- oate
[0766] Prepared analogously to Example 76a) from 4-tert-butyl
2-ethoxycarbonyl-succinate and
4-bromomethyl-1,2-diethyl-benzene.
138 Yield: 97% of theory R.sub.f: 0.35 (silica gel, PE/EtOAc
4:1)
[0767] 86b) 4-(3,4-diethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic
acid
[0768] Prepared analogously to Example 76b) from tert-butyl
(3,4-diethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoate.
[0769] Yield: 100% of theory
[0770] 86c) diethyl
2-(3,4-diethyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydr-
o-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate
[0771] Prepared analogously to Example 76c) from
4-(3,4-diethyl-phenyl)-3,- 3-bis-ethoxycarbonyl-butanoic acid and
3-piperidin-4-yl-3,4-dihydro-1H-qui- nazolin-2-one.
139 Yield: 50% of theory R.sub.f: 0.6 (silica gel, EtOAc)
[0772] 86d)
2-(3,4-diethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinaz-
olin-3-yl)-piperidin-1-yl]-butanoic Acid
[0773] Prepared analogously to Example 76d) from diethyl
(3,4-diethyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-
-piperidin-1-yl]-ethyl}-malonate
140 Yield: 67% of theory R.sub.f: 0.6 (silica gel, PE/EtOAc/glacial
acetic acid 7:3:0.3)
[0774] 86e)
2-(3,4-diethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidi-
n-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan--
1,4-dione
[0775] Prepared analogously to Example 76e) from
2-(3,4-diethyl-benzyl)-4--
oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic
acid and 1-methyl-4-piperidin-4-yl-piperazine
141 Yield: 16% of theory ESI-MS: (M + H).sup.+ 643 R.sub.f: 0.3
(silica gel, MeOH)
Example 87
[0776]
2-(3,4-diethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-y-
l]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-d-
ione 236
[0777] Prepared analogously to Example 76e) from
2-(3,4-diethyl-benzyl)-4--
oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic
acid and 1-(1-methyl-piperidin-4-yl)-piperazine.
142 Yield: 18% of theory ESI-MS: (M + H).sup.+ 643 R.sub.f: 0.15
(silica gel, MeOH/NH.sub.3 10:0.3)
Example 88
[0778] methyl
{1'-[4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piper-
idin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butyryl]-[4,4']bip-
iperidinyl-1-yl}-acetate 237
[0779] 88a) tert-butyl
3,3-bis-ethoxycarbonyl-4-(5,6,7,8-tetrahydro-naphth-
alen-2-yl)-butanoate
[0780] Prepared analogously to Example 76a) from 4-tert-butyl
2-ethoxycarbonyl-succinate and
6-bromomethyl-1,2,3,4-tetrahydro-naphthale- ne.
143 Yield: 66% of theory
[0781] b)
3,3-bis-ethoxycarbonyl-4-(5,6,7,8-tetrahydro-naphthalen-2-yl)-bu-
tanoic acid
[0782] Prepared analogously to Example 76b) from tert-butyl
3,3-bis-ethoxycarbonyl-4-(5,6,7,8-tetrahydro-naphthalen-2-yl)-butanoate
144 Yield: 100% of theory
[0783] 88c) diethyl
2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-p-
iperidin-1-yl]-ethyl}-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-malonat-
e
[0784] Prepared analogously to Example 76c) from
3,3-bis-ethoxycarbonyl-4--
(5,6,7,8-tetrahydro-naphthalen-2-yl)-butanoic acid and
3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.
145 Yield: 71% of theory
[0785] 88d)
4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1--
yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butanoic Acid
[0786] Prepared analogously to Example 76d) from diethyl
2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethy-
l}-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-malonate.
146 Yield: 95% of theory
[0787] 88e) methyl
{1'-[4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)--
piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butyryl]-[4,4-
']bipiperidinyl-1-yl}-acetate
[0788] Prepared analogously to Example 76e) from
4-oxo-4-[4-(2-oxo-1,4-dih-
ydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen--
2-ylmethyl)-butanoic acid and methyl
[4,4']bipiperidinyl-1-yl-acetate.
147 Yield: 6% of theory EI-MS: (M).sup.+ 697
Example 89
[0789]
{1'-[4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1--
yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butyryl]-[4,4']bipiperidi-
nyl-1-yl}-acetic Acid 238
[0790] Prepared analogously to Example 66) from methyl
{1'-[4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2--
(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butyryl]-[4,4']bipiperidinyl-1--
yl}-acetate
148 Yield: 17% of theory ESI-MS: (M + H).sup.+ 684
Example 90
[0791] methyl
(1'-{2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-qui-
nazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate
239
[0792] 90a) tert-butyl
3,3-bis-ethoxycarbonyl-4-indan-5-yl-butanoate Prepared analogously
to Example 76a) from 4-tert-butyl 2-ethoxycarbonyl-succinate and
5-bromomethyl-indane.
