U.S. patent application number 10/208253 was filed with the patent office on 2004-02-12 for use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine acid amides in the treatment of tumors or for immunosuppression.
This patent application is currently assigned to Klinge Pharma GmbH. Invention is credited to Biedermann, Elfi, Hasmann, Max, Loser, Roland, Rattel, Benno, Reiter, Friedemann, Schein, Barbara, Seibel, Klaus, Vogt, Klaus.
Application Number | 20040029861 10/208253 |
Document ID | / |
Family ID | 8166665 |
Filed Date | 2004-02-12 |
United States Patent
Application |
20040029861 |
Kind Code |
A1 |
Biedermann, Elfi ; et
al. |
February 12, 2004 |
Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine acid
amides in the treatment of tumors or for immunosuppression
Abstract
The invention relates to the use of pharmacologically valuable
pyridyl alkane, pyridyl alkene and/or pyridyl alkine acid amides
according to general formula (I) in the treatment of tumors or for
immunosuppression. 1
Inventors: |
Biedermann, Elfi;
(Vaterstetten, DE) ; Hasmann, Max; (Neuried,
DE) ; Loser, Roland; (Feldafing, DE) ; Rattel,
Benno; (Munich, DE) ; Reiter, Friedemann;
(Putzbrunn, DE) ; Schein, Barbara; (Neufahrn,
DE) ; Seibel, Klaus; (Grafelfing, DE) ; Vogt,
Klaus; (Munich, DE) |
Correspondence
Address: |
FITCH EVEN TABIN AND FLANNERY
120 SOUTH LA SALLE STREET
SUITE 1600
CHICAGO
IL
60603-3406
US
|
Assignee: |
Klinge Pharma GmbH
|
Family ID: |
8166665 |
Appl. No.: |
10/208253 |
Filed: |
July 30, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10208253 |
Jul 30, 2002 |
|
|
|
09216482 |
Dec 18, 1998 |
|
|
|
6451816 |
|
|
|
|
09216482 |
Dec 18, 1998 |
|
|
|
PCT/EP97/03244 |
Jun 20, 1997 |
|
|
|
Current U.S.
Class: |
514/211.15 ;
514/235.5; 514/332; 514/340 |
Current CPC
Class: |
A61K 31/553 20130101;
C07D 413/12 20130101; C07D 451/02 20130101; C07D 491/04 20130101;
C07D 401/14 20130101; A61K 31/519 20130101; A61K 31/4427 20130101;
A61K 31/55 20130101; A61K 31/4439 20130101; A61K 31/5377 20130101;
A61K 31/4545 20130101; A61K 31/444 20130101; C07D 401/12 20130101;
C07D 405/14 20130101; A61K 31/675 20130101; A61K 31/4709 20130101;
A61K 31/4725 20130101; C07D 409/14 20130101; C07F 9/59
20130101 |
Class at
Publication: |
514/211.15 ;
514/235.5; 514/332; 514/340 |
International
Class: |
A61K 031/553; A61K
031/5377; A61K 031/444; A61K 031/4439 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 1997 |
DE |
196 24 668.7 |
Claims
1. Use of one or more of the compounds of formula (I) 547wherein
R.sup.1 hydrogen, halogen, cyano, trifluoromethyl, hydroxy,
benzyloxy, aminocarbonyl, carboxy, phenyl, phenoxy, phenylthio,
pyridyloxy, pyridylthio, alkyl, especially C.sub.1-C.sub.6-alkyl,
alkenyl, especially C.sub.3-C.sub.6-alkenyl, alkinyl, especially
C.sub.3-C.sub.6-alkinyl, hydroxyalkyl, especially
C.sub.1-C.sub.6-hydroxyalkyl, alkoxy, especially
C.sub.1-C.sub.6-alkoxy, alkenyloxy, especially
C.sub.3-C.sub.6-alkenyloxy- , alkinyloxy, especially
C.sub.3-C.sub.6-alkinyloxy, alkanoyloxy, especially
C.sub.1-C.sub.7-alkanoyloxy, alkoxycarbonyloxy, especially
C.sub.2-C.sub.7-alkoxycarbonyloxy, alkylthio, especially
C.sub.1-C.sub.6-alkylthio, alkenylthio, especially
C.sub.3-C.sub.6-alkenylthio, alkinylthio, especially
C.sub.3-C.sub.6-alkinylthio, cycloalkyl, especially
C.sub.3-C.sub.8-cycloalkyl, cycloalkyloxy, especially
C.sub.3-C.sub.8-cycloalkyloxy, cycloalkylthio, especially
C.sub.3-C.sub.8-cycloalkylthio, alkoxycarbonyl, especially
C.sub.2-C.sub.7-alkoxycarbonyl, alkylaminocarbonyl, especially
C.sub.2-C.sub.7-alkylaminocarbonyl, dialkylaminocarbonyl,
especially C.sub.3-C.sub.13-dialkylaminocarbonyl, or NRSR.sup.6,
wherein R.sup.5 and R.sup.6 are selected independently of each
other from hydrogen, alkyl, especially C.sub.1-C.sub.6-alkyl,
alkenyl, especially C.sub.3-C.sub.6-alkenyl and alkinyl, especially
C.sub.3-C.sub.6-alkinyl, R.sup.2 is hydrogen, halogen, cyano,
hydroxy, trifluoromethyl, benzyloxy, alkyl, especially
C.sub.1-C.sub.6-alkyl, alkoxy, especially C.sub.1-C.sub.6-alkoxy or
alkanoyloxy, especially C.sub.1-C.sub.7-alkanoy- loxy, wherein
R.sup.1 and R.sup.2, if they are adjacent, optionally form a bridge
which is selected from --(CH.sub.2).sub.4--, --(CH.dbd.C).sub.2--
and --CH.sub.2O--CR.sup.7R.sup.8--O--, wherein R.sup.7 and R.sup.8
are, independently of each other, hydrogen or alkyl, especially
C.sub.1-C.sub.6-alkyl, R.sup.3 is hydrogen, halogen, alkyl,
especially C.sub.1-C.sub.6-alkyl, trifluoromethyl or hydroxyalkyl,
especially C.sub.1-C.sub.6-hdroxyalkyl and R.sup.4 is hydrogen,
hydroxy, benzyloxy, alkyl, especially C.sub.1-C.sub.6-alkyl,
alkenyl, especially C.sub.3-C.sub.6-alkenyl, alkinyl, especially
C.sub.3-C.sub.6-alkinyl, cycloalkyl, especially
C.sub.3-C.sub.6-cycloalkyl or alkoxy, especially
C.sub.1-C.sub.6-alkoxy, k is 0 or 1, A is alkylene, especially
C.sub.1-C.sub.6-alkylene, which is optionally substituted once to
three-fold by alkyl, especially C.sub.1-C.sub.3-alkyl, hydroxy,
alkoxy, especially C.sub.1-C.sub.3-alkoxy, fluorine or phenyl, or
1,2-cyclopropylene or alkenylene with at least than two C-atoms,
especially C.sub.2-C.sub.6-alkenylene, which is optionally
substituted once to three-fold by C.sub.1-C.sub.3-alkyl, hydroxy,
C.sub.1-C.sub.3-alkoxy, fluorine, cyano or phenyl, alkadienylene
with at least four C-atoms, especially
C.sub.4-C.sub.6-alkadienylene, which is optionally substituted once
or twice by C.sub.1-C.sub.3-alkyl, fluorine, cyano or phenyl,
1,3,5-hexatrienylene, which is optionally substutited by
C.sub.1-C.sub.3-alkyl, fluorine, cyano, or phenyl, ethinylene or
alkylene with at least two C-atoms, especially
C.sub.2-C.sub.6-alkylene in which a methylene unit can be
isosterically replaced by O, S, NR.sup.9, CO, SO or SO.sub.2,
wherein the substitution, with the exception of .dbd.CO, cannot be
adjacent to the amide group and wherein R.sup.9 is selected from
hydrogen, alkyl, especially C.sub.1-C.sub.6-alkyl, alkenyl,
especially C.sub.3-C.sub.6-alkenyl, alkinyl, especially
C.sub.3-C.sub.6-alkinyl, acyl, especially C.sub.1-C.sub.6-acyl or
alkylsulfonyl, especially C.sub.1-C.sub.6-alkylsulfonyl, D is
selected from alkylene, especially C.sub.1-C I-alkylene, optionally
substituted once or twice by alkyl, especially
C.sub.1-C.sub.6-alkyl, hydroxy, or alkoxy, especially
C.sub.1-C.sub.6-alkoxy, alkenylene with at least two C-atoms,
especially C.sub.2-C.sub.10-alkenylene, which is optionally
substituted once or twice by alkyl, especially
C.sub.1-C.sub.6-alkyl, hydroxy, or alkoxy, especially
C.sub.1-C.sub.6-alkoxy, wherein the double bond can also be to ring
E, alkinylene with at least three C-atoms, especially
C.sub.3-C.sub.10-alkinylene, optionally substituted once or twice
by alkyl, especially C.sub.1-C.sub.6-alkyl, hydroxy or alkoxy,
especially C.sub.1-C.sub.6-alkoxy, and alkylene, especially
C.sub.1-C.sub.10-alkylen- e, alkenylene with at least two C-atoms,
especially C.sub.2-C.sub.1-alkenylene or alkinylene with at least
three C-atoms, especially C.sub.3-C.sub.1-alkinylene, whereby one
to three methylene units are each isosterically replaced by O, S,
NR.sup.10, CO, SO or SO.sub.2 wherein R.sup.10 has the same meaning
as R.sup.9 but is selected independently thereof, E is selected
from 548 wherein the heterocyclic ring can also optionally have a
double bond and n and p can be, independently of one another 0, 1,
2 or 3, with the proviso that n+p.ltoreq.4 and q is 2 or 3,
R.sup.11 is hydrogen, alkyl, especially C.sub.1-C.sub.6-alkyl,
hydroxy, hydroxymethyl, carboxy or alkoxycarbonyl with at least two
C-atoms, especially C.sub.2-C.sub.7-alkoxycarbonyl and R.sup.12 is
hydrogen, alkyl, especially C.sub.1-C.sub.6-alkyl or or an oxo
group adjacent to the nitrogen atom, wherein R.sup.11 and R.sup.12
optionally together, form an alkylene bridge with 1, 2, 3, 4 or 5
C-atoms, especially a C.sub.1-C.sub.3-alkylene bridge under
formation of a bicyclic ring system, G is selected from hydrogen,
G1, G2, G3, G4 and GS, wherein G1 represents the residue
--(CH.sub.2).sub.r--(CR.sup.14R.sup- .16).sub.s--R.sup.13 (G1)
wherein r is an integer from 1 to 3 or 0 and s is 0 or 1, R.sup.13
is selected from hydrogen, alkyl, especially C.sub.1-C.sub.6-alkyl,
alkenyl with at least three C-atoms, especially
C.sub.3-C.sub.6-alkenyl, alkinyl with at least three C-atoms,
especially C.sub.3-C.sub.6-alkinyl, cycloalkyl with at least three
C-atoms, especially C.sub.3-C.sub.8-cycloalkyl, saturated, five to
seven membered heterocycles, which can contain one or two
hetero-atoms from the group N and/or S and/or O, benzyl or phenyl,
monocyclic aromatic five or six-membered heterocycles, which can
contain one to three hetero-atoms from the group N and/or S and/or
O and are either bound directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein the linkage can occur either over an
aromatic or a hydrated ring and either directly or over a methylene
group, anellated bi- and tricyclic aromatic or partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms can be selected from
N and/or S and/or O and the linkage can occur either over an
aromatic or a hydrated ring and either directly or over a methylene
group, R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof, R.sup.15 is selected from hydrogen, hydroxy,
methyl, benzyl, phenyl, monocyclic aromatic five- or six-membered
heterocycles, which can contain one to three hetero-atoms selected
from the group N and/or S and/or O and are either bound directly or
over a methylene group, anellated bi- and tricyclic aromatic or
partially hydrated carbocyclic ring systems with 8 to 16 ring atoms
and at least one aromatic ring, wherein the linkage can occur
either over an aromatic or a hydrated ring and either directly or
over a methylene group, anellated bi- and tricyclic aromatic or
partially hydrated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein one to three ring
atoms can be selected from N and/or S and/or O and the linkage can
occur either over an aromatic or a hydrated ring and either
directly or over a methylene group, G2 is the residue 549 wherein
the substituents R.sup.13 and R.sup.15 can have the above meaning
or the grouping NR.sup.13R.sup.15 can also be a nitrogen
heterocycle bound over the nitrogen atom, selected from saturated
or unsaturated monocyclic, four- to eight-membered heterocycles,
which, aside from the essential nitrogen atom, can optionally
contain one or two further hetero-atoms selected from the group N
and/or S and/or O, or saturated or unsaturated bi- or tricyclic,
anellated or bridged heterocycles with 8 to 16 ring atoms, which,
aside from the essential nitrogen atom, can optionally contain one
or two further hetero-atoms selected from the group N and/or S
and/or O, G3 is the residue --SO.sub.2 (CH.sub.2).sub.r R.sup.13
(G3) and G4 is the residue 550 wherein Ar.sup.1 and Ar.sup.2 are
selected independendy from one another from phenyl, pyridyl or
naphthyl and G.sub.5 is the residue --COR.sup.16 (G5) wherein
R.sup.16 is selected from trifluoromethyl, alkoxy, especially
C.sub.1-C.sub.6-alkoxy, alkenyloxy, especially
C.sub.3-C.sub.6-alkenyloxy- , or benzyloxy, wherein any aryl
residues and/or aromatic ring systems in the substituents R.sup.1,
R.sup.2, R.sup.4, R.sup.13, R.sup.14, R.sup.15, R.sup.16, Ar.sup.1
and Ar.sup.2 and/or in the ring system --NR.sup.13R.sup.15 can be
substituted independently from each other by one to three of the
same or different residues which are selected from halogen, cyano,
alkyl, especially C.sub.1-C.sub.6-alkyl, trifluoromethyl,
cycloalkyl, especially C.sub.3-Cg-cycloalkyl, phenyl, benzyl,
hydroxy, alkoxy, especially C.sub.1-C.sub.6-alkoxy, alkoxy,
substituted entirely or partially by fluorine, substituted alkoxy,
especially C.sub.1-C.sub.6-alkoxy, benzyloxy, phenoxy, mercapto,
alkylthio, especially C.sub.1-C.sub.6-alkylthio, carboxy,
alkoxycarbonyl, especially C.sub.1-C.sub.6-alkoxycarbonyl,
benzyloxycarbonyl, nitro, amino, monoalkylamino, especially
mono-C.sub.1-C.sub.6-alkylamino, dialkylamino, especially
di-(C.sub.1-C.sub.6-alkyl)-amino and methylenedioxy for two
adjacent groups on the aromatic ring or ring system, wherein each
of the residues alkyl, alkenyl, alkinyl, hydroxyalkyl, alkoxy,
alkenyloxy, alkinyloxy, alkanoyloxy, alkoxycarbonyl,
alkoxycarbonyloxy, alkylthio, alkenylthio, alkinylthio, alkylene,
acyl, alkylsulfonyl, alkenylene, alkinylene, cycloalkyl,
cycloalkyloxy, alkoxycarbonyl, alkylaminocarbonyl or
dialkylaminocarbonyl of the substituents R.sup.1 to R.sup.14 can
have 1 to 2 or 4, 6, 8, 10 or 12 C-atoms and/or 2 or 3 to 5, 7, 9,
11 or 13 and/or 15 C-atoms or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
or 15 C-atoms depending on the structure, as well as stereoisomers
and/or mixtures thereof and pharmacologically acceptable acid
addition salts thereof for the production of medicaments for
cytostatic or immunomodulatory and/or immunosuppressive
treatment.