149 Yield: 100% of theory
[0793] 90b) 3,3-bis-ethoxycarbonyl-4-indan-5-yl-butanoic Acid
[0794] Prepared analogously to Example 76b) from tert-butyl
3,3-bis-ethoxycarbonyl-4-indan-5-yl-butanoate
150 Yield: 100% of theory
[0795] 90c) diethyl
2-indan-5-ylmethyl-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-
-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate
[0796] Prepared analogously to Example 76c) from
3,3-bis-ethoxycarbonyl-4-- indan-5-yl-butanoic acid and
3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-- one.
151 Yield: 61% of theory
[0797] 90d)
2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-
-3-yl)-piperidin-1-yl]-butanoic Acid
[0798] Prepared analogously to Example 76d) from diethyl
2-indan-5-ylmethyl-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-p-
iperidin-1-yl]-ethyl}-malonate
152 Yield: 100% of theory
[0799] 90e) methyl
(1'-{2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2-
H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acet-
ate
[0800] Prepared analogously to Example 76e) from and
2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-pipe-
ridin-1-yl]-butanoic acid and methyl
[4,4']bipiperidinyl-1-yl-acetate.
153 Yield: 5% of theory ESI-MS: (M + H).sup.+ 684
Example 91
[0801]
((1'-{2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoli-
n-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic
Acid 240
[0802] Prepared analogously to Example 66) from methyl
(1'-{2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-
-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate
154 Yield: 10% of theory ESI-MS: (M + H).sup.+ 670
Example 92
[0803]
1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihy-
dro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-
-ylmethyl)-butan-1,4-dione 241
[0804] Prepared analogously to Example 76e) from
4-oxo-4-[4-(2-oxo-1,4-dih-
ydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen--
2-ylmethyl)-butanoic acid and
1-methyl-4-piperidin-4-yl-piperazine.
155 Yield: 46% of theory retention time (HPLC): 6.0 min (method
A)
Example 93
[0805]
1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-q-
uinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethy-
l)-butan-1,4-dione 242
[0806] Prepared analogously to Example 76e) from
4-oxo-4-[4-(2-oxo-1,4-dih-
ydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen--
2-ylmethyl)-butanoic acid and 1-methyl-[4,4']bipiperidinyl.
156 Yield: 44% of theory retention time (HPLC): 6.5 min (method
A)
Example 94
[0807]
2-indan-5-ylmethyl-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-
-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione
243
[0808] Prepared analogously to Example 76e) from and
2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-pipe-
ridin-1-yl]-butanoic acid and
1-methyl-4-piperidin-4-yl-piperazine
157 Yield: 51% of theory retention time (HPLC): 5.7 min (method
A)
Example 95
[0809]
2-indan-5-ylmethyl-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-o-
xo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1,4-dione
244
[0810] Prepared analogously to Example 76e) from and
2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-pipe-
ridin-1-yl]-butanoic acid and 1-methyl-[4,4']bipiperidinyl.
158 Yield: 51% of theory retention time (HPLC): 6.2 min (method
A)
[0811] The following compounds may be prepared by the processes
described:
Example 96
[0812]
1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-q-
uinazolin-3-yl)-piperidin-1-yl]-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro--
naphthalen-2-ylmethyl)-butan-1,4-dione 245
Example 97
[0813]
1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihy-
dro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,5,8,8-tetramethyl-5,6,7,8-tet-
rahydro-naphthalen-2-ylmethyl)-butan-1,4-dione 246
Example 98
[0814]
1-[1,4']bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-
-yl)-piperidin-1-yl]-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen--
2-ylmethyl)-butan-1,4-dione 247
Example 99
[0815]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
{(R)-1-(3,4-bis-pentafluoroethyl-benzyl)-2-[4-(4-methyl-pipe-
razin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 248
Example 100
[0816]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
{(R)-1-(3-ethyl-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1--
yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 249
Example 101
[0817]
(R)-1-(3,4-diethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl-
)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-c-
arboxylate 250
Example 102
[0818]
(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-ethyl-piperidin-4-yl)-piperazin--
1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-pipe-
ridine-1-carboxylate 251
Example 103
[0819]
(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(5,6,7,8-tetrahydro-
-naphthalen-2-ylmethyl)-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepi-
n-3-yl)-piperidine-1-carboxylate 252
Example 104
[0820]
(S)-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzo-
diazepin-3-yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1-yl)-butan-1-