2. Use according to claim 1, characterized in that compounds used
in the production of medicaments are contained in formula (I)
551wherein R.sup.1 is a hydrogen, halogen, cyano,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkinyl, trifluoromethyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.6-hydroxyalkyl, hydroxy,
C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkinyloxy, benzyloxy, C.sub.1-C.sub.7-alkanoyloxy,
C.sub.2-C.sub.7-alkoxycarbonyloxy, C.sub.1-C.sub.6-alkylthio,
C.sub.3-C.sub.6-alkenylthio, C.sub.3-C.sub.6-alkinylthio,
C.sub.3-C.sub.8-cycloalkyloxy, C.sub.3-C.sub.8-cycloalkylthio,
C.sub.2-C.sub.7-alkoxycarbonyl, aminocarbonyl,
C.sub.2-C.sub.7-alkylamino- carbonyl,
C.sub.3-C.sub.13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy,
phenylthio, pyridyloxy, pyridylthio, or NR.sup.5R.sup.6, wherein
R.sup.5 and R.sup.6 are selected independently from each other from
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl and
C.sub.3-C.sub.6-alkinyl, R.sup.2 is hydrogen, halogen, cyano,
C.sub.1-C.sub.6-alkyl, trifluoromethyl, hydroxy,
C.sub.1-C.sub.6-alkoxy, benzyloxy or C.sub.1-C.sub.7-alkanoyloxy,
wherein R.sup.1 and R.sup.2, in case they are adjacent, optionally
form a bridge which is selected from the bridge members
--(CH.sub.2).sub.4-- and --(CH.dbd.CH).sub.2-- and
--CH.sub.2O--CR.sup.7R.sup.8--O--, wherein R.sup.7 and R.sup.8 are,
independently from each other, hydrogen or C.sub.1-C.sub.6-alkyl,
R.sup.3 is hydrogen, halogen, C.sub.1-C.sub.6-alkyl,
trifluoromethyl or C.sub.1-C.sub.6-hydroxyalkyl and R.sup.4 is
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkinyl, C.sub.3-C.sub.6-cycloalkyl, hydroxy,
C.sub.1-C.sub.6-alkoxy or benzyloxy, k is 0 or 1, A is
C.sub.1-C.sub.6-alkylene, which is optionally substituted once to
three-fold by C.sub.1-C.sub.3-alkyl, hydroxy,
C.sub.1-C.sub.3-alkoxy, fluorine or phenyl, or 1,2-cyclopropylene
or C.sub.2-C.sub.6-alkenylene, which is optionally substituted once
to three-fold by C.sub.1-C.sub.3-alkyl, hydroxy,
C.sub.1-C.sub.3-alkoxy, fluorine, cyano or phenyl,
C.sub.4-C.sub.6-alkadienylene, which is optionally substituted once
or twice by C.sub.1-C.sub.3-alkyl, fluorine, cyano or phenyl
1,3,5-hexatrienylene, which is optionally substituted by
C.sub.1-C.sub.3-alkyl, fluorine, cyano or phenyl ethynylene or
C.sub.2-C.sub.6-alkylene, wherein a methylene unit can be
isosterically replaced by O, S, NR.sup.9, CO, SO or SO.sub.2,
wherein the isosteric substitution, with the exception of CO,
cannot be adjacent to the amide group, and R.sup.9 is selected from
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkinyl, C.sub.1-C.sub.6-acyl or
C.sub.1-C.sub.6-alkylsulfonyl, D is selected from
C.sub.1-C.sub.6-alkylen- e, optionally substituted once or twice by
C.sub.1-C.sub.6-alkyl, hydroxy, or C.sub.1-C.sub.6-alkoxy,
C.sub.2-C.sub.10-alkenylene, which is optionally substituted once
or twice by C.sub.1-C.sub.6-alkyl, hydroxy, or
C.sub.1-C.sub.6-alkoxy, wherein the double bond can also be to ring
E, C.sub.3-C.sub.1-alkinylene, optionally substituted once or twice
by C.sub.1-C.sub.6-alkyl, hydroxy, or C.sub.1-C.sub.6-alkoxy, and
C.sub.1-C.sub.10-alkylene, C.sub.2-C.sub.10-alkenylene or
C.sub.3-C.sub.10-alkinylene, wherein one to three methylene units
are each isosterically replaced by O, S, NR.sup.10, CO, SO or
SO.sub.2, wherein R.sup.10 has the same meaning as R.sup.9, but is
selected independently therefrom, E is selected from 552 wherein
the heterocyclic ring can optionally have a double bond and n and p
can be, independently of each other, 0, 1, 2 or 3, with the proviso
that n+p.ltoreq.4 and q is 2 or 3, R.sup.11 is hydrogen,
C.sub.1-C.sub.6-alkyl, hydroxy, hydroxymethyl, carboxy or
C.sub.2-C.sub.7-alkoxycarbonyl and R.sup.12 hydrogen,
C.sub.1-C.sub.6-alkyl or an oxo group adjacent to the nitrogen
atom, wherein R.sup.11 and R.sup.12 optionally together form a
C.sub.1-C.sub.3-alkylene bridge under formation of a bi-cyclic ring
system, G is selected from hydrogen, G1, G2, G3, G4 and G5, wherein
G1 represents the residue
--(CH.sub.2).sub.r--(CR.sup.14R.sup.15).sub.s--R.s- up.13 (G1)
wherein r is an integer from 1 to 3 or 0 and s is 0 or 1, R.sup.13
is selected from hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkinyl,
C.sub.3-C.sub.8-cycloal- kyl, saturated, five- to seven-membered
heterocycles, which can contain one or two hetero-atoms from the
group N and/or S and/or O, benzyl or phenyl, monocyclic aromatic
five or six-membered heterocycles, which can contain one to three
hetero-atoms from the group N and/or S and/or O and are either
bound directly or over a methylene group, anellated bi- and
tricyclic aromatic or partially hydrated carbocyclic ring systems
with 8 to 16 ring atoms and at least one aromatic ring, wherein the
linkage can occur either over an aromatic or a hydrated ring and
either directly or over a methylene group, anellated bi- and
tricyclic aromatic or partially hydrated heterocyclic ring systems
with 8 to 16 ring atoms and at least one aromatic ring, wherein one
to three ring atoms can be selected from N and/or S and/or O and
the linkage can occur either over an aromatic, ring or a hydrated
ring and either directly or over a methylene group, R.sup.14 has
the same meaning as R.sup.13, but is selected independently
thereof, R.sup.15 is selected from hydrogen, hydroxy, methyl,
benzyl, phenyl, monocyclic aromatic five- or six-membered
heterocycles, which can contain one to three hetero-atoms selected
from the group N and/or S and/or O and are either bound directly or
over a methylene group, anellated bi- and tricyclic aromatic or
partially hydrated carbocyclic ring systems with 8 to 16 ring atoms
and at least one aromatic ring, wherein the linkage can occur
either over an aromatic or a hydrated ring and either directly or
over a methylene group, anellated bi- and tricyclic aromatic or
partially hydrated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring, wherein one to three ring
atoms can be selected from N and/or S and/or O and the linkage can
occur either over an aromatic ring or a hydrated ring and either
directly or over a methylene group, G2 is the residue 553 wherein
the substituents R.sup.13 and R.sup.15 can have the above meaning
or the grouping --NR.sup.13R.sup.15 can also he a nitrogen
heterocycle bound over the nitrogen atom, selected from saturated
or unsaturated monocyclic, four- to eight-membered heterocycles,
which, aside from the essential nitrogen atom, can optionally
contain one or two further hetero-atoms selected from the group N
and/or S and/or O, or saturated or unsaturated bi- or tricyclic,
anellated or bridged heterocycles with 8 to 16 ring atoms, which,
aside from the essential nitrogen atom, can optionally contain one
or two tirther hetero-atoms selected from the group N and/or S
and/or O, G3 is the residue --SO.sub.2--(CH.sub.2).sub.r R.sup.13
(G3) and G4 is the residue 554 wherein Ar.sup.1 and Ar.sup.2 are
selected independently from one another from phenyl, pyridyl or
naphthyl and G5 is the residue COR.sup.16 (G5) wherein R.sup.16 is
selected from trifluoromethyl, C.sub.1-C.sub.6-alkoxy,
C.sub.3-C.sub.6-alkenyloxy, or benzyloxy, and wherein aromatic ring
systems in the substituents R.sup.1, R.sup.2, R.sup.4, R.sup.13,
R.sup.14, R.sup.15, R.sup.16 Ar.sup.1 and Ar.sup.2 and/or in the
ring system --NR.sup.13R.sup.15 can be substituted independently
from each other by one to three of the same or different residues
which are selected from halogen, cyano, C.sub.1-C.sub.6-alkyl,
trifluoromethyl, C.sub.3-C.sub.8-Cycloalkyl, phenyl, benzyl,
hydroxy, C.sub.1-C.sub.6-alkoxy, which can optionally be entirely
or partially substituted by fluorine, benzyloxy, phenoxy, mercapto,
C.sub.1-C.sub.6-alkylthio, carboxy, C.sub.1-C.sub.6-alkoxycarbonyl,
benzyloxycarbonyl, nitro, amino, mono-C.sub.1-C.sub.6-alkylamino or
di-(C.sub.1-C.sub.6-alkyl)-amino and methylenedioxy for two
adjacent groups on the aromatic ring or ring system, their
stereoisomers thereof and/or their mixtures thereof and
pharmacologically acceptable acid addition salts.
3. Use of the compounds according to claim 1 or 2, characterized in
that the substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.13, R.sup.14,
R.sup.15 and R.sup.16 as well as A and D indicated for formula (I)
have the following meaning in connection with the given
substitutions according to this formula 555wherein halogen is
fluorine, chlorine, bromine or iodine, C.sub.1-C.sub.6-alkyl can be
straight chain or branched and is preferably a methyl-, ethyl-,
propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert-butyl-,
cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-, neopentyl-,
cyclopropylethyl-, cyclobutylmethyl- or a hexyl group, alkylene is
for example methylene, ethylene, propylene, tetramethylene,
pentamethylene, hexamethylene, heptamethylene, octamethylene,
nonamethylene or decamethylene, C.sub.3-C.sub.6-alkenyl can be
straight chain or branched and is preferably an allyl-, 2-butenyl-,
3-butenyl-, 2-methyl-2-propenyl-, 2-pentenyl-, 4-pentenyl-,
2-methyl-2-butenyl-, 3-methyl-2-butenyl-, 2-hexenyl-, 5-hexenyl-,
4-methyl-3-pentenyl- or 2,2-dimethyl-3-butenyl group, alkenylene is
for example ethenylene, propenylene, butenylene, pentenylene,
hexenylene, hexathenylene, heptenylene, octenylene, nonenylene or
decenylene, C.sub.3-C.sub.6-alkinyl can be straight chain or
branched and is preferably a propargyl-, 2-butinyl-, 3-butinyl-,
4-pentinyl-, 5-hexinyl- or 4-methyl-2-pentinyl group, alkinylene is
for example propinylene, butinylene, pentinylene, hexinylene,
heptinylene, octinylene, noninylene or decinylene,
C.sub.3-C.sub.8-cycloalkyl is preferably cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
C.sub.1-C.sub.6-hydroxyalkyl contains a hydroxyl group in one of
the above-named C.sub.1-C.sub.6-alkyl residues, especially in the
form of the hydroxymethyl- and hydroxyethyl group, wherein
C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkinyloxy each contain, aside from the oxygen
atom, one of the C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-
and/or C.sub.3-C.sub.6-alkinyl groups named above and the methoxy-,
ethoxy-, isopropoxy-, tert-butoxy-, allyloxy- and propargyloxy
groups are preferred and is to be understood as among
C.sub.1-C.sub.6-alkoxy entirely or partially substituted with
fluorine, for example difluormethoxy, trifluormethoxy or
2,2,2-trifluorethoxy, C.sub.1-C.sub.6-alkylthio,
C.sub.3-C.sub.6-alkenylthio, C.sub.3-C.sub.6-alkinylthio each
contain, aside from the sulfur atom, one of the
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl- or
C.sub.3-C.sub.6-alkinyl groups named above, especially the
methylthio-, ethylthio-, isopropylthio- and tert-butylthio groups,
C.sub.3-C.sub.8-cycloalkyloxy and C.sub.3-C.sub.8-cycloalkylthio
are preferred as cyclopentyloxy- and cyclopentylthio- and/or
cylohexyloxy- and cyclohexylthio groups,
C.sub.1-C.sub.7-alkanoyloxy groups contain, aside from the oxygen
atom, an aliphatic acyl residue with 1 to 7 carbon atoms,
especially the acetoxy-, propionyloxy- and pivaloyloxy groups,
C.sub.2-C.sub.7-alkoxycarbonyl groups contain, aside from the
carbonyl group, one of the C.sub.1-C.sub.6-alkoxy groups mentioned
above, especially the methoxycarbonyl-, ethoxycarbonyl-,
isopropoxycarbonyl-, isobutoxycarbonyl-and tert-butoxycarbonyl
group, C.sub.2-C.sub.7-alkoxyca- rbonyloxy groups contain, aside
from the oxygen atom, one of the C.sub.2-C.sub.7-alkoxycarbonyl
residues mentioned above, especially the methoxycarbonyloxy-,
ethoxycarbonyloxy-, isopropoxycarbonyloxy-,
isobutoxycarbonyloxy-and tertbutoxycarbonyl group as well as the
allyloxycarbonyloxy group, C.sub.2-C.sub.7-alkylaminocarbonyl and
C.sub.3-C.sub.13-dialkylaminocarbonyl groups contain, beside the
carbonyl group, an alkylamino- and/or dialkylamino residue, whose
C.sub.1-C.sub.6-alkyl groups have the above meanings, wherein the
dimethylaminocarbonyl-, diethylaminocarbonyl- and the
diisopropylaminocarbonyl groups are preferred, and aside from the
unsubstituted amino group, one of the following
C.sub.1-C.sub.6-alkylamin- o groups and/or
di-(C.sub.1-C.sub.6-alkyl)amino groups are to be understood under
the amino groups of the formula NR.sup.5R.sup.6,
C.sub.1-C.sub.6-alkylamino contains one of the
C.sub.1-C.sub.6-alkyl groups mentioned above, especially in form of
the methylamino-, ethylamino-, propylamino-, isopropylamino-,
butylamino- and the tert-butylamino group,
di-(C.sub.1-C.sub.6-alkyl)amino carries two of the same or
different of the above named C.sub.1-C.sub.6-alkyl groups on the
nitrogen atom, especially in form of the dimethylamino-,
diethylamino-, dipropylamino-, diisopropylamino-,
isopropylmethylamino-, dibutylamino- or tert-butylmethylamino
group, C.sub.1-C.sub.6-acyl is the residue of an aliphatic
saturated or unsaturated, straight chain, branched or cyclic
carboxylic acid, especially in form of the formyl-, acetyl-,
propionyl-acryloyl-, butyryl-, isobutyryl-, methacryloyl-,
cyclopropylcarbonyl-, pentanoyl-, pivaloyl-, cyclobutylcarbonyl-,
hexanoyl- and the dimethylacryloyl group,
C.sub.1-C.sub.6-alkansulfonyl is preferably the methanesulfonyl-,
ethanesulfonyl-, propanesulfonyl-, butanesulfonyl-,
pentanesulfonyl- and the hexanesulfonyl group, saturated rive- to
seven-membered heterocycles with one or two hetero-atoms are
especially tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, hexahydroazepinyl, piperazinyl,
hexahydrodiazepinyl or morpholinyl, monocyclic aromatic five- or
six-membered heterocycles with one to three heteroatoms are
especially furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl,
pyrimidinyl or triazinyl, anellated bi and tricydic aromatic or
partially hydrated carbocycic ring systems with 8 to 16 ring atoms
and at least one aromatic ring are preferably benzocyclobutyl,
indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl,
biphenylenyl, fluorenyl, anthryl, dihydroanthryl, phenanthryl,
dihydrophenanthryl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or
tetrahydrodibenzocyclooctenyl, wherein mono- or dioxo-derivates,
wherein, the residues of indanone, tetralone, anthrone,
anthraquinone, fluorenone, phenanthrone, dibenzocycloheptenone,
dihydrodibenzocycloheptenone or tetrahydrodibenzocyclooctenone are,
for example, also to be understood as partially hydrated
carbocyclic ring systems, anellated bi- and tricyclische aromatic
or partially hydrated heterocyclic ring systems with 8 to 16 ring
atoms and at least one aromatic ring are, for example,
imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl,
dihydrobenzothienyl, indolyl, indolinyl, benzimidazolyl, indazolyl,
benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl,
benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl,
thiazolopyridyl, isothiazolopyridyl, imidazopyridyl,
pyrazolopyridyl, thienopyrimidinyl, chromanyl, benzopyranyl,
quinolyl, isoquinolyl, dihydroquinolyl, tetrahydroquinolyl,
benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl,
carbazolyl, tetrahydrocarbazolyl, pyridoindolyl, acridinyl,
phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl,
dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl,
octahydrodibenzothiepinyl, dihydrodibenzazepinyl,
octahydrodibenzazepinyl, benzocycloheptapyridyl,
dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl,
dihydropyridobenzoxepinyl, dihydropyridobenzoxazepinyl,
dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl, wherein
their mono- or dioxo-derivates and/or optionally their possible
tautomeres are also to be understood as partially hydrated
heterocyclic ring systems, for example, the residues of indolinone,
isatin, benzoxazolone and/or their tautomeres hydroxybenzoxazol, of
benzisoxazolone, benzothiazolone, benzoisothiazolone and
benzimidazolone and/or their tautomeres, hydroxybenzisoxazol,
hydroxybenzothiazol, hydroxybenzoisothiazol and
hydroxybenzimidazol, of indazolinone, of oxazolopyridinone,
thiazolopyridinones, pyrazolopyridinones and imidazopyridinones
and/or their tautomeres hydroxyoxazolopyridine,
hydroxythiazolopyridines, hydroxypyrazolopyridines and
hydroxyimidazopyridines, the residues of chromanone, chromone,
quinolinone, dihydroquinolinone, tetrahydrocarbazolone, acridone,
of dihydrodibenzoxepinones, benzocycloheptathiophenones,
dihydrothienobenzothiepinones, dihydrodibenzothiepinones,
dihydrodibenzoazepinones, benzocycloheptapyridinones,
dihydropyridobenzoxazepinones, dihydrodibenzothiazepinones and of
dihydropyridobenzothiazepinones, saturated and unsaturated
monocyclic, four- to eight-membered heterocycles are
--NR.sup.13R.sup.15 as a grouping which, aside from the essential
nitrogen atom, can optionally contain one or two further
hetero-atoms selected from N and/or S and/or O, for example
azetidine, pyrrolidine, piperidine, (1H)tetrahydropyridine,
hexabydroazepine, (1H)tetrahydroazepine, octahydroazocine,
pyrazolidine, piperazine, hexahydrodiazepine, morpholine,
hexahydrooxazepine, thiomorpholine or thiomorpholine-1,1-dioxide,
saturated or unsaturated bi- or tricyclic, anellated or bridged
heterocycles with 8 to 16 ring atoms, represent --NR.sup.13R.sup.15
as a grouping which, aside from the essential nitrogen atom
optionally contain one or two further hetero-atoms, selected from N
and/or S and/or O, for example 5-aza-bicyclo[2.1.1]hexane- ,
2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane,
2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane,
8-a-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane,
9-aza-bicyclo[3.3.1]nonane, indoline, isoindoline,
(1H)dihydroquinoline, (1H)-tetrahydroquinoline,
(2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4 Hz
dihydrobenzoxazine, (4H)-dihydrobenothiazine,
(1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine,
(1H)tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine,
(5H)-tetrahydrobenzo[b]thiazepine,
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine,
1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine,
(10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine,
(5H)-octahydrodibenzazepin- e, (5H)-dihydrodibenzodiazcpine, (11H)
dihydrodibenzo[b,e]oxazepine, (11H)dihydrodibenzo[b,e]thiazepine,
(10H)-dihydrodibenzo[b,f]oxazepine,
(10H)-dihydrodibenzo[b,f]thiazepine or
(5H)-tetrahydrodibenzazocine, as well as optionally possible
tautomeres in the case of substitution of the heterocycle as such
or in an anellated ring system by free hydroxy-, mercapto- and/or
amino groups, and their stereoisomers such as, if applicable,
cis/trans-isomers, endo/exo-isomers, optic isomers such as
enantiomers, diastereomers as pure isomers or mixtures and/or
racemic mixtures as well as the pharmacologically acceptable acid
addition salts with inorganic or organic acids, wherein the
hydrochlorides, hydrobromides, hydrolodides, sulfates and
phosphates, are preferred as addition salts with suitable inorganic
acids and acetates, benzoates, 4-methoxybenzoate, 2- or
4-hydroxybenzoate, 4-chlorobenzoate, ascorbate, salicylate,
formiate, glutarate, tricarballylate, citrates, fumarates,
gluconates, malates, maleates, methanesulfonates, lactates,
oxalates, succinates, tartrates and toluolsulfonates, for example
p-toluolsulfonate are preferred as addition salts of organic
acids.
4. Use of compounds according to claims 1-3, characterized in that
the substitutents labelled in formula (I) 556have the following
meanings: R.sup.1 is hydrogen, halogen, cyano,
C.sub.1-C.sub.6-alkyl, trifluoromethyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.4-hydroxyalkyl- , hydroxy, C.sub.1-C.sub.4-alkoxy,
benzyloxy, C.sub.1-C.sub.4-alkanoyloxy, C.sub.1-C.sub.4-alkylthio,
C.sub.2-C.sub.5-alkoxycarbonyl, aimnocarbonyl,
C.sub.3-C.sub.9-dialkylaminocarbonyl, carboxy, phenyl, phenoxy,
pyridyloxy or NR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are
selected independently from each other form hydrogen and
C.sub.1-C.sub.6-alkyl, R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.6-alkyl, trifluoromethyl or hydroxy, wherein R.sup.1
and R.sup.2, in the case they are adjacent, optionally form a
bridge which are selected from the group of bridge members
--(CH.sub.2).sub.4-- and --(CH.dbd.CH).sub.2-- and
--CH.sub.2O--CR.sup.7R.sup.8--O--, wherein R.sup.7 and R.sup.8 can
be, independently from each other, hydrogen and
C.sub.1-C.sub.6-alkyl, R.sup.3 is selected from hydrogen, halogen
and C.sub.1-C.sub.6-alkyl and R.sup.4 is selected from hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl, hydroxy,
C.sub.1-C.sub.6-alkoxy and benyloxy, k is 0 or 1, A is
C.sub.1-C.sub.6-alkylene, which is optionally substituted once to
three-fold by C.sub.1-C.sub.3-alkyl, hydroxy, fluorine or phenyl,
1,2-cyclopropylene, C.sub.2-C.sub.6-alkenylene, which is optionally
substituted one to three-fold by C.sub.1-C.sub.3-alkyl, hydroxy,
fluorine, cyano, or phenyl, C.sub.4-C.sub.6-alkadienylene, which is
optionally substituted once or twice by C.sub.1-C.sub.3-alkyl,
fluorine, cyano, or phenyl, 1,3,5-hexatrienylene, which is
optionally substituted by C.sub.1-C.sub.3-alkyl, fluorine, or
cyano, ethinylene or C.sub.2-C.sub.6-alkylene, wherein a methylene
unit can be isosterically replaced by O, S, NR.sup.9, CO, SO or
SO.sub.2, and wherein the isosteric substitute, with the exception
of .dbd.CO, cannot be adjacent to the amide group, and wherein
R.sup.9 is hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.6-acyl or
methanesulfonyl, D is selected from C.sub.1-C.sub.10-alkylene,
which is optionally substituted once or twice by
C.sub.1-C.sub.3-alkyl or hydroxy, C.sub.2-C.sub.10-alkenylene,
optionally substituted once or twice by C.sub.1-C.sub.3-alkyl or
hydroxy, wherein the double bond can also be to ring E or
C.sub.3-C.sub.10-alkinyl- ene, which is optionally substituted once
or twice by C.sub.1-C.sub.3-alkyl or hydroxy, and can be selected
as well from C.sub.1-C.sub.10-alkylene, C.sub.2-C.sub.10-alkenylene
or C.sub.3-C.sub.10-alkinylene, in which one to three methylene
units are isosterically replaced by O, S, NR.sup.10, CO, SO or
SO.sub.2, wherein R.sup.10 has the same meaning as R.sup.9, but is
selected independently therefrom, E is 557 wherein the heterocyclic
ring can optionally have a double bond and n and p can be,
independent of each other, 0, 1, 2 or 3, with the proviso that
n+p.ltoreq.4, q is 2 or 3, R.sup.11 is selected from hydrogen,
C.sub.1-C.sub.3-alkyl, hydroxy, hydroxymethyl, carboxy or
C.sub.2-C.sub.7-alkoxycarbonyl and R.sup.12 is selected from
hydrogen or an oxo group adjacent to the nitrogen atom, G is
selected from hydrogen, G1, G2, G3, G4 and G5, wherein G1
represents the residue
--(CH.sub.2).sub.r--(CR.sup.14R.sup.15).sub.s--R.sup.13 (G1)
wherein r is 0, 1 or 2 and s is 0 or 1, R.sup.13 is selected from
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkinyl, C.sub.3-C.sub.8-cycloalkyl, benzyl,
phenyl, monocyclic aromatic five- or six-membered heterocycles,
which contain one to three hetero-atoms from the group N and/or S
and/or O and are either bound directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, whereby the bond can occur either over an aromatic
or a hydrated ring and either directly or over a methylcne group,
anellated bi- and tricyclic aromatic or partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms can be selected from
the groups N and/or S and/or O and the bond can occur either over
an aromatic or a hydrated ring and either directly or over a
methylene group, R.sup.14 has the same meaning as R.sup.13, but is
selected independently thereof, R.sup.15 is selected from hydrogen,
hydroxy, methyl, benzyl or phenyl, monocyclic aromatic five- or
six-membered heterocycles, which can contain one to three
hetero-atoms selected from the group N and/or S and/or O and are
bound either directly or over a methylene group, anellated bi- and
tricyclic aromatic or partially hydrated carbocyclic ring systems
with 8 to 16 ring atoms and at least einem aromatic ring, wherein
the bond can occur either over an aromatic or a hydrated ring and
either directly or over a methylene group, anellated bi- and
tricyclic aromatic or partially hydrated heterocyclic ring systems
with 8 to 16 ring atoms and at least one aromatic ring, wherein one
to three ring atoms can be selected from the group N and/or S
and/or O and the bond can occur either over an aromatic or a
hydrated ring and either directly or over a methylene group, G2 is
selected from the residues 558 wherein the substituents R.sup.13
and R.sup.15 the can have the above meaning, or the group
--NR.sup.13R.sup.15 can also be a nitrogen heterocycle bound over
the nitrogen atom, selected from saturated or unsaturated
monocyclic, four- to eight-membered heterocycles, which, aside from
the essential nitrogen atom, can optionally contain one or two
further hetero-atoms selected from N and/or S and/or O, or
saturated or unsaturated bi- or tricyclic, anellated or bridged
heterocycles with 8 to 16 ring atoms, which, aside from the
essential nitrogen atom, can optionally contain one or two further
hetero-atoms selected from N and/or S and/or O, G3 is the residue
--SO.sub.2--(CH.sub.2).sub.r R.sup.13 (G3), G4 is the residue 559
wherein Ar.sup.1 and Ar.sup.2 are selected independently of each
other from phenyl, pyridyl or naphthyl, G5 is the residue
--COR.sup.16 (G5) wherein R.sup.16 is trifluoromethyl,
C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-alkenyloxy or benzyloxy and
aromatic ring systems in which the substituents R.sup.1, R.sup.2,
R.sup.4, R.sup.13, R.sup.14, R.sup.15, R.sup.16, Ar.sup.1 and
Ar.sup.2 and/or in the ring system --NR.sup.13R.sup.15 can carry
independently of each other one to three of the same or different
substituents from the series halogen, cyano, C.sub.1-C.sub.6-alkyl,
trifluoromethyl, C.sub.3-C.sub.8-cycloalkyl, phenyl, benzyl,
hydroxy, C.sub.1-C.sub.6-alkoxy, which is optionally entirely or
partially substituted by fluorine, benzyloxy, phenoxy, mercapto,
C.sub.1-C.sub.6-alkylthio, carboxy, C.sub.1-C.sub.6-alkoxycarbo-
nyl, benzyloxycarbonyl, nitro, amino,
mono-C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)-amino,
wherein two adjacent groups on the aromatic ring or ring system can
form an additional ring over a methylenedioxy bridge.
5. The use of compounds according to claims 14, characterized in
that the substiutents labelled in formula (I) 560have the following
meanings: R.sup.1 is hydrogen, halogen, cyano, methyl,
trifluoromethyl, hydroxy, C.sub.1-C.sub.4-alkoxy, ethylthio,
methoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, carboxy, and
phenoxy, R.sup.2 is hydrogen, halogen, trifluoromethyl or hydroxy,
R.sup.3 is hydrogen or halogen, R.sup.4 is selected from hydrogen,
C.sub.1-C.sub.3-alkyl, hydroxy and C.sub.1-C.sub.3-alkoxy, k is 0
or 1, A is C.sub.2-C.sub.6-alkylene, which is optionally
substituted once or twice by C.sub.1-C.sub.3-alkyl, hydroxy or
fluorine, as well as C.sub.2-C.sub.6-alkenylene, which is
optionally substituted once or twice by C.sub.1-C.sub.3-alkyl,
hydroxy or fluorine, C.sub.4-C.sub.6-alkadienylene, which is
optionally substituted by is C.sub.1-C.sub.3-alkyl or by one or two
fluorine atoms, 1,3,5-hexatrienylene, which is optionally
substituted by fluorine, or C.sub.2-C.sub.6-alkylene, wherein a
methylene unit can be isosterically replaced by O, S, CO or
SO.sub.2, and the isosteric substitute, with the exception of
.dbd.CO cannot be adjacent to the amide group and, D is
C.sub.1-C.sub.8-alkylene, which is optionally substituted once
twice by methyl or hydroxy, C.sub.2-C.sub.8-alkenylene, which is
optionally substituted once or twice by methyl or hydroxy, wherein
the double bond can also be to ring E, C.sub.3-C.sub.8-alkinylene,
which is optionally substituted once or twice by methyl or hydroxy,
as well as C.sub.1-C.sub.8-alkylene, C.sub.2-C.sub.8-alkenylene or
C.sub.3-C.sub.8-alkinylene, in which one to three methylene units
can be isosterically replaced by O, S, NH, N(CH.sub.3),
N(COCH.sub.3), N(SO.sub.2CH.sub.3), CO, SO or SO.sub.2, 561 wherein
the heterocyclic ring can optionally have a double bond and n and p
can be independent of each other 0, 1, 2 or 3, with the proviso
that n+p.ltoreq.3, q is 2 or 3, R.sup.11 is selected from hydrogen,
C.sub.1-C.sub.3-alkyl, hydroxy, hydroxymethyl and R.sup.12 is
selected from hydrogen or an oxo group which is adjacent to the
nitrogen atom, G is hydrogen or G1, G2, G3, G4 and G5, wherein G1
represents the residue --(CH.sub.2).sub.r--(CR.sup.14R-
.sup.15).sub.s--R.sup.13 (G3) wherein r is 0, 1 or 2 and s is 0 or
1, R.sup.13 is selected from hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.8-cycloalkyl, benzyl or phenyl, benzocyclobutyl,
indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl,
tetrahydronaphthyl, oxotetrahydronaphthyl, biphenylenyl, fluorenyl,
oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl,
dioxodihydroanthryl, phenanthryl, dihydrophenanthryl,
oxodihydrophenanthryl, dibenzocycloheptenyl,
oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl,
oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl,
tetrahydrodibenzocyclooctenyl and oxotetrahydrodibenzocyclooctenyl
bound directly or over a methylene group, furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl,
pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl,
benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl,
indolyl, indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl,
oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl,
benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl,
oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl,
indazolyl, oxoindazolinyl, benzofurazanyl, benzothiadiazolyl,
benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl,
thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl,
imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl,
oxodihydropyrazolopyridyl, thienopyrimidinyl, chromanyl,
chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl,
dihydroquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl,
oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl,
naphthyridinyl, carbazolyl, tetrahydrocarbazolyl,
oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl,
oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl,
oxodihydrodibenzoxepinyl, benzocycloheptathienyl,
oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl,
oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl,
oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl,
dihydrodibenzazepinyl, oxodihydrodibenzazepiny- l,
octahydrodibenzazepinyl, benzocycloheptapyridyl,
oxobenzocycloheptapyridyl, dihydropyridobenzodiazepinyl,
dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl,
dihydropyridobenzoxazepinyl, oxodihydropyridobenzoxazepinyl,
dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl,
dihydropyridobenzothiazepinyl, oxodihydropyridobenzothiazepinyl,
bound directly or over a methylene group, R.sup.14 has the same
meaning as R.sup.13, but is selected independently therefrom,
R.sup.15 is selected from hydrogen, hydroxy, methyl, benzyl or
phenyl, indanyl, indenyl, naphthyl, dihydronaphthyl,
tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl,
pyrimidinyl, triazinyl, benzofuryl, benzothienyl, indolyl,
indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl,
quinolyl or tetrahydroquinolyl bound directly or over a methylene
group, G2 is selected from the residues 562 wherein the
substituents R.sup.13 and R.sup.15 can have the above meanings, or
represents the grouping --NR.sup.13R.sup.15 each over the
nitrogen-bound ring atom of azetidine, pyrrolidine, piperidine,
(1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine,
octahydroazocine, pyrazolidine, piperazine, hexyhydrodiazepine,
morpholine, hexahydrooxazepine, thiomorpholine,
thiomorpholine-1,1-dioxide, 5-aza-bicyclo[2.1.1]hexane,
2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane,
2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane,
8-aza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane,
9-azabicyclo[3.3.1]nonane, indoline, isoindoline,
(1H)-dihydroquinoline, (1H)-tetrahydroquinoline,
(2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline,
(4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine,
(1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine,
(1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine,
(5H)-tetrahydrobenzo[b]thiazepine,
1,2,3,4-tetrahydro-9H-pyrido[3,4b]indole, (10H)-dihydroacridine,
1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine,
(10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine,
(5H)-Octahydrodibenzazepin- e, (5H)-dihydrodibenzodiazepine,
(11H)-dihydrodibenzo[b,e]oxazepine,
(11H)-dihydrodibenzo[b,e]thiazepine,
(10H)-dihydrodibenzo[b,f]oxazepine,
(10H)-dihydrodibenzo[b,f]thiazepine or
(5H)-tetrahydrodibenzazocine, G3 is the residue
--SO.sub.2--(CH.sub.2).sub.r R.sup.13 (G3), G4 is the residue 563
wherein Ar.sup.1 and Ar.sup.2 are selected independently of each
other from phenyl, pyridyl or naphthyl, G5 is the residue
--COR.sup.16 (G5) wherein R.sup.16 is trifluoromethyl,
C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-alkenyloxy or benzyloxy and
aromatic ring systems in which the substituents can be substituted
independently of each other by one to three of the same or
different substituents from the series halogen, cyano,
C.sub.1-C.sub.6-alkyl, trifluoromethyl, C.sub.3-C.sub.8-Cycloalkyl,
phenyl, benzyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy, which can be entirely or partially
substituted by fluorine, can carry benzyloxy, phenoxy, mercapto,
C.sub.1-C.sub.6-alkylthio, carboxy, C.sub.1-C.sub.6-alkoxycarbo-
nyl, benzyloxycarbonyl, nitro, amino,
mono-C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)-amino,
wherein two adjacent groups in the ring or ring system can form an
additional ring over a methylenedioxy bridge.