,4-dione 253
Example 105
[0821]
(S)-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzo-
diazepin-3-yl)-piperidin-1-yl]-1'-(4-piperidin-4-yl-piperazin-1-yl)-butan--
1,4-dione 254
Example 106
[0822]
(S)-2-(3,4-diethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-
-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1--
yl]-butan-1,4-dione 255
Example 107
[0823]
(S)-2-(3,4-diethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-
-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1--
yl]-butan-1,4-dione 256
Example 108
[0824]
(S)-1-[1,4']bipiperidinyl-1'-yl-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo--
1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butan-1,4-dione
257
Example 109
[0825]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic Acid
{(R)-1-(3,4-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piper-
azin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 258
Example 110
[0826]
(S)-2-(3,4-bis-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-y-
l)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)--
piperidin-1-yl]-butan-1,4-dione 259
Example 111
[0827]
(R)-1-(3,4-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-y-
l)-piperidin-1-yl]-2-oxo-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazep-
in-3-yl)-piperidine-1-carboxylate 260
Example 112
[0828]
(S)-2-(3,4-diethyl-benzyl)-1-(4-dimethylamino-piperidin-1-yl)-4-[4--
(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butan-1,-
4-dione 261
Example 113
[0829]
(R)-1-(3,4-diethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-
-ethyl
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylate 262
Example 114
[0830] 5
[(R)-2-(4-amino-piperidin-1-yl)-1-(3,4-diethyl-benzyl)-2-oxo-ethy-
l]-amide
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1--
carboxylate 263
Example 115
[0831]
4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic
Acid
[2-[1,4']bipiperidinyl-1'-yl-1-(3,4-dimethyl-benzyl)-2-oxo-ethyl]-am-
ide 264
Example 116
[0832] 5
(S)-2-(3,4-diethyl-benzyl)-1-(1'-methyl-4,4'-bipiperidinyl-1-yl)--
4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-but-
an-1,4-dione 265
Example 117
[0833]
(S)-1-4,4'-bipiperidinyl-1-yl-2-(3,4-diethyl-benzyl)-4-[4-(2-oxo-1,-
2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butan-1,4-dione
266
Example 118
[0834]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(4-ethyl-3-trifluoromethyl-benzyl)-2-[4-(4-methyl-pip-
erazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 267
Example 119
[0835]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(4-ethyl-3-trifluoromethyl-benzyl)-2-[4-(1-methyl-pip-
eridin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 268
Example 120
[0836]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(4-ethyl-3-trifluoromethyl-benzyl)-2-(1'-methyl-4,4'--
bipiperidinyl-1-yl)-2-oxo-ethyl]-amide 269
Example 121
[0837]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(4-ethyl-3-trifluoromethyl-
-benzyl)-2-oxo-ethyl]-amide 270
Example 122
[0838]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4-ethyl-3-trifluo-
romethyl-benzyl)-2-oxo-ethyl]-amide 271
Example 123
[0839]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3-ethyl-4-trifluoromethyl-benzyl)-2-[4-(4-methyl-pip-
erazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide 272
Example 124
[0840]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-{(R)-1-(3-ethyl-4-trifluoromethyl-benzyl)-2-[4-(1-methyl-pip-
eridin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide 273
Example 125
[0841]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-1-(3-ethyl-4-trifluoromethyl-benzyl)-2-(1'-methyl-4,4'--
bipiperidinyl-1-yl)-2-oxo-ethyl]-amide 274
Example 126
[0842]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-1,4'-bipiperidinyl-1'-yl-1-(3-ethyl-4-trifluoromethyl-
-benzyl)-2-oxo-ethyl]-amide 275
Example 127
[0843]
4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-ca-
rboxylic
acid-[(R)-2-(4-dimethylamino-piperidin-1-yl)-1-(3-ethyl-4-trifluo-
romethyl-benzyl)-2-oxo-ethyl]-amide 276
[0844] The following Examples describe the preparation of
pharmaceutical formulations which contain as active substance any
desired compound of general formula (I):
Example I
[0845]
159 Capsules for powder inhalation containing 1 mg of active
ingredient Composition: 1 capsule for powder inhalation contains:
active ingredient 1.0 mg lactose 20.0 mg hard gelatine capsules
50.0 mg 71.0 mg
[0846] Method of Preparation:
[0847] The active ingredient is ground to the particle size
required for inhaled substances. The ground active ingredient is
homogeneously mixed with the lactose. The mixture is transferred
into hard gelatine capsules.
Example II
[0848]
160 Inhalable solution for Respimat .RTM. containing 1 mg of active
ingredient Composition: 1 puff contains: active ingredient 1.0 mg
benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg purified
water ad 15.0 .mu.l
[0849] Method of Preparation:
[0850] The active ingredient and benzalkonium chloride are
dissolved in water and transferred into Respimat.RTM.
cartridges.