6. The use of compounds according to claims 1-5, characterized in
that the substituents labelled in formula (I) 564have the following
meaning: R.sup.1 is hydrogen, halogen, cyano, methyl,
trifluoromethyl, hydroxy, methoxy or methoxycarbonyl, R.sup.2 is
hydrogen or halogen, R.sup.3 is hydrogen, R.sup.4 is selected from
hydrogen, C.sub.1-C.sub.3-alkyl or hydroxy, k is 0 or 1, A is
selected from C.sub.2-C.sub.6-alkylene, which is optionally
substituted once or twice by hydroxy or fluorine, or
C.sub.2-C.sub.6-alkenylene, which is optionally substituted once or
twice by hydroxy or fluorine, C.sub.4-C.sub.6-alkadienylene, which
is optionally substituted by one or two fluorine atoms,
1,3,5-hexatrienylene or C.sub.2-C.sub.6-alkylene, wherein a
methylene unit can be isosterically replaced by O, S or CO, and the
isosteric substitute, with the exception of .dbd.CO, cannot be
adjacent to the amide group and, D is C.sub.2-C.sub.8-alkylene,
which is optionally substituted by methyl or hydroxy
C.sub.2-C.sub.8-alkenylene, which is optionally substituted by
methyl or hydroxy, wherein the double bond can also be to ring E,
or C.sub.2-C.sub.8-alkylene, C.sub.2-C.sub.8-alkenylene, wherein
one to three methylene units can be isosterically replaced by O,
NH, N(CH.sub.3), N(COCH.sub.3), N(SO.sub.2CH.sub.3) or CO, E is
selected from the residues 565 wherein the heterocyclic ring can
optionally have a double bond and n and p can be, independent of
each other, 0, 1, 2 or 3, with the proviso that n+p.ltoreq.3 and q
is 2 R.sup.11 is hydrogen, methyl or hydroxyl and R.sup.12 is
hydrogen or an oxo group adjacent to the nitrogen atom, G is
selected from hydrogen, C.sub.3-C.sub.8-cycloalky- l,
methoxycarbonyl, tertbutoxycarbonyl, benzyloxycarbonyl,
trifluoracetyl, diphenylphosphinoyl or the residues 566 wherein r
is 0, 1 or 2 and s is 0 or 1, R.sup.13 is hydrogen, methyl, benzyl
or phenyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl,
tetrahydronaphtbyl, oxotetrahydronaphthyl, fluorineenyl,
oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl,
dioxodihydroanthryl, dibenzocycloheptenyl, oxodibenzocycloheptenyl,
dihydrodibenzocyclohepteny- l, oxodihydrodibenzocycloheptenyl bound
directly or over a methylene group, furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl,
pyrazinyl, pyridazinyl, pyrimidinyl, imidazothiazolyl, benzofuryl,
dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl,
indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl,
oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl,
benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl,
oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl,
benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl,
oxodihydrooxazolopyridyl, thiazolopyridyl,
oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl,
oxodihydroimidazopyridyl, pyrazolopyridyl, thienopyrimidinyl,
chromanyl, chromanonyl, benzopyranyl, chromonyl, quinolyl,
isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl,
tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl,
quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl,
tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl,
acridinyl, oxodihydroacridinyl, phenothiazinyl,
dihydrodibenzoxepinyl, benzocycloheptathienyl,
oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl,
oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl,
oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl,
oxodihydrodibenzazepinyl, octahydrodibenzazepinyl,
benzocycloheptapyridyl, oxobenzocycloheptapyridyl,
dihydropyridobenzoxepinyl, dihydrodibenzothiazepinyl,
oxodihydrodibenzothiazepinyl bound directly or over a methylene
group, R.sup.14 is hydrogen, methyl, benzyl or phenyl, R.sup.15 is
selected from hydrogen, hydroxy, methyl, benzyl, phenyl, naphthyl,
furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl,
oxadiazolyl, thiadiazolyl, pyridyl, benzofuryl, benzothienyl,
indolyl, indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,
chromanyl, quinolyl or tetrahydroquinolyl, bound directly or over a
methylene group, wherein in formula (I) 567the group
NR.sup.13R.sup.15 can be selected from pyrrolidine, piperidine,
(1H)tetrahydropyridine, hexahydroazepine, Octahydroazocine,
piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine,
2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptan- e,
2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane,
2,5-diazabicyclo[2.2.2]octane, indoline, isoindoline,
(1H)-dihydroquinoline, (1H)tetrahydroquinoline,
(2H)-tetrahydroisoquinoli- ne, (1H)-tetrahydroquinoxaline,
(4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine,
(1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine,
(SH)-tetrahydrobenzo[b]oxazepine,
(5H)-tetrahydrobenzo[b]thiazepine,
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]ind- ol, (10H)-dihydroacridine,
1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine,
(5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine,
(11H)-dihydrodibenzo[b,e]thiazepine,
(10H)-dihydrodibenzo[b,f]oxaze-pine or
(5H)-tetrahydrodibenzazocine.
7. The use of compounds according to claims 1-6, characterized in
that the substituents in labelled the formula (I) 568have the
following meanings: R.sup.1 is hydrogen, fluorine, chlorine,
bromine, methyl, trifluoromethyl or hydroxy, R.sup.2 and R.sup.3
are hydrogen, R.sup.4 is hydrogen or hydroxy, k is 0 or 1, A is
selected from C.sub.2-C.sub.6-alkylene, which is optionally
substitued once or twice by hydroxy or fluorine or,
C.sub.2-C.sub.4-alkylene, which is optionally substituted by
fluorine, C.sub.4-alkadienylene, which is optionally substituted by
fluorine, D is selected from C.sub.2-C.sub.6-alkylene,
C.sub.2-C.sub.6-alkenylene, wherein the double bond can also be to
ring E, and C.sub.2-C.sub.6-alkylene and
C.sub.2-C.sub.6-alkenylene, wherein a methylene unit can be
isosterically replaced by O, NH, N(CH.sub.3) or CO or an ethylene
group can be isosterically replaced by NH--CO and/or CO--NH or a
propylene group can be isosterically replaced by NH--CO--O and/or
O--CO--NH, E is selected from pyrrolidine, piperidine,
1,2,5,6-tetrahydropyridine, hexahydroazepine, morpholine and
hexahydro-1,4-oxazepine, wherein the heterocyclic ring optionally
adjacent to the nitrogen atom, can be substituted by an oxo group,
G is selected from hydrogen, tert-butoxycarbonyl,
diphenylphosphinoyl, or one of the residues 569 wherein r is 0 or 1
and s is 0 or 1, R.sup.13 is hydrogen, methyl, benzyl or phenyl,
indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, fluorenyl,
oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl,
dioxodihydroanthryl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl bound directly or over a methylene
group, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl,
oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,
imidazothiazolyl, benzofuryl, benzothienyl, indolyl, oxoindolinyl,
dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzothiazolyl,
oxobenzthiazolinyl, benzimidazolyl, oxobenzimidazolinyl,
benzofurazanyl, benzotriazolyl, oxazolopyridyl,
oxodihydrooxazolopyridyl, thiazolopyridyl,
oxodihydrothiazolopyridyl, chromanyl, chromanonyl, benzopyranyl,
chromonyl, quinolyl, isoquinolyl, oxodihydroquinolinyl,
tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl,
quinazolinyl, acridinyl, oxodihydroacridinyl, phenothiazinyl,
dihydrodibenzoxepinyl, benzocycloheptathienyl,
dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl,
oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl,
oxodihydrodibenzazepinyl, octahydrodibenzazepinyl,
benzocycloheptapyridyl, oxobenzocycloheptapyridyl,
dihydrodibenzothiazepinyl bound directly or over a methylene group,
R.sup.14 is hydrogen, methyl, benzyl or phenyl, R.sup.15 is
hydrogen, hydroxy, methyl, benzyl or phenyl, naphthyl, furyl,
thienyl, pyridyl, benzofuryl, benzothienyl, indolyl, benzoxazolyl,
benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or
tetrahydroquinolyl bound directly or over a methylene group,
wherein in the formula 570the group NR.sup.13R.sup.15 can be
selected from pyrrolidine, piperidine, hexahydroazepine,
morpholine, 2,5-diazabicyclo[2.2.1]heptane, indoline, isoindoline,
(1H)-dihydroquinoline, (1H)-tetrahydroquinoline,
(2H)-tetrahydroisoquinoline, (1H)tetrahydrobenzo[b]azepine,
(1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine,
(5H)tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydroacridanone,
(5H)-dihydrodibenzazepine, (11H)-dihydrodibenzo[b,e]-oxazepine or
(11H)-dihydrodibenzo[b,e]thiazepine and wherein aromatic ring
systems in the substituents can be substituted, independently of
each other, by one to three of the same or different substituents
from the series halogen, cyano, C.sub.1-C.sub.6'-alkyl,
trifluoromethyl, C.sub.3-C.sub.8-cycloalky- l, phenyl, benzyl,
hydroxy, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy, which can
be entirely or partially substituted by fluorine, can carry
benzyloxy, phenoxy, mercapto, C.sub.1-C.sub.6-alkylth- io, carboxy,
C.sub.1-C.sub.6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino,
mono-C.sub.1-C.sub.6-alkylamino or di-(C.sub.1-C.sub.6-alkyl)-amin-
o, whereby two adjacent groups on the aromatic ring or ring system
for an additional ring over a methylenedioxy bridge.
8. The use of compounds according to claims 1-7, characterized in
that the substituents labelled in the formula (I) 571have the
following meanings: R.sup.1 is hydrogen, fluorine, methyl,
trifluoromethyl or hydroxy, R.sup.2 and R.sup.3 are hydrogen,
R.sup.4 is hydrogen or hydroxy, k is 0, A is ethylene, propylene or
butylene which can be each optionally substituted by hydroxy or
once or twice by fluorine, or ethenylene and/or vinylene or
1,3-butadienylene D is selected from C.sub.2-C.sub.6-alkylene or
C.sub.2-C.sub.6-alkenylene, wherein the double bond can also be to
ring E, E is selected from pyrrolidine, piperidine,
hexahydroazepine or morpholine, G is selected from benzyl,
phenethyl, fluorenylmethyl, anthrylmethyl, diphenylmethyl,
fluorenyl or dihydrodibenzocycloheptenyl, furylmethyl,
thienylmethyl, thiazotylmethyl, pyridylmethyl, benzothienylmethyl,
quinolylmethyl, phenyl-thienylmethyl, phenyl-pyridylmethyl,
dihydrodibenzoxepinyl, dihydrodibenzothiepinyl, acetyl, pivaloyl,
phenylacetyl, diphenylacetyl, diphenylpropionyl, naphthyl acetyl,
benzoyl, naphthoyl, anthrylcarbonyl, oxofluorenylcarbonyl,
oxodihydroanthrylcarbonyl or dioxodihydroanthrylcarbonyl, furoyl,
pyridylcarbonyl, chromonylcarbonyl, quinolylcarbonyl,
naphthylaminocarbonyl, dibenzylaminocarbonyl,
benzylphenylaminocarbonyl, diphenylaminocarbonyl,
indolinyl-1-carbenyl, dihydrodibenzazepin-N-carbonyl,
tetrahydroquinolinyl-N-carbonyl,
tetrahydrobenzo[b]azepinyl-N-carbonyl, methanesulfonyl,
phenylsulfonyl, p-toluolsulfonyl, naphthylsulfonyl,
quinolinsulfonyl and diphenylphosphinoyl, wherein aromatic ring
systems can be substituted independently of each other by one to
three of the same or different substituents from the series
halogen, cyano, C.sub.1-C.sub.6-alkyl, trifluoromethyl,
C.sub.3-C.sub.8-cycloalkyl, phenyl, benzyl, hydroxy,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy, which can be
entirely or partially substituted by fluorine, benzyloxy, phenoxy,
mercapto, C.sub.1-C.sub.6-alkylthio, carboxy,
C.sub.1-C.sub.6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino,
mono-C.sub.1-C.sub.6-alkylamino or
di-(C.sub.1-C.sub.6-alkyl)-amino, wherein two adjacent groups in
the ring or ring system can form an additional ring over a
methylendioxy bridge.
9. Use according to one of the claims 1-8, characterized in that
one or more of the following compounds and/or pharmaceutically
acceptable acid addition salts thereof are used for the production
of the medicament
N-[2-(1-benzylpiperidin-4-yl)-ethyl]-3-(pyridin-3-yl)-propionamide,
N-{2-[1-(2-phenylethyl)-piperidin-4-yl]-ethyl}-3-(pyridin-3-yl)-propionam-
ide,
N-{2-[1-(4-phenylbutyl)-piperidin-4-yl]-ethyl}-3-(pyridin-3-yl)-propi-
onamide,
N-{2-[1-(4-hydroxy-4-phenylbutyl)-piperidin-4-yl]-ethyl}-3-(pyrid-
in-3-yl)-propionamide,
N-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-3-(pyr-
idin-3-yl)-propionamide,
N-[3-(1-diphenylmethylpiperidin-4-yl)-propyl]-3-(-
pyridin-3-yl)-propionamide, or
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl-
]-3-(pyridin-3-yl)-propionamide.
10. Use according to any one of the claims 1-8, characterized in
that one or more of the following compounds and/or
pharmacologically acceptable acid addition salts thereof are used
for the production of a medicament
N-[4(1-benzylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,
N-{4-[1-(2-phenylethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamid-
e,
N-{4-[1-(4-biphenylylmethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-ac-
rylamide,
N-{4-[1-(1-naphthylmethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-y-
l)-acrylamide,
N-{4-[1-(9-anthrymethyl)-piperidin-4-yl]-butyl}-3-(pyridin--
3-yl)-acrylamide,
N-{4-[1-(Cyclohexylphenylmethyl)-piperidin-4-yl]-butyl}--
3-(pyridin-3-yl)-acrylamide, or
N-{4-[1-(10,11-dihydro-5H-dienzo[a,d]cyclo-
heptene-5-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide.
11. Use according to any one of the claims 1-8, characterized in
that one or more of the following compounds and/or
pharmacologically acceptable acid addition salts thereof are used
for the production of a medicament
N-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-3-(pyridin-3-yl)-acrylamide,
N-[3-(1-diphenylmethylpiperidin-4-yl)-propyl]-3-(pyridin-3-yl)-acrylamide-
,
N-[5-(1-diphenylmethylpiperidin-4-yl)-pentyl]-3-(pyridin-3-yl)-acrylamid-
e,
N-[6-(1-diphenylmethylpiperidin-4-yl)-hexyl]-3-(pyridin-3-yl)-acrylamid-
e, or
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pe-
ntadiene acid amide.
12. Use according to any one of the claims 1-8, characterized in
that one or more of the following compounds and/or
pharmacologically acceptable acid addition salts thereof are used
for the production of a medicament
N-(4-{1-[bis-(4-fluorophenyl)-methyl]-piperidin-4-yl)-butyl}-3-(pyridin-3-
-yl)-acrylamide,
N-(4-{1-[bis-(2-chlorophenyl)-methyl]-piperidin-4-yl}-but-
yl)-3-(pyridin-3-yl)-acrylamide,
N-[4-(1-diphenylmethylpiperidin-4-yl)-but-
yl]-3-(2-fluoropyridin-3-yl)-acrylamide, or
N-[4-(1-diphenylmethylpiperidi-
n-4-yl)-butyl]-3-(6-fluoropyridin-3-yl)-acrylamide.
13. Use according to any one of the claims 1-8, characterized in
that one or more of the following compounds are used for the
production of a medicament
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)--
acrylamide,
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)--
acrylamide dihydrochloride or,
N-[4-(1-diphenylmethylpiperidin-4-yl)butyl]-
-3-(pyridin-3-yl)-acrylamide methanesulfonate.
14. Use according to any one of the claims 1-13 characterized in
that the compounds according to the general formula (I) are
combined with one or more other active ingredients for the
respective indications such as cytostatic agents or
immunosuppressive agents.
15. Medicament for cytostatic or immunomodulatory and/or
immunosuppressive treatment in human or veterinary medicine,
characterized in that it comprises a compound according to formula
(I) corresponding to the substituent definitions given in claims
1-13 in combination with a cytostatic agent or an immunosuppressive
agent, optionally together with further active ingredients suitable
in the named indications and suitable carriers, adjuvents and
additives.
16. Medicament according to claim 15 for cytostatic treatment,
characterized in that together with a compound according to formula
(I) and aside from pharmaceutically acceptable carriers and
adjuvents, it comprises in combination one or more cytostatic
agents from the series of anti-metabolites such as, cytarabine,
5-fluoruracil, 6-mercaptopurine or methotrexate, alkylating agents
such as busulfan, carmustine, cisplatin, carboplatin,
cyclophosphamide, dacarbazine, melphalan or thiotepa,
DNA-intercalating substances and topoisomerase inhibitors such as
actinomycin D, daunorubicin, doxorubicin, mitomycin C,
mitoxantrone, etoposide, topotecan or irinotecan, spindle poisons
such as vincristine, navelbin, taxol, or taxoter, hormonally active
agents such as tamoxifen, flutiamide, formestan or goserelin or
from the series of other cytostatic agents with complex modes of
action such as L-asparaginase, bleomycin or hydroxyurea or from the
group of the modulators of P-glycoprotein, MRP,
glutathione-S-transferase, metallothionein, optionally together
with futher medicines effective in these indications.
17. Medicament according to claim 15 for immunosuppressive
treatment, characterized in that, together with a compounds
according to formula (I) and aside from pharmaceutically acceptable
carriers and adjuvents, it optionally comprises in combination one
or more immunosuppressive agents from the series of the
cyclosporins, such as cyclosporin A, tacrolimus, raparnycin, the
group of antimetabolites such as methotrexate and azathioprine and
the group of glucocorticoids, optionally together with further
medicines effective in these indications.
18. Use according to one of the claims 1-14, characterized in that
the production of the medicament serves for the treatment of tumors
in connection with the indications gynacological tumors, ovarian
carcinomas, testicle tumors, prostate carcinomas, skin cancer,
kidney cancer, bladder tumors, esophagus carcinomas, stomach
cancer, rectal carcinomas, pancreas carcinomas, thyroid cancer,
adrenal tumors, various types of leukemia and lymphomas, Hodgkin's
disease, tumor illnesses of the CNS, soft-tissue sarcomas, bone
sarcomas, benign and malignant mesotheliomas, especially intestine
cancer, liver cancer, breast cancer, bronchial and lung carcinomas,
melanomas, acute and chronic leukemias and benign papillomatosis
tumors.
19. N-(4-diphenylmethyl-morpholin-2-ylmethyl)-3-
(pyridin-3-yl)-acrylamide
Description
[0001] The invention relates to the use of pyridyl aklane, pyridyl
alkene and/or pyridyl alkine acid amides, especially in the
treatment of tumor conditions and/or as cytostatic agents or as
immunosuppressive agents as well as medicaments with an amount of
these compounds in combination with other cytostatic agents or
immunosuppresive agents.
[0002] A strong need exists for the enrichment of cytostatic
therapy to provide pharmaceuticals and/or medicaments which not
only possess a strong activity, but also exert diminished side
effects in comparison to many classical cancerostatic agents,
whereby treatment of a broad as possible spectrum of tumors should
be made accessible. Furthermore, effective cytostatic agents for an
efficient therapy should be made available. Active ingredients of
this type should also be exceptionally suitable in the mentioned
indications for a combination therapy, be it in connection with
other cytostatic agents or with radiation (for example X-rays,
radioactive elements, such as cobalt, or linear accelerator, etc.),
with operative procedures, heat treatment, etc. As a consequence,
further subject-matter of the invention relates to new medicaments
in the form of combinations of the compounds defined below and used
according to the invention together with other compounds or
immunosuppressive agents customary in the therapy of tumors.
[0003] In this connection, a strong need also exists in tumor
therapy to open up new possibilities which were not usable up to
now in these indications, for example for overcoming or preventing
resistances.
[0004] This object was successfully solved in a completely
suprising manner by making available the specially structured
pyridyl derivatives defined below.
[0005] It was known that various pyridine compounds substituted in
a specific manner have pharmacologically useful properties which
lie however in completely different indication areas.
[0006] Thus, .omega.-pyridyl alkane and/or alkene amides with
anti-allergic activity are described in EP 0 210 782 which are
referred to as having a 5-lipoxygenase-inhibiting and
anti-histamine action, wherein the amide components of these
compounds contain a piperizine or homopiperizine ring and the
pyridine ring can be linked together in the 2-, 3- or 4-position.
JP 63,179,869 describes further pyridyl amides, .omega.-pyridyl
alkane and alkene amides as anti-allergic effective substances
containing a substituted piperidine ring in the amine component.
Such compounds with the same properties are mentioned in Chem.
Pharm. Bull 37, 100-105 (1989) and in J. Med. Chem.
1989,583-593.
[0007] Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides,
wherein the amide portion is bound over an aryl substituted alkyl
chain with a piperidine ring or piprazine ring, are described for
example in EP-A-0 428 434 or in EP-A-0 512 902 as antagonists of
the neurokinin receptor and subtance P. Furthermore,
pyridyl(alkyl)carbonamides, pyridyl(alkyl)sulfonamides and
analogous ureas, wherein the amide portion is bound over an alkyl
chain with a piperidine ring are disclosed in EP-A-0 479 601 as
active ingredients with anti-arrhythmic properties.
[0008] In WO 91/15 485, the production of pyridine-3,5-dicarboxylic
acid esters and amides as well as their use for the treatment of
tumor conditions is described. These compounds differ from the
compounds according to the invention described below in very
important structural features, for example by the dicarboxyl
grouping on the pyridine ring or the absence of the hydrocarbon
chain between the pyridine ring and the amide grouping. The
compounds disclosed in WO 89/07 443 in the form of optically pure
R(-)-Ni-guldipine and further analogous dihydropyridines with
cytotoxic activity have larger structural differences. However, the
compounds according to the invention unexpectedly possess a better
activity and a wider spectrum of action despite the large
structural differences.
[0009] Further structurally closely related compounds are
represented by the antagonists of the histimine-H.sub.1-receptor
described in EP-A-0 343 307 which discloses a series of substituted
piperidine derivatives without naming concrete examples for special
3-pyridyl substitutions.
[0010] EP-A-0 330 026 also discloses substituted piperidine
derivatives with possible, generic pyridyl substitutions for which,
however, merely a single concrete example is disclosed, namely
(E)-3-(3-pyridyl)-N-[2-(1-be-
nzylpiperidin-4-yl)ethyl]-2-propenamide hydrochloride. These
compounds are distinguished by an anti-cholinesterase activity, an
anti-amnesia activity as well as activities directed against
hyperkinesia, senile demensia, mania and Alzheimer's disease.
[0011] In view of this art, the finding that the compounds
according to the general formula (I) defined below have activities
which make them particularly suitable in an excellent manner for
the therapy of tumor illnesses was completely unexpected. Equally
unexpected was the pharmacological finding that the compounds
according to the invention also possess immunosuppressive
properties besides cytostatic activity.
[0012] Considering the above-mentioned completely different known
medical indications of known piperidine derivatives, such as
neurokinin receptor antagonism, hyperkineses, amnesias, allergies,
or rhythm disorders, the activity of the compounds used according
to the invention with the structural modifications as they are
defined below with respect to the present general formula, and the
combinations according to the invention in the form of the detected
excellent cytostatic or immunomodulatory activity with advantageous
therapeutic properties was completely surprising for the person
skilled in the art.
[0013] Pharmacological test results from which this conclusion must
be drawn, as well as the concrete tumor indications and combination
possibilities are detailed and illustrated in the last part of the
description.
[0014] Therefore, subject-matter of the invention relates to the
use of one or more compounds of formula (I) 2
[0015] wherein
[0016] R.sup.1 is hydrogen, halogen, cyano, trifluoromethyl,
hydroxy, benzyloxy,
[0017] aminocarbonyl, carboxy, phenyl, phenoxy, phenylthio,
pyridyloxy, pyridylthio,
[0018] alkyl, especially C.sub.1-C.sub.6-alkyl,
[0019] alkenyl, especially C.sub.3-C.sub.6-alkenyl,
[0020] alkinyl, especially C.sub.3-C.sub.6-alkinyl,
[0021] hydroxyalkyl, especially C.sub.1-C.sub.6-hydroxyalkyl,
[0022] alkoxy, especially C.sub.1-C.sub.6-alkoxy,
[0023] alkenyloxy, especially C.sub.3-C.sub.6-alkenyloxy,
[0024] alkinyloxy, especially C.sub.3-C.sub.6-alkinyloxy,
[0025] alkanoyloxy, especially C.sub.1-C.sub.7-alkanoyloxy,
[0026] alkoxycarbonyloxy, especially
C.sub.2-C.sub.7-alkoxycarbonyloxy,
[0027] alkylthio, especially C.sub.1-C.sub.6-alkylthio,
[0028] alkenylthio, especially C.sub.3-C.sub.6-alkenylthio,
[0029] alkinylthio, especially C.sub.3-C.sub.6-alkinylthio,
[0030] cycloalkyl, especially C.sub.3-C.sub.8-cycloalkyl,
[0031] cycloalkytoxy, especially C.sub.3-C.sub.8-cycloalkyloxy,
[0032] cycloalkylthio, especially
C.sub.3-C.sub.8-cycloalkylthio,
[0033] alkoxycarbonyl, especially
C.sub.2-C.sub.7-alkoxycarbonyl,
[0034] alkylaminocarbonyl, especially
C.sub.2-C.sub.7-alkylaminocarbonyl,
[0035] dialkylaminocarbonyl, especially
C.sub.3-C.sub.13-dialkylaminocarbo- nyl, or
[0036] NR.sup.5R.sup.6, wherein
[0037] R.sup.5 and
[0038] R.sup.6 are selected independently of each other from
hydrogen,
[0039] alkyl, especially C.sub.1-C.sub.6-alkyl,
[0040] alkenyl, especially C.sub.3-C.sub.6-alkenyl and
[0041] alkinyl, especially C.sub.3-C.sub.6-alkinyl,
[0042] R.sup.2 is hydrogen, halogen, cyano, hydroxy,
trifluoromethyl, benzyloxy,
[0043] alkyl, especially C.sub.1-C.sub.6-alkyl,
[0044] alkoxy, especially C.sub.1-C.sub.6-alkoxy or
[0045] alkanoyloxy, especially C.sub.1-C.sub.7-alkanoyloxy,
[0046] wherein R.sup.1 and R.sup.2, if they are adjacent,
optionally form a bridge which is selected from
--(CH.sub.2).sub.4--, --(CH.dbd.CH).sub.2-- and
--CH.sub.2O--CR.sup.7R.sup.8--O--, wherein
[0047] R.sup.7 and
[0048] R.sup.8 are, independently of each other, hydrogen or alkyl,
especially C.sub.1-C.sub.6-alkyl,
[0049] R.sup.3 is hydrogen, halogen, alkyl, especially
C.sub.1-C.sub.6-alkyl, trifluoromethyl or hydroxyalkyl, especially
C.sub.1-C.sub.6-hdroxyalkyl and
[0050] R.sup.4 is hydrogen, hydroxy, benzyloxy,
[0051] alkyl, especially C.sub.1-C.sub.6-alkyl,
[0052] alkenyl, especially C.sub.3-C.sub.6-alkenyl,
[0053] alkinyl, especially C.sub.3-C.sub.6-alkinyl,
[0054] cycloalkyl, especially C.sub.3-C.sub.6-cycloalkyl or
[0055] alkoxy, especially C.sub.1-C.sub.6-alkoxy,
[0056] k is 0 or 1,
[0057] A is alkylene, especially C.sub.1-C.sub.6-alkylene, which is
optionally substituted once to three-fold by alkyl, especially
C.sub.1-C.sub.3-alkyl, hydroxy, alkoxy, especially
C.sub.1-C.sub.3-alkoxy, fluorine or phenyl, or
[0058] 1,2-cyclopropylene or
[0059] alkenylene with at least two C-atoms, especially
C.sub.2-C.sub.6-alkenylene, which is optionally substituted once to
three-fold by C.sub.1-C.sub.3-alkyl, hydroxy,
C.sub.1-C.sub.3-alkoxy, fluorine, cyano or phenyl,
[0060] alkadienylene with at least four C-atoms, especially
C.sub.4-C.sub.6-alkadienylene, which is optionally substituted once
or twice by C.sub.1-C.sub.3-alkyl, fluorine, cyano or phenyl,
[0061] 1,3,5-hexatrienylene, which is optionally substutited by
C.sub.1-C.sub.3-alkyl, fluorine, cyano, or phenyl,
[0062] ethinylene or
[0063] alkylene with at least two C-atoms, especially
C.sub.2-C.sub.6-alkylene in which a methylene unit can be
isosterically replaced by O, S, NR.sup.9, CO, SO or SO.sub.2,
wherein the isosteric substitution, with the exception of .dbd.CO,
cannot be adjacent to the amide group and wherein
[0064] R.sup.9 is selected from hydrogen, alkyl, especially
C.sub.1-C.sub.6-alkyl, alkenyl, especially C.sub.3-C.sub.6-alkenyl,
alkinyl, especially C.sub.3-C.sub.6-alkinyl, acyl, especially
C.sub.1-C.sub.6-acyl or alkylsulfonyl, especially
C.sub.1-C.sub.6-alkylsu- lfonyl,
[0065] D is selected from alkylene, especially
C.sub.1-C.sub.10-alkylene, optionally substituted once or twice by
alkyl, especially C.sub.1-C.sub.6-alkyl, hydroxy, or alkoxy,
especially C.sub.1-C.sub.6-alkoxy,
[0066] alkenylene with at least two C-atoms, especially
C.sub.2-C.sub.10-alkenylene, which is optionally substituted once
or twice by alkyl, especially C.sub.1-C.sub.6-alkyl, hydroxy,
[0067] or alkoxy, especially C.sub.1-C.sub.6-alkoxy, wherein the
double bond can also be to ring E,
[0068] alkinylene with at least three C-atoms, especially
C.sub.3-C.sub.10-alkinylene, optionally substituted once or twice
by alkyl, especially C.sub.1-C.sub.6-alkyl, hydroxy or alkoxy,
especially C.sub.1-C.sub.6-alkoxy, and
[0069] alkylene, especially C.sub.1-C.sub.10-alkylene, alkenylene
with at least two C-atoms, especially C.sub.2-C.sub.10-alkenylene
or alkinylene with at least three C-atoms, especially
C.sub.3-C.sub.10-alkinylene, whereby one to three methylene units
are each isosterically replaced by O, S, NR.sup.10, CO, SO or
SO.sub.2 wherein
[0070] R.sup.10 has the same meaning as
[0071] R.sup.9 but is selected independently thereof,
[0072] E is selected from 3
[0073] wherein the heterocyclic ring can also optionally have a
double bond and
[0074] n and
[0075] p can be, independently of one another, 0, 1, 2 or 3, with
the proviso that n+p<4 and
[0076] q is 2 or 3,
[0077] R.sup.11 is hydrogen, alkyl, especially
C.sub.1-C.sub.6-alkyl, hydroxy, hydroxymethyl, carboxy or
alkoxycarbonyl with at least two C-atoms, especially
C.sub.2-C.sub.7-alkoxycarbonyl and
[0078] R.sup.12 is hydrogen, alkyl, especially
C.sub.1-C.sub.6-alkyl or or an oxo group adjacent to the nitrogen
atom, wherein
[0079] R.sup.11 and R.sup.12 optionally together, form an alkylene
bridge with 1, 2, 3, 4 or 5 C-atoms, especially a
C.sub.1-C.sub.3-alkylene bridge under formation of a bicyclic ring
system,
[0080] G is selected from hydrogen,
[0081] G1, G2, G3, G4 and G5, wherein
[0082] G.sub.1 represents the residue
--(CH.sub.2).sub.r--(CR.sup.14R.sup.15).sub.s--R.sup.13 (G1)
[0083] wherein
[0084] r is an integer from 1 to 3 or O and
[0085] s is 0 or 1,
[0086] R.sup.13 is selected from hydrogen, alkyl, especially
C.sub.1-C.sub.6-alkyl, alkenyl with at least three C-atoms,
especially C.sub.3-C.sub.6-alkenyl, alkinyl with at least three
C-atoms, especially C.sub.3-C.sub.6-alkinyl, cycloalkyl with at
least three C-atoms, especially C.sub.3-C.sub.8-cycloalkyl,
[0087] saturated, five to seven membered heterocycles, which can
contain one or two hetero-atoms from the group N and/or S and/or O,
benzyl or phenyl,
[0088] monocyclic aromatic five or six-membered heterocycles, which
can contain one to three hetero-atoms from the group N and/or S
and/or O and are either bound directly or over a methylene
group,
[0089] anellated bi- and tricyclic aromatic or partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein the linkage can occur either over an
aromatic or a hydrated ring and either directly or over a methylene
group,
[0090] anellated bi- and tricyclic aromatic or partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms can be selected from
N and/or S and/or O and the linkage can occur either over an
aromatic or a hydrated ring and either directly or over a methylene
group,
[0091] R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof,
[0092] R.sup.15 is selected from hydrogen, hydroxy, methyl, benzyl,
phenyl,
[0093] monocyclic aromatic five- or six-membered heterocycles,
which can contain one to three hetero-atoms selected from the group
N and/or S and/or O and are either bound directly or over a
methylene group,
[0094] anellated bi- and tricyclic aromatic or partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein the linkage can occur either over an
aromatic or a hydrated ring and either directly or over a methylene
group,
[0095] anellated bi- and tricyclic aromatic or partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms can be selected from
N and/or S and/or O and the linkage can occur either over an
aromatic or a hydrated ring and either directly or over a methylene
group,
[0096] G2 is the residue 4
[0097] wherein the substituents R.sup.13 and R.sup.15 can have the
above meaning or the grouping
NR.sup.13R.sup.15
[0098] can also be a nitrogen heterocycle bound over the nitrogen
atom, selected from
[0099] saturated or unsaturated monocyclic, four- to eight-membered
heterocycles, which, aside from the essential nitrogen atom, can
optionally contain one or two further hetero-atoms selected from
the group N and/or S and/or O, or
[0100] saturated or unsaturated bi- or tricyclic, anellated or
bridged heterocycles with 8 to 16 ring atoms, which, aside from the
essential nitrogen atom, can optionally contain one or two further
hetero-atoms selected from the group N and/or S and/or O,
[0101] G3 is the residue
SO.sub.2--(CH.sub.2).sub.rR.sup.13 (G3)
[0102] and
[0103] G4 is the residue 5
[0104] wherein
[0105] Ar.sup.1 and Ar.sup.2 are selected independently from one
another from phenyl, pyridyl or naphthyl and
[0106] G5 is the residue
COR.sup.16 (G5)
[0107] wherein
[0108] R.sup.16 is selected from trifluoromethyl, alkoxy,
especially C.sub.1-C.sub.6-alkoxy, alkenyloxy, especially
C.sub.3-C.sub.6-alkenyloxy- , or benzyloxy,
[0109] wherein any aryl residues and/or aromatic ring systems in
the substituents R.sup.1, R.sup.2, R.sup.4, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, Ar.sup.1 and Ar.sup.2 and/or in the ring system
--NR.sup.13R.sup.15 can be substituted independently from each
other by one to three of the same or different residues which are
selected from halogen, cyano, alkyl, especially
C.sub.1-C.sub.6-alkyl, trifluoromethyl, cycloalkyl, especially
C.sub.3-C.sub.8-cycloalkyl, phenyl, benzyl, hydroxy, alkoxy,
especially C.sub.1-C.sub.6-alkoxy, alkoxy, substituted entirely or
partially by fluorine, substituted alkoxy, especially
C.sub.1-C.sub.6-alkoxy, benzyloxy, phenoxy, mercapto, alkylthio,
especially C.sub.1-C.sub.6-alkylthio, carboxy, alkoxycarbonyl,
especially C.sub.1-C.sub.6-alkoxycarbonyl, benzyloxycarbonyl,
nitro, amino, monoalkylamino, especially
mono-C.sub.1-C.sub.6-alkylamino, dialkylamino, especially
di-(C.sub.1-C.sub.6-alkyl)-amino and methylenedioxy for two
adjacent groups on the aromatic ring or ring system,
[0110] wherein each of the residues alkyl, alkenyl, alkinyl,
hydroxyalkyl, alkoxy, alkenyloxy, alkinyloxy, alkanoyloxy,
alkoxycarbonyl, alkoxycarbonyloxy, alkylthio, alkenylthio,
alkinylthio, alkylene, acyl, alkylsulfonyl, alkenylene, alkinylene,
cycloalkyl, cycloalkyloxy, alkoxycarbonyl, alkylaminocarbonyl or
dialkylaminocarbonyl of the substituents R.sup.1 to R.sup.14 can
have 1 to 2 or 4, 6, 8, 10 or 12 C-atoms and/or 2 or 3 to 5, 7, 9,
11 or 13 and/or 15C-atoms or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
or 15C-atoms depending on the structure, as well as
[0111] stereoisomers and/or mixtures thereof and pharmacologically
acceptable
[0112] acid addition salts thereof
[0113] for the production of medicaments for cytostatic or
immunomodulatory and/or immunosuppressive treatment.