Example III
[0851]
161 Inhalable solution for nebulisers containing 1 mg of active
ingredient Composition: 1 vial contains: active ingredient 0.1 g
sodium chloride 0.18 g benzalkonium chloride 0.002 g purified water
ad 20.0 ml
[0852] Method of Preparation:
[0853] The active ingredient, sodium chloride and benzalkonium
chloride are dissolved in water.
Example IV
[0854]
162 Propellant gas-operated metering aerosol containing 1 mg of
active ingredient Composition: 1 puff contains: active ingredient
1.0 mg lecithin 0.1% propellant gas ad 50.0 .mu.l
[0855] Method of Preparation:
[0856] The micronised active ingredient is homogeneously suspended
in the mixture of lecithin and propellant gas. The suspension is
transferred into a pressurised container with a metering valve.
Example V
[0857]
163 Nasal spray containing 1 mg of active ingredient Composition:
active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium
chloride 0.025 mg disodium edetate 0.05 mg purified water ad 0.1
ml
[0858] Method of Preparation:
[0859] The active ingredient and the excipients are dissolved in
water and transferred into a suitable container.
Example VI
[0860]
164 Injectable solution containing 5 mg of active substance per 5
ml Composition: active substance 5 mg glucose 250 mg human serum
albumin 10 mg glycofurol 250 mg water for injections ad 5 ml
[0861] Preparation:
[0862] Glycofurol and glucose are dissolved in water for injections
(WfI); human serum albumin is added; active ingredient is dissolved
with heating; made up to specified volume with WfI; transferred
into ampoules under nitrogen gas.
Example VII
[0863]
165 Injectable solution containing 100 mg of active substance per
20 ml Composition: active substance 100 mg monopotassium dihydrogen
phosphate = 12 mg KH.sub.2PO.sub.4 disodium hydrogen phosphate = 2
mg Na.sub.2HPO.sub.4.2H.sub.2O sodium chloride 180 mg human serum
albumin 50 mg Polysorbate 80 20 mg water for injections ad 10
ml
[0864] Preparation:
[0865] Polysorbate 80, sodium chloride, monopotassium dihydrogen
phosphate and disodium hydrogen phosphate are dissolved in water
for injections (WfI); human serum albumin is added; active
ingredient is dissolved with heating; made up to specified volume
with WfI; transferred into ampoules.
Example VIII
[0866]
166 Lyophilisate containing 10 mg of active substance Composition:
Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg
water for injections ad 2 ml
[0867] Preparation:
[0868] Mannitol is dissolved in water for injections (WfI); human
serum albumin is added; active ingredient is dissolved with
heating; made up to specified volume with WfI; transferred into
vials; freeze-dried.
167 Solvent for lyophilisate: Polysorbate 80 = Tween 80 20 mg
mannitol 200 mg water for injections ad 10 ml
[0869] Preparation:
[0870] Polysorbate 80 and mannitol are dissolved in water for
injections (WfI); transferred into ampoules.
Example IX
[0871]
168 Tablets containing 20 mg of active substance Composition:
active substance 20 mg lactose 120 mg maize starch 40 mg magnesium
stearate 2 mg Povidone K 25 18 mg
[0872] Preparation:
[0873] Active substance, lactose and maize starch are homogeneously
mixed; granulated with an aqueous solution of Povidone; mixed with
magnesium stearate; compressed in a tablet press; weight of tablet
200 mg.
Example X
[0874]
169 Capsules containing 20 mg active substance Composition: active
substance 20 mg maize starch 80 mg highly dispersed silica 5 mg
magnesium stearate 2.5 mg
[0875] Preparation:
[0876] Active substance, maize starch and silica are homogeneously
mixed; mixed with magnesium stearate; the mixture is packed into
size for 3 hard gelatine capsules in a capsule filling machine.
Example XI
[0877]
170 Suppositories containing 50 mg of active substance Composition:
active substance 50 mg hard fat (Adeps solidus) q.s. ad 1700 mg
[0878] Preparation:
[0879] Hard fat is melted at about 38.degree. C.; ground active
substance is homogeneously dispersed in the molten hard fat; after
cooling to about 35.degree. C. it is poured into chilled
moulds.
Example XII
[0880]
171 Injectable solution containing 10 mg of active substance per 1
ml Composition: active substance 10 mg mannitol 50 mg human serum
albumin 10 mg water for injections ad 1 ml
[0881] Preparation:
[0882] Mannitol is dissolved in water for injections (WfI); human
serum albumin is added; active ingredient is dissolved with
heating; made up to specified volume with WfI; transferred into
ampoules under nitrogen gas.
* * * * *