[0114] A preferred embodiment according to the invention relates to
the use of compounds of formula (I) 6
[0115] for the production of medicaments for the indications named
above, wherein in the general formula (I)
[0116] R.sup.1 is a hydrogen, halogen, cyano,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkinyl, trifluoromethyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-hydroxyalkyl, hydroxy,
C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-alkinyloxy, benzyloxy, C.sub.1-C.sub.7-alkanoyloxy,
C.sub.2-C.sub.7-alkoxycarbonyloxy, C.sub.1-C.sub.6-alkylthio,
C.sub.3-C.sub.6-alkenylthio, C.sub.3-C.sub.6-alkinylthio,
C.sub.3-Cg-cycloalkyloxy, C.sub.3-C.sub.8-cycloalkylthio,
C.sub.2-C.sub.7-alkoxycarbonyl, aminocarbonyl,
C.sub.2-C.sub.7-alkylamino- carbonyl,
C.sub.3-C.sub.13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy,
phenylthio, pyridyloxy, pyridylthio, or NR.sup.5R.sup.6,
wherein
[0117] R.sup.5 and
[0118] R.sup.6 are selected independently from each other from
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl and
C.sub.3-C.sub.6-alkinyl,
[0119] R.sup.2 is hydrogen, halogen, cyano, C.sub.1-C.sub.6-alkyl,
trifluoromethyl, hydroxy, C.sub.1-C.sub.6-alkoxy, benzyloxy or
C.sub.1-C.sub.7-alkanoyloxy,
[0120] wherein R.sup.1 and R.sup.2, in case they are adjacent,
optionally form a bridge which is selected from the bridge
members
[0121] --(CH.sub.2).sub.4-- and --(CH.dbd.CH).sub.2-- and
--CH.sub.2O--CR.sup.7R.sup.8--O--, wherein
[0122] R.sup.7 and
[0123] R.sup.8 are, independently from each other, hydrogen or
C.sub.1-C.sub.6-alkyl,
[0124] R.sup.3 is hydrogen, halogen, C.sub.1-C.sub.6-alkyl,
trifluoromethyl or C.sub.1-C.sub.6-hydroxyalkyl and
[0125] R.sup.4 is hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl- , C.sub.3-C.sub.6-alkinyl,
C.sub.3-C.sub.6-cycloalkyl, hydroxy, C.sub.1-C.sub.6-alkoxy or
benzyloxy,
[0126] k is 0 or 1,
[0127] A is C.sub.1-C.sub.6-alkylene, which is optionally
substituted once to three-fold by C.sub.1-C.sub.3-alkyl, hydroxy,
C.sub.1-C.sub.3-alkoxy, fluorine or phenyl, or
[0128] 1,2-cyclopropylene or
[0129] C.sub.2-C.sub.6-alkenylene, which is optionally substituted
once to three-fold by C.sub.1-C.sub.3-alkyl, hydroxy,
C.sub.1-C.sub.3-alkoxy, fluorine, cyano or phenyl,
[0130] C.sub.4-C.sub.6-alkadienylene, which is optionally
substituted once or twice by C.sub.1-C.sub.3-alkyl, fluorine, cyano
or phenyl
[0131] 1,3,5-hexatrienylene, which is optionally substituted by
C.sub.1-C.sub.3-alkyl, fluorine, cyano or phenyl
[0132] ethynylene or
[0133] C.sub.2-C.sub.6-alkylene, wherein a methylene unit can be
isosterically replaced by O, S, NR.sup.9, CO, SO or SO.sub.2,
wherein the isosteric substitution, with the exception of .dbd.CO,
cannot be adjacent to the amide group, and
[0134] R.sup.9 is selected from hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkinyl,
C.sub.1-C.sub.6-acyl or C.sub.1-C.sub.6-alkylsulfonyl,
[0135] D is selected from C.sub.1-C.sub.10-alkylene, optionally
substituted once or twice by C.sub.1-C.sub.6-alkyl, hydroxy, or
C.sub.1-C.sub.6-alkoxy,
[0136] C.sub.2-C.sub.10-alkenylene, which is optionally substituted
once or twice by C.sub.1-C.sub.6-alkyl, hydroxy, or
C.sub.1-C.sub.6-alkoxy, wherein the double bond can also be to ring
E,
[0137] C.sub.3-C.sub.10-alkinylene, optionally substituted once or
twice by C.sub.1-C.sub.6-alkyl, hydroxy, or C.sub.1-C.sub.6-alkoxy,
and
[0138] C.sub.1-C.sub.10-alkylene, C.sub.2-C.sub.10-alkenylene or
C.sub.3-C.sub.10-alkinylene, wherein one to three methylene units
are each isosterically replaced by O, S, NR.sup.10, CO, SO or
SO.sub.2, wherein
[0139] R.sup.10 has the same meaning as R.sup.9, but is selected
independently therefrom,
[0140] E is selected from 7
[0141] wherein the heterocyclic ring can optionally have a double
bond and
[0142] n and
[0143] p can be, independently of each other, 0, 1, 2 or 3, with
the proviso that n+p.ltoreq.4 and
[0144] q is 2 or 3,
[0145] R.sup.11 is hydrogen, C.sub.1-C.sub.6-alkyl, hydroxy,
hydroxymethyl, carboxy or C.sub.2-C.sub.7-alkoxycarbonyl and
[0146] R.sup.12 hydrogen, C.sub.1-C.sub.6-alkyl or an oxo group
adjacent to the nitrogen atom, wherein
[0147] R.sup.11 and R.sup.12 optionally together form a
C.sub.1-C.sub.3-alkylene bridge under formation of a bi-cyclic ring
system,
[0148] G is selected from hydrogen,
[0149] G1, G2, G3, G4 and G5, wherein
[0150] G1 represents the residue
(CH.sub.2).sub.r--(CR.sup.14R.sup.15).sub.s--R.sup.13 (G1)
[0151] wherein
[0152] r is an integer from 1 to 3 or 0 and
[0153] s is 0 or 1,
[0154] R.sup.13 is selected from hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkinyl,
C.sub.3-C.sub.8-cycloal- kyl,
[0155] saturated, five- to seven-membered heterocycles, which can
contain one or two hetero-atoms from the group N and/or S and/or
O,
[0156] benzyl or phenyl,
[0157] monocyclic aromatic five or six-membered heterocycles, which
can contain one to three hetero-atoms from the group N and/or S
and/or O and are either bound directly or over a methylene
group,
[0158] anellated bi- and tricyclic aromatic or partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein the linkage can occur either over an
aromatic or a hydrated ring and either directly, or over a
methylene group,
[0159] anellated bi- and tricyclic aromatic or partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms can be selected from
N and/or S and/or O and the linkage can occur either over an
aromatic ring or a hydrated ring and either directly or over a
methylene group,
[0160] R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof,
[0161] R.sup.15 is selected from hydrogen, hydroxy, methyl, benzyl,
phenyl,
[0162] monocyclic aromatic five- or six-membered heterocycles,
which can contain one to three hetero-atoms selected from the group
N and/or S and/or O and are either bound directly or over a
methylene group,
[0163] anellated bi- and tricyclic aromatic or partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein the linkage can occur either over an
aromatic or a hydrated ring and either directly or over a methylene
group,
[0164] anellated bi- and tricyclic aromatic or partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms can be selected from
N and/or S and/or O and the linkage can occur either over an
aromatic ring or a hydrated ring and either directly or over a
methylene group,
[0165] G2 is the residue 8
[0166] wherein the substituents R.sup.13 and R.sup.15 can have the
above meaning or the grouping
NR.sup.13R.sup.15
[0167] can also be a nitrogen heterocycle bound over the nitrogen
atom, selected from
[0168] saturated or unsaturated monocyclic, four- to eight-membered
heterocycles, which, aside from the essential nitrogen atom, can
optionally contain one or two further hetero-atoms selected from
the group N and/or S and/or O, or
[0169] saturated or unsaturated bi- or tricyclic, anellated or
bridged heterocycles with 8 to 16 ring atoms, which, aside from the
essential nitrogen atom, can optionally contain one or two further
hetero-atoms selected from the group N and/or S and/or O,
[0170] G3 is the residue
SO.sub.2--(CH.sub.2).sub.rR.sup.13 (G3)
[0171] and
[0172] G4 is the residue 9
[0173] wherein
[0174] Ar.sup.1 and Ar.sup.2 are selected independently from one
another from phenyl, pyridyl or naphthyl and
[0175] G.sup.5 is the residue
COR.sup.16 (G5)
[0176] wherein
[0177] R.sup.16 is selected from trifluoromethyl,
C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-alkenyloxy, or benzyloxy,
and wherein
[0178] aromatic ring systems in the substituents R.sup.1, R.sup.2,
R.sup.4, R.sup.13, R.sup.14, R.sup.15, R.sup.16, Ar.sup.1 and
Ar.sup.2 and/or in the ring system --NR.sup.13R.sup.15 can be
substituted independently from each other by one to three of the
same or different residues which are selected from halogen, cyano,
C.sub.1-C.sub.6-alkyl, trifluoromethyl, C.sub.3-C.sub.8-Cycloalkyl,
phenyl, benzyl, hydroxy, C.sub.1-C.sub.6-alkoxy, which can
optionally be entirely or partially substituted by fluorine,
benzyloxy, phenoxy, mercapto, C.sub.1-C.sub.6-alkylthio, carboxy,
C.sub.1-C.sub.6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino,
mono-C.sub.1-C.sub.6-alkylamino or di-(C.sub.1-C.sub.6-alkyl)-amino
and methylenedioxy for two adjacent groups on the aromatic ring or
ring system,
[0179] stereoisomers thereof and/or mixtures thereof and
pharmacologically acceptable
[0180] acid addition salts.
[0181] A further preferred embodiment of the invention constitutes
the use of compounds for the indications named above, which are
distinguished in that substituents R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.13, R.sup.14, R.sup.15 and R.sup.16 as well as A and D
indicated for formula (I) have the following meaning in connection
with the given substitutions according to this formula 10
[0182] wherein
[0183] halogen is fluorine, chlorine, bromine or iodine,
[0184] C.sub.1-C.sub.6-alkyl can be straight chain or branched and
is preferably a methyl-, ethyl-, propyl-, isopropyl-, butyl-,
isobutyl-, sec-butyl-, tert-butyl-, cyclopropylmethyl-, pentyl-,
isopentyl-, tert-pentyl-, neopentyl-, cyclopropylethyl-,
cyclobutylmethyl- or a hexyl group, alkylene is for example
methylene, ethylene, propylene, tetramethylene, pentamethylene,
hexamethylene, heptamethylene, octamethylene, nonamethylene or
decamethylene,
[0185] C.sub.3-C.sub.6-alkenyl can be straight chain or branched
and is preferably an allyl-, 2-butenyl-, 3-butenyl-,
2-methyl-2-propenyl-, 2-pentenyl-, 4-pentenyl-,
2-methyl-2-butenyl-, 3-methyl-2-butenyl-, 2-hexenyl-, 5-hexenyl-,
4-methyl-3-pentenyl- or 2,2-dimethyl-3-butenyl group,
[0186] alkenylene is for example ethenylene, propenylene,
butenylene, pentenylene, hexenylene, hexathenylene, heptenylene,
octenylene, nonenylene or decenylene,
[0187] C.sub.3-C.sub.6-alkinyl can be straight chain or branched
and is preferably a propargyl-, 2-butinyl-, 3-butinyl-,
4-pentinyt-, 5-hexinyl- or 4-methyl-2-pentinyl group,
[0188] alkinylene is for example propinylene, butinylene,
pentinylene, hexinylene, heptinylene, octinylene, noninylene or
decinylene,
[0189] C.sub.3-C.sub.8-cyloalkyl is preferably cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
[0190] C.sub.1-C.sub.6-hydroxyalkyl contains a hydroxyl group in
one of the above-named C.sub.1-C.sub.6-alkyl residues, especially
in the form of the hydroxymethyl- and hydroxyethyl group,
wherein
[0191] C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-alkenyloxy,
C.sub.3-C.sub.6-aklinyloxy each contain, aside from the oxygen
atom, one of the C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-
and/or C.sub.3-C.sub.6-alkinyl groups named above and the methoxy-,
ethoxy-, isopropoxy-, tert-butoxy-, allyloxy- and propargyloxy
group are preferred and is to be understood as among
C.sub.1-C.sub.6-alkoxy entirely or partially substituted with
fluorine, for example difluormethoxy, trifluormethoxy or
2,2,2-trifluorethoxy,
[0192] C.sub.1-C.sub.6-alkylthio, C.sub.3-C.sub.6-alkenylthio,
C.sub.3-C.sub.6-alkinylthio each contain, aside from the sulfur
atom, one of the C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.6-alkenyl-
or C.sub.3-C.sub.6-alkinyl group named above, especially the
methylthio-, ethylthio-, isopropylthio- and tert-butylthio
groups,
[0193] C.sub.3-C.sub.8-cycloalkyloxy and
C.sub.3-C.sub.8-cydoalkylthio are preferred as cyclopentyloxy- and
cyclopentylthio- and/or cylohexyloxy- and cyclohexylthio
groups,
[0194] C.sub.1-C.sub.7-alkanoyloxy groups contain, aside from the
oxygen atom, an aliphatic acyl residue with 1 to 7 carbon atoms,
especially the acetoxy-, propionyloxy- and pivaloyloxy group,
[0195] C.sub.2-C.sub.7-alkoxycarbonyl groups contain, aside from
the carbonyl group, one of the C.sub.1-C.sub.6-alkoxy groups
mentioned above, especially the methoxycarbonyl-, ethoxycarbonyl-,
isopropoxycarbonyl-, isobutoxycarbonyl-and tert-butoxycarbonyl
group,
[0196] C.sub.2-C.sub.7-alkoxycarbonyloxy groups contain, aside from
the oxygen atom, one of the C.sub.2-C.sub.7-alkoxycarbonyl residues
mentioned above, especially the methoxycarbonyloxy-,
ethoxycarbonyloxy-, isopropoxycarbonyloxy-,
isobutoxycarbonyloxy-and tert-butoxycarbonyl group as well as the
allyloxycarbonyloxy group,
[0197] C.sub.2-C.sub.7-alkylaminocarbonyl and
C.sub.3-C.sub.13-dialkylamin- ocarbonyl groups contain, beside the
carbonyl group, an alkylamino- and/or dialkylamino residue, whose
C.sub.1-C.sub.6-alkyl groups have the above meanings, wherein the
dimethylaminocarbonyl-, diethylaminocarbonyl- and the
diisopropylatninocarbonyl groups are preferred, and aside from the
unsubstituted amino group, one of the following
C.sub.1-C.sub.6-alkylamin- o groups and/or
di-(C.sub.1-C.sub.6-alkyl)amino groups are to be understood under
the amino groups of the formula NR.sup.5R.sup.6,
[0198] C.sub.1-C.sub.6-alkylamino contains one of the
C.sub.1-C.sub.6-alkyl groups mentioned above, especially in form of
the methylamino-, ethylamino-, propylamino-, isopropylamino-,
butylamino- and the tert-butylamino group,
[0199] di-(C.sub.1-C.sub.6-alkyl)amino carries two of the same or
different of the above named C.sub.1-C.sub.6-alkyl groups on the
nitrogen atom, especially in form of the dimethylamino-,
diethylamino-, dipropylamino-, diisopropylamino-,
isopropylmethylamino-, dibutylamino- or tert-butylmethylamino
group,
[0200] C.sub.1-C.sub.6-acyl is the residue of an aliphatic
saturated or unsaturated, straight chain, branched or cyclic
carboxylic acid, especially in form of the formyl-, acetyl-,
propionyl-, acryloyl-, butyryl-, isobutyryl-, methacryloyl-,
cyclopropylcarbonyl-, pentanoyl-, pivaloyl-, cyclobutylcarbonyl-,
hexanoyl- and the dimethylacryloyl group,
[0201] C.sub.1-C.sub.6-alkansulfonyl is preferably the
methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-,
butanesulfonyl-, pentanesulfonyl- and the hexanesulfonyl group,
saturated five- to seven-membered heterocycles with one or two
hetero-atoms are especially tetrahydrofuryl, tetrahydrothienyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, hexahydroazepinyl,
piperazinyl, hexahydrodiazepinyl or morpholinyl,
[0202] monocyclic aromatic five- or six-membered heterocycles with
one to three hetero-atoms are especially furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl,
pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl,
[0203] anellated bi- and tricyclic aromatic or partially hydrated
carbocyclc ring systems with 8 to 16 ring atoms and at least one
aromatic ring are preferably benzocyclobutyl, indanyl, indenyl,
naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl,
fluorenyl, anthryl, dihydroanthryl, phenanthryl,
dihydrophenanthryl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or
tetrahydrodibenzocyclooctenyl, wherein mono- or dioxo-derivates,
wherein the residues of indanone, tetralone, anthrone,
anthraquinone, fluorenone, phenanthrone, dibenzocycloheptenone,
dihydrodibenzocycloheptenone or tetrahydrodibenzocyclooctenone are
for example also to be understood as partially hydrated carbocyclic
ring systems,
[0204] anellated bi- and tricyclische aromatic or partially
hydrated heterocyclic ring systems with 8 to 16 ring atoms and at
least one aromatic ring are, for example, imidazothiazolyl,
benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl,
indolyl, indolinyl, benzimidazolyl, indazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzofurazanyl,
benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl,
isothiazolopyridyl, imidazopyridyl, pyrazolopyridyl,
thienopyrimidinyl, chromanyl, benzopyranyl, quinolyl, isoquinolyl,
dihydroquinolyl, tetrahydroquinolyl, benzodioxanyl, quinoxalinyl,
quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl,
pyridoindolyl, acridinyl, phenothiazinyl, dihydrodibenzoxepinyl,
benzocycloheptathienyl, dihydrothienobenzothiepiny- l,
dihydrodibenzothiepinyl, octahydrodibenzothiepinyl,
dihydrodibenzazepinyl, octahydrodibenzazepinyl,
benzocycloheptapyridyl, dihydropyridobenzodiazepinyl,
dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl,
dihydropyridobenzoxazepinyl, dihydrodibenzothiazepinyl or
dihydropyridobenzothiazepinyl, wherein their mono- or
dioxo-derivates and/or optionally their possible tautomeres are
also to be understood as partially hydrated heterocyclic ring
systems, for example, the residues of indolinone, isatin,
benzoxazolone and/or its tautomeres hydroxybenzoxazol, of
benzisoxazolone, benzothiazolone, benzoisothiazolone and
benzimidazolone and/or their tautomeres, hydroxybenzisoxazol,
hydroxybenzothiazol, hydroxybenzoisothiazol and
hydroxybenzimidazol, of indazolinone, of oxazolopyridinone,
thiazolopyridinones, pyrazolopyridinones and imidazopyridinones
and/or their tautomeres hydroxyoxazolopyridine,
hydroxythiazolopyridines, hydroxypyrazolopyridines and
hydroxyimidazopyridines, the residues of chromanone, chromone,
quinolinone, dihydroquinolinone, tetrahydrocarbazolone, acridone,
of dihydrodibenzoxepinones, benzocycloheptathiophenones,
dihydrothienobenzothiepinones, dihydrodibenzothiepinones,
dihydrodibenzoazepinones, benzocycloheptapyridinones,
dihydropyridobenzoxazepinones, dihydrodibenzothiazepinones and of
dihydropyridobenzothiazepinones,
[0205] saturated and unsaturated monocyclic, four- to
eight-membered heterocycles are --NR.sup.13R.sup.15 as a grouping
which, aside from the essential nitrogen atom, can optionally
contain one or two further betero-atoms selected from N and/or S
and/or O, for example azetidine, pyrrolidine, piperidine,
(1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine,
octahydroazocine, pyrazolidine, piperazine, hexahydrodiazepine,
morpholine, hexahydrooxazepine, thiomorpholine or
thiomorpholine-1,1-dioxide, saturated or unsaturated bi- or
tricyclic, anellated or bridged heterocycles with 8 to 16 ring
atoms, represent --NR.sup.3R.sup.15 as a grouping which, aside from
the essential nitrogen atom optionally contain one or two further
hetero-atoms, selected from N and/or S and/or O, for example
5-aza-bicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane,
7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane,
2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane,
2,5-diaza-bicyclo[2.2.2]octane, 9-aza-bicyclo[3.3.1]nonane,
indoline, isoindoline, (1H)-dihydroquinoline,
(1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline,
(1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine,
(4H)-dihydrobenothiazine, (1H)-tetrahydrobenzo[b]azepine,
(1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine,
(5H)-tetrahydrobenzo[b]oxazepine,
(SH)-tetrahydrobenzo[b]thiazepine,
1,2,3,4-tetrahydro-9H-pyrido[3,4-blindol, (10H)-dihydroacridine,
1,2,3,4-tetrahydroacridanone, (10H)phenoxazin, (10H)phenothiazine,
(5H)-dibenzazepine, (5H)-dihydrodibenzazepine,
(5H)-octahydrodibenzazepin- e, (5H)-dihydrodibenzodiazepine,
(11H)-dihydrodibenzo[b,e]oxazepine,
(11H)-dihydrodibenzo[b,e]thiazepine,
(10H)-dihydrodibenzo[b,f]oxazepine,
(10H)-dihydrodibenzo[b,f]thiazepine or
(SH)-tetrahydrodibenzazocine, as well as optionally possible
[0206] tautomeres in the case of substitution of the heterocycle as
such or in an anellated ring system by free hydroxy-, mercapto-
and/or amino groups, and their
[0207] stereoisomers such as, if applicable, cis/trans-isomers,
endo/exo-isomers, optic isomers such as enantiomers, diastereomers
as pure isomers or mixtures and/or racemic mixtures as well as the
pharmacologically acceptable acid addition salts with inorganic or
organic acids, wherein the hydrochlorides, hydrobromides,
hydroiodides, sulfates and phosphates, are preferred as addition
salts with suitable inorganic acids and acetates, benzoates,
4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate,
ascorbate, salicylate, formiate, glutarate, tricarballylate,
citrates, fumarates, gluconates, malates, maleates,
methanesulfonates, lactates, oxalates, succinates, tartrates and
toluolsulfonates, for example p-toluolsulfonate are preferred as
addition salts of organic acids.
[0208] The use of compounds in which the substitutents labelled in
formula (I) 11
[0209] have the following meanings, are especially preferred:
[0210] R.sup.1 is hydrogen, halogen, cyano, C.sub.1-C.sub.6-alkyl,
trifluoromethyl, C.sub.3-C.sub.8-cycloallyl,
C.sub.1-C.sub.4-hydroxyalkyl- , hydroxy, C.sub.1-C.sub.4-alkoxy,
benzyloxy, C.sub.1-C.sub.4-alkanoyloxy, C.sub.1-C.sub.4-alkylthio,
C.sub.2-C.sub.5-alkoxycarbonyl, aminocarbonyl,
C.sub.3-C.sub.9-dialkylaminocarbonyl, carboxy, phenyl, phenoxy,
pyridyloxy or NR.sup.5R.sup.6, wherein
[0211] R.sup.5 and
[0212] R.sup.6 are selected independently from each other form
hydrogen and C.sub.1-C.sub.6-alkyl,
[0213] R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6-alkyl,
trifluoromethyl or hydroxy, wherein
[0214] R.sup.1 and R.sup.2, in the case they are adjacent,
optionally form a bridge which are selected from the group of
bridge members --(CH.sub.2).sub.4-- and --(CH.dbd.CH).sub.2-- and
--CH.sub.2O--CR.sup.7R.sup.8--O--, wherein
[0215] R.sup.7 and
[0216] R.sup.8 can be, independently from each other, hydrogen and
C.sub.1-C.sub.6-alkyl,
[0217] R.sup.3 is selected from hydrogen, halogen and
C.sub.1-C.sub.6-alkyl and
[0218] R.sup.4 is selected from hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, hydroxy, C.sub.1-C.sub.6-alkoxy and
benzyloxy,
[0219] k is 0 or 1,
[0220] A is C.sub.1-C.sub.6-alkylene, which is optionally
substituted once to three-fold by C.sub.1-C.sub.3-alkyl, hydroxy,
fluorine or phenyl,
[0221] 1,2-cyclopropylene, C.sub.2-C.sub.6-alkenylene, which is
optionally substituted one to three-fold by C.sub.1-C.sub.3-alkyl,
hydroxy, fluorine, cyano, or phenyl,
[0222] C.sub.4-C.sub.6-alkadienylene, which is optionally
substituted once or twice by C.sub.1-C.sub.3-alkyl, fluorine,
cyano, or phenyl,
[0223] 1,3,5-hexatrienylene, which is optionally substituted by
C.sub.1-C.sub.3-alkyl, fluorine, or cyano,
[0224] ethinylene or
[0225] C.sub.2-C.sub.6-alkylene, wherein a methylene unit can be
isosterically replaced by O, S, NR.sup.9, CO, SO or SO.sub.2, and
wherein the isosteric substitute, with the exception of .dbd.CO,
cannot be adjacent to the amide group, and wherein
[0226] R.sup.9 is hydrogen, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.6-acyl or methanesulfonyl,
[0227] D is selected from C.sub.1-C.sub.10-alkylene, which is
optionally substituted once or twice by C.sub.1-C.sub.3-alkyl or
hydroxy,
[0228] C.sub.2-C.sub.10-alkenylene, optionally substituted once or
twice by C.sub.1-C.sub.3-alkyl or hydroxy, wherein the double bond
can also be to ring E or
[0229] C.sub.3-C.sub.10-alkinylene, which is optionally substituted
once or twice by C.sub.1-C.sub.3-alkyl or hydroxy, and can be
selected as well from
[0230] C.sub.1-C.sub.10-alkylene, C.sub.2-C.sub.10-alkenylene or
C.sub.3-C.sub.10-alkinylene, in which one to three methylene units
are isosterically replaced by O, S, NR.sup.10, CO, SO or SO.sub.2,
wherein
[0231] R.sup.10 has the same meaning as R.sup.9, but is selected
independently therefrom, 12
[0232] wherein the heterocyclic ring can optionally have a double
bond and
[0233] n and p can be, independent of each other, 0, 1, 2 or 3,
with the proviso that n+p<4,
[0234] q is 2 or 3,
[0235] R.sup.11 is selected from hydrogen, C.sub.1-C.sub.3-alkyl,
hydroxcy, hydroxymethyl, carboxy or C.sub.2-C.sub.7-alkoxycarbonyl
and
[0236] R.sup.12 is selected from hydrogen or an oxo group adjacent
to the nitrogen atom,
[0237] G is selected from hydrogen,
[0238] G1, G2, G3, G4 and G5, wherein
[0239] G1 represents the residue
--(CH.sub.2).sub.r--(CR.sup.14R.sup.15).sub.s--R.sup.13 (G1)
[0240] wherein
[0241] r is 0, 1 or 2 and
[0242] s is 0 or 1,
[0243] R.sup.13 is selected from hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkinyl,
C.sub.3-C.sub.8-cycloal- kyl,
[0244] benzyl, phenyl,
[0245] monocyclic aromatic five- or six-membered heterocycles,
which contain one to three hetero-atoms from the group N and/or S
and/or O and are either bound directly or over a methylene
group,
[0246] anellated bi- and tricyclic aromatic or partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, whereby the bond can occur either over an aromatic
or a hydrated ring and either directly or over a methylene
group,
[0247] anellated bi- and tricyclic aromatic or partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms can be selected from
the groups N and/or S and/or O and the bond can occur either over
an aromatic or a hydrated ring and either directly or over a
methylene group,
[0248] R.sup.14 has the same meaning as R.sup.13, but is selected
independently thereof,
[0249] R.sup.15 is selected from hydrogen, hydroxy, methyl, benzyl
or phenyl,
[0250] monocyclic aromatic five- or six-membered heterocycles,
which can contain one to three hetero-atoms selected from the group
N and/or S and/or O and are bound either directly or over a
methylene group,
[0251] anellated bi- and tricyclic aromatic or partially hydrated
carbocyclic ring systems with 8 to 16 ring atoms and at least einem
aromatic ring, wherein the bond can occur either over an aromatic
or a hydrated ring and either directly or over a methylene
group,
[0252] anellated bi- and tricyclic aromatic or partially hydrated
heterocyclic ring systems with 8 to 16 ring atoms and at least one
aromatic ring, wherein one to three ring atoms can be selected from
the group N and/or S and/or O and the bond can occur either over an
aromatic or a hydrated ring and either directly or over a methylene
group,
[0253] G2 is selected from the residues 13
[0254] wherein the substituents R.sup.13 and R.sup.15 the can have
the above meaning, or the grouping
NR.sup.13R.sup.15
[0255] can also be a nitrogen heterocycle bound over the nitrogen
atom, selected from
[0256] saturated or unsaturated monocyclic, four- to eight-membered
heterocycles, which, aside from the essential nitrogen atom, can
optionally contain one or two further hetero-atoms selected from N
and/or S and/or O, or
[0257] saturated or unsaturated bi- or tricyclic, anellated or
bridged heterocycles with 8 to 16 ring atoms, which, aside from the
essential nitrogen atom, can optionally contain one or two further
hetero-atoms selected from N and/or S and/or O,
[0258] G3 is the residue
--SO.sub.2--(CH.sub.2).sub.r R.sup.13 (G3),
[0259] G4 is the residue 14
[0260] wherein
[0261] Ar.sup.1 and
[0262] Ar.sup.2 are selected independently of each other from
phenyl, pyridyl or naphthyl,
[0263] G5 is the residue
--COR.sup.16 (G5)
[0264] wherein
[0265] R.sup.16 is trifluoromethyl, C.sub.1-C.sub.6-alkoxy,
C.sub.3-C.sub.6-alkenyloxy or benzyloxy and
[0266] aromatic ring systems in which the substituents R.sup.1,
R.sup.2, R.sup.4, R.sup.13, R.sup.14, R.sup.15, R.sup.16, Ar.sup.1
and Ar.sup.2 and/or in the ring system --NR.sup.13R.sup.15 can
carry independently of each other one to three of the same or
different substituents from the series halogen, cyano,
C.sub.1-C.sub.6-alkyl, trifluoromethyl, C.sub.3-C.sub.8-cycloalkyl,
phenyl, benzyl, hydroxy, C.sub.1-C.sub.6-alkoxy, which is
optionally entirely or partially substituted by fluorine,
benzyloxy, phenoxy, mercapto, C.sub.1-C.sub.6-alkylthio, carboxy,
C.sub.1-C.sub.6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino,
mono-C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)-amino,
wherein two adjacent groups on the aromatic ring or ring system can
form an additional ring over a methylenedioxy bridge.
[0267] The use of compounds in which the substiutents labelled in
formula (I) 15
[0268] have the following meanings are particularly preferred:
[0269] R.sup.1 is hydrogen, halogen, cyano, methyl,
trifluoromethyl, hydroxy, C.sub.1-C.sub.4-alkoxy, ethylthio,
methoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, carboxy, and
phenoxy,
[0270] R.sup.2 is hydrogen, halogen, trifluoromethyl or
hydroxy,
[0271] R.sup.3 is hydrogen or halogen,
[0272] R.sup.4 is selected from hydrogen, C.sub.1-C.sub.3alkyl,
hydroxy and C.sub.1-C.sub.3-alkoxy,
[0273] k is 0 or 1,
[0274] A is C.sub.2-C.sub.6-alkylene, which is optionally
substituted once or twice by C.sub.1-C.sub.3-alkyl, hydroxy or
fluorine, as well as
[0275] C.sub.2-C.sub.6-alkenylene, which is optionally substituted
once or twice by C.sub.1-C.sub.3-alkyl, hydroxy or fluorine
[0276] C.sub.4-C.sub.6-alkadienylene, which is optionally
substituted by is C.sub.1-C.sub.3-alkyl or by one or two fluorine
atoms,
[0277] 1,3,5-hexatrienylene, which is optionally substituted by
fluorine, or
[0278] C.sub.2-C.sub.6-alkylene, wherein a methylene unit can be
isosterically replaced by O, S, CO or SO.sub.2, and the isosteric
substitute, with the exception of .dbd.CO, cannot be adjacent to
the amide group and,
[0279] D is C.sub.1-Cg-alkylene, which is optionally substituted
once twice by methyl or hydroxy,
[0280] C.sub.2-C.sub.8-alkenylene, which is optionally substituted
once or twice by methyl or hydroxy, wherein the double bond can
also be to ring E,
[0281] C.sub.3-C.sub.8-alkinylene, which is optionally substituted
once or twice by methyl or hydroxy, as well as
[0282] C.sub.1-C.sub.8-alkylene, C.sub.2-C.sub.8-alkenylene or
C.sub.3-C.sub.8-alkinylene, in which one to three methylene units
can be isosterically replaced by O, S, NH, N(CH.sub.3),
N(COCH.sub.3), N(SO.sub.2CH.sub.3), CO, SO or SO.sub.2,
[0283] E is 16
[0284] wherein the heterocyclic ring can optionally have a double
bond and
[0285] n and
[0286] p can be independent of each other 0, 1, 2 or 3, with the
proviso that n+p<3,
[0287] q is 2 or 3,
[0288] R.sup.11 is selected from hydrogen, C.sub.1-C.sub.3-alkyl,
hydroxy, hydroxymethyl and
[0289] R.sup.12 is selected from hydrogen or an oxo group which is
adjacent to the nitrogen atom,
[0290] G is hydrogen or
[0291] G1, G2, G3, G4 and G5, wherein
[0292] G1 represents the residue
--(CH.sub.2).sub.r--(CR.sup.14R.sup.16).sub.s--R.sup.13 (G1)
[0293] wherein
[0294] r is 0, 1 or 2 and
[0295] s is 0 or 1,
[0296] R.sup.13 is selected from hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.8-cycloalkyl, benzyl orphenyl, benzocyclobutyl,
indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl,
tetrahydronaphthyl, oxotetrahydronaphthyl, biphenylenyl, fluorenyl,
oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl,
dioxodihydroanthryl, phenanthryl, dihydrophenanthryl,
oxodihydrophenanthryl, dibenzocycloheptenyl,
oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl,
oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl,
tetrahydrodibenzocyclooctenyl and oxotetrahydrodibenzocyclooctenyl,
bound directly or over a methylene group,
[0297] furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl,
imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl,
dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl,
dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl,
oxobenzisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl,
benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl,
oxobenzimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl,
benzothiadiazolyl, benzotriazolyl, oxazolopyridyl,
oxodihydrooxazolopyridyl, thiazolopyridyl,
oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl,
oxodihydroimidazopyridyl, pyrazolopyridyl,
oxodihydropyrazolopyridyl, thienopyrimidinyl, chromanyl,
chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl,
dihydroquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl,
oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl,
naphthyridinyl, carbazolyl, tetrahydrocarbazolyl,
oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl,
oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl,
oxodihydrodibenzoxepinyl, benzocycloheptathienyl,
oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl,
oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl,
oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl,
dihydrodibenzazepinyl, oxodihydrodibenzazepiny- l,
octahydrodibenzazepinyl, benzocycloheptapyridyl,
oxobenzocycloheptapyridyl, dihydropyridobenzodiazepinyl,
dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl,
dihydropyridobenzoxazepinyl, oxodihydropyridobenzoxazepinyl,
dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl,
dihydropyridobenzothiazepinyl, oxodihydropyridobenzothiazepinyl,
bound directly or over a methylene group,
[0298] R.sup.14 has the same meaning as R.sup.13, but is selected
independently therefrom,
[0299] R.sup.15 is selected from hydrogen, hydroxy, methyl, benzyl
or phenyl,
[0300] indanyl, indenyl, naphthyl, dihydronaphthyl,
tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, pyrazolyl, imidazoyl, oxadiazolyl,
thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl,
pyrimidinyl, triazinyl, benzofuryl, benzothienyl, indolyl,
indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl,
quinolyl or tetrahydroquinolyl bound directly or over a methylene
group,
[0301] G2 is selected from the residues 17
[0302] wherein the substituents R.sup.13 and R.sup.15 can have the
above meanings, or represents the grouping
NR.sup.13R.sup.15
[0303] each over the nitrogen-bound ring atom of azetidine,
pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine,
(1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine,
hexyhydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine,
thiomorpholine-1,1-dioxide, 5-aza-bicyclo[2.1.1]hexane,
2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane,
2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane,
8-aza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane,
9-azabicyclo[3.3.1]nonane, indoline, isoindoline,
(1H)-dihydroquinoline, (1H)-tetrahydroquinoline,
(2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline,
(4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine,
(1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine,
(1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine,
(5H)-tetrahydrobenzolb]thiazepine,
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, (10H)-dihydroacridine,
1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine,
(10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine,
(5H)-Octahydrodibenzazepin- e, (SH)-dihydrodibenzodiazepine,
(1H)-dihydrodibenzo[b,e]oxazepine,
(11)-dihydrodibenzo[b,e]thiazepine,
(10H)-dihydrodibenzo[b,f]oxazepine,
(10H)-dihydrodibenzo[b,f]thiazepine or
(5H)-tetrahydrodibenzazocine,
[0304] G3 is the residue
--SO.sub.2--(CH.sub.2).sub.r R.sup.13 (G3),
[0305] G4 is the residue 18
[0306] wherein
[0307] Ar.sup.1 and
[0308] Ar.sup.2 are selected independently of each other from
phenyl, pyridyl or naphthyl,
[0309] G5 is the residue
--COR.sup.16 (G5)
[0310] wherein
[0311] R.sup.16 is trifluoromethyl, C.sub.1-C.sub.6-alkoxy,
C.sub.3-C.sub.6-alkenyloxy or benzyloxy and
[0312] aromatic ring systems in which the substituents can be
substituted independently of each other by one to three of the same
or different substituents from the series halogen, cyano,
C.sub.1-C.sub.6-alkyl, trifluoromethyl, C.sub.3-C.sub.8-Cycloalkyl,
phenyl, benzyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy, which can be entirely or partially
substituted by fluorine, can carry benzyloxy, phenoxy, mercapto,
C.sub.1-C.sub.6-alkylthio, carboxy, C.sub.1-C.sub.6-alkoxycarbo-
nyl, benzyloxycarbonyl, nitro, amino,
mono-C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)-amino,
wherein two adjacent groups in the ring or ring system can form an
additional ring over a methylenedioxy bridge.
[0313] A further preferred embodiment of the invention is in the
use of compounds which are distinguished in that the labelled
substituents in formula (I) 19
[0314] have the following meaning:
[0315] R.sup.1 is hydrogen, halogen, cyano, methyl,
trifluoromethyl, hydroxy, methoxy or methoxycarbonyl,
[0316] R.sup.2 is hydrogen or halogen,
[0317] R.sup.3 is hydrogen,
[0318] R.sup.4 is selected from hydrogen, C.sub.1-C.sub.3-alkyl or
hydroxy,
[0319] k is 0 or 1,
[0320] A is selected from C.sub.2-C.sub.6-alkylene, which is
optionally substituted once or twice by hydroxy or fluorine, or
[0321] C.sub.2-C.sub.6-alkenylene, which is optionally substituted
once or twice by hydroxy or fluorine,
[0322] C.sub.4-C.sub.6-alkadienylene, which is optionally
substituted by one or two fluorine atoms,
[0323] 1,3,5-hexatrienylene or
[0324] C.sub.2-C.sub.6-alkylene, wherein a methylene unit can be
isosterically replaced by O, S or CO, and the isosteric substitute,
with the exception of .dbd.CO, cannot be adjacent to the amide
group and,
[0325] D is C.sub.2-C.sub.8-alkylene, which is optionally
substituted by methyl or hydroxy,
[0326] C.sub.2-C.sub.8-alkenylene, which is optionally substituted
by methyl or hydroxy, wherein the double bond can also be to ring
E, or
[0327] C.sub.2-C.sub.8-alkylene, C.sub.2-Cg-alkenylene, wherein one
to three methylene units can be isosterically replaced by O, NH,
N(CH.sub.3), N(COCH.sub.3), N(SO.sub.2CH.sub.3) or CO,
[0328] E is selected from the residues 20
[0329] wherein the heterocyclic ring can optionally have a double
bond and
[0330] n and p can be, independent of each other, 0, 1, 2 or 3,
with the proviso that n+p.ltoreq.3 and
[0331] q is 2
[0332] R.sup.11 is hydrogen, methyl or hydroxyl and
[0333] R.sup.12 is hydrogen or an oxo group adjacent to the
nitrogen atom,
[0334] G is selected from hydrogen, C.sub.3-C.sub.8-cycloalkyl,
methoxycarbonyl, tertbutoxycarbonyl, benzyloxycarbonyl,
trifluoroacetyl, diphenylphosphinoyl or the residues 21
[0335] wherein
[0336] r is 0, 1 or 2 and
[0337] s is 0 or 1,
[0338] R.sup.13 is hydrogen, methyl, benzyl or phenyl,
[0339] indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl,
tetrahydronaphthyl, oxotetrahydronaphthyl, fluorenyl, oxofluorenyl,
anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl,
dibenzocycloheptenyl, oxodibenzocycloheptenyl,
dihydrodibenzocyclohepteny- l, oxodihydrodibenzocycloheptenyl bound
directly or over a methylene group,
[0340] furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,
imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl,
dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl,
dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl,
oxobenzisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl,
benzolsothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl,
oxobenzimidazolinyl, benzofurazanyl, benzothiadiazolyl,
benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl,
thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl,
imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl,
thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl, chromonyl,
quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl,
tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl,
quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl,
tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl,
acridinyl, oxodihydroacridinyl, phenothiazinyl,
dihydrodibenzoxepinyl, benzocycloheptathienyl,
oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl,
oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl,
oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl,
oxodihydrodibenzazepinyl, octahydrodibenzazepinyl,
benzocycloheptapyridyl, oxobenzocycloheptapyridyl,
dihydropyridobenzoxepinyl, dihydrodibenzothiazepinyl,
oxodihydrodibenzothiazepinyl bound directly or over a methylene
group,
[0341] R.sup.14 is hydrogen, methyl, benzyl or phenyl,
[0342] R.sup.15 is selected from hydrogen, hydroxy, methyl, benzyl,
phenyl,
[0343] naphthyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, benzofuryl,
benzothienyl, indolyl, indolinyl, benzoxazolyl, benzothiazolyl,
benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl, bound
directly or over a methylene group, wherein in formula (I) 22
[0344] the group NR.sup.13R.sup.15 can be selected from
pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine,
Octahydroazocine, piperazine, hexahydrodiazepine, morpholine,
hexahydrooxazepine, 2-azabicyclo[2.2.1]heptane,
7-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane,
8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, indoline,
isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline,
(2H)-tetrahydroisoquinol- ine, (1H)-tetrahydroquinoxaline,
(4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine,
(1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine,
(5H)-tetrahydrobenzo[b]oxazepine,
(5H)-tetrahydrobenzo[b]thiazepine,
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]ind- ol, (10H)-dihydroacridine,
1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine,
(5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine,
(11H)-dihydrodibenzo[b,e]thiazepine,
(10H)-dihydrodibenzo[b,f]oxaze-pine or
(5H)-tetrahydrodibenzazocine.
[0345] The use of compounds in which the labelled substituents in
the formula (I) 23
[0346] have the following meanings are very particularly
preferred:
[0347] R.sup.1 is hydrogen, fluorine, chlorine, bromine, methyl,
trifluoromethyl or hydroxy,
[0348] R.sup.2 and
[0349] R.sup.3 are hydrogen,
[0350] R.sup.4 is hydrogen or hydroxy,
[0351] k is 0 or 1,
[0352] A is selected from C.sub.2-C.sub.6-alkylene, which is
optionally substitued once or twice by hydroxy or fluorine or,
[0353] C.sub.2-C.sub.4-alkylene, which is optionally substituted by
fluorine,
[0354] C.sub.4-alkadienylene, which is optionally substituted by
fluorine,
[0355] D is selected from C.sub.2-C.sub.6-alkylene,
C.sub.2-C.sub.6-alkenylene, wherein the double bond can also be to
ring E, and C.sub.2-C.sub.6-alkylene and
C.sub.2-C.sub.6-alkenylene, wherein a methylene unit can be
isosterically replaced by O, NH, N(CH.sub.3) or CO or an ethylene
group can be isosterically replaced by NH--CO and/or CO--NH or a
propylene group can be isosterically replaced by NH--CO--O and/or
O--CO--NH,
[0356] E is selected from pyrrolidine, piperidine,
1,2,5,6-tetrahydropyrid- ine, hexahydroazepine, morpholine and
hexahydro-1,4-oxazepine, wherein the heterocyclic ring optionally
adjacent to the nitrogen atom, can be substituted by an oxo
group,
[0357] G is selected from hydrogen, tert-butoxycarbonyl,
diphenylphosphinoyl, or one of the residues 24
[0358] wherein
[0359] r is 0 or 1 and
[0360] s is 0 or 1,
[0361] R.sup.13 is hydrogen, methyl, benzyl or phenyl,
[0362] indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl,
fluorenyl, oxofluorenyl, anthryl, dihydroanthryl,
oxodihydroanthryl, dioxodihydroanthryl, dibenzocycloheptenyl,
dihydrodibenzocycloheptenyl bound directly or over a methylene
group,
[0363] furyl, thienyl, oxazolyl, thiazolyl, imidazolyl,
oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,
imidazothiazolyl, benzofuryl, benzothienyl, indolyl, oxoindolinyl,
dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzothiazolyl,
oxobenzthiazolinyl, benzimidazolyl, oxobenzimidazolinyl,
benzofurazanyl, benzotriazolyl, oxazolopyridyl,
oxodihydrooxazolopyridyl, thiazolopyridyl,
oxodihydrothiazolopyridyl, chromanyl, chromanonyl, benzopyranyl,
chromonyl, quinolyl, isoquinolyl, oxodihydroquinolinyl,
tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl,
quinazolinyl, acridinyl, oxodihydroacridinyl, phenothiazinyl,
dihydrodibenzoxepinyl, benzocycloheptathienyl,
dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl,
oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl,
oxodihydrodibenzazepinyl, octahydrodibenzazepinyl,
benzocycloheptapyridyl, oxobenzocycloheptapyridyl,
dihydrodibenzothiazepinyl bound directly or over a methylene
group,
[0364] R.sup.14 is hydrogen, methyl, benzyl or phenyl,
[0365] R.sup.15 is hydrogen, hydroxy, methyl, benzyl or phenyl,
[0366] naphthyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl,
indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl,
quinolyl or tetrahydroquinolyl bound directly or over a methylene
group, wherein in the formula 25
[0367] the group NR.sup.13R.sup.15 can be selected from
pyrrolidine, piperidine, hexahydroazepine, morpholine,
2,5-diazabicyclo[2.2.1]heptane, indoline, isoindoline,
(1H)dihydroquinoline, (1H)-tetrahydroquinoline,
(2H)-tetrahydroisoquinoline, (1H)-tetrahydrobenzo[b]azepine,
(1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine,
(5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydroacridanone,
(5H)-dihydrodibenzazepine, (11H)-dihydrodibenzo[b,e]-oxazepine or
(11H)-dihydrodibenzo[b,e]thiazepine and
[0368] wherein aromatic ring systems in the substituents can be
substituted, independently of each other, by one to three of the
same or different substituents from the series halogen, cyano,
C.sub.1-C.sub.6-alkyl, trifluoromethyl, C.sub.3-C.sub.8-cycloalkyl,
phenyl, benzyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy, which can be entirely or partially
substituted by fluorine, can carry benzyloxy, phenoxy, mercapto,
C.sub.1-C.sub.6-alkylthio, carboxy, C.sub.1-C.sub.6-alkoxycarbonyl,
benzyloxycarbonyl, nitro, amino, mono-C.sub.1-C.sub.6-alkylamino or
di-(C.sub.1-C.sub.6-alkyl)-amino, whereby two adjacent groups on
the aromatic ring or ring system for an additional ring over a
methylenedioxy bridge.
[0369] The use of compounds is especially preferred which
distinguish themselves in that the labelled substituents in the
formula (I) 26
[0370] have the following meanings:
[0371] R.sup.1 is hydrogen, fluorine, methyl, trifluoromethyl or
hydroxy,
[0372] R.sup.2 and
[0373] R.sup.3 are hydrogen,
[0374] R.sup.4 is hydrogen or hydroxy,
[0375] k is 0,
[0376] A is ethylene, propylene or butylene which can each be
optionally substituted by hydroxy or once or twice by fluorine,
or
[0377] ethenylene and/or vinylene or
[0378] 1,3-butadienylene
[0379] D is selected from C.sub.2-C.sub.6-alkylene or
C.sub.2-C.sub.6-alkenylene, wherein the double bond can also be to
ring E,
[0380] E is selected from pyrrolidine, piperidine, hexahydroazepine
or morpholine,
[0381] G is selected from benzyl, phenethyl, fluorenylmethyl,
anthrylmethyl, diphenylmethyl, fluorenyl or
dihydrodibenzocycloheptenyl,
[0382] furylmethyl, thienylmethyl, thiazolylmethyl, pyridylmethyl,
benzothienylmethyl, quinolylmethyl, phenyl-thienylmethyl,
phenyl-pyridylmethyl, dihydrodibenzoxepinyl,
dihydrodibenzothiepinyl,
[0383] acetyl, pivaloyl, phenylacetyl, diphenylacetyl,
diphenylpropionyl, naphthylacetyl, benzbyl, naphthoyl,
anthrylcarbonyl, oxofluorenylcarbonyl, oxodihydroanthrylcarbonyl or
dioxodihydroanthrylcarbonyl,
[0384] furoyl, pyridylcarbonyl, chromonylcarbonyl,
quinolylcarbonyl,
[0385] naphthylaminocarbonyl, dibenzylaminocarbonyl,
benzylphenylaminocarbonyl, diphenylaminocarbonyl,
indolinyl-1-carbonyl, dihydrodibenzazepin-N-carbonyl,
tetrahydroquinolinyl-N-carbonyl,
tetrahydrobenzo[b]azepinyl-N-carbonyl,
[0386] methanesulfonyl, phenylsulfonyl, p-toluolsulfonyl,
naphthylsulfonyl, quinolinsulfonyl and
[0387] diphenylphosphinoyl,
[0388] wherein aromatic ring systems can be substituted
independently of each other by one to three of the same or
different substituents from the series halogen, cyano,
C.sub.1-C.sub.6-alkyl, trifluoromethyl, C.sub.3-Cg-cycloalkyl,
phenyl, benzyl, hydroxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy, which can be entirely or partially
substituted by fluorine, benzyloxy, phenoxy, mercapto,
C.sub.1-C.sub.6-alkylthio, carboxy, C.sub.1-C.sub.6-alkoxycarbonyl,
benzyloxycarbonyl, nitro, amino, mono-C.sub.1-C.sub.6-alkylamino or
di-(C.sub.1-C.sub.6-alkyl)-amino, wherein two adjacent groups in
the ring or ring system can form an additional ring over a
methylendioxy bridge.
[0389] A series of compounds with the respective substituent
definitions are listed as follows in Table 1 for illustration of
the use according to the invention without any intended
restriction.
1TABLE 1 Exemplifying compounds of formula (I) according to the
invention 27 Nr R.sup.1 k A R.sup.4 D--E--G 1 H 0 CH.dbd.CH H 28 2
H 0 CH.dbd.CH H 29 3 H 0 CH.sub.2CH.sub.2CH.sub.- 2CH.sub.2 H 30 4
H 0 CH.dbd.CH H 31 5 H 0 CH.dbd.CH H 32 6 H 0 CH.sub.2CH.sub.2 H 33
7 H 0 CH.dbd.CH--CH.dbd.CH H 34 8 H 0 CH.dbd.CH H 35 9 H 0
CH.sub.2CH.sub.2 H 36 10 H 0 CH.dbd.CH H 37 11 H 0 CH.sub.2CH.sub.2
H 38 12 H 0 CH.dbd.CH H 39 13 H 0 CH.dbd.CH H 40 14 H 0
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 41 15 H 0 CH.dbd.CH--CH.dbd.CH H
42 16 H 0 CH.sub.2CH.sub.2 H 43 17 H 0 CH.dbd.CH H 44 18 H 0
CH.sub.2CH.sub.2 H 45 19 H 0 CH.dbd.CH H 46 20 H 0 CH.sub.2CH.sub.2
H 47 21 H 0 CH.sub.2CH.sub.2 H 48 22 H 0 CH.dbd.CH H 49 23 H 0
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 50 24 H 0 CH.dbd.CH--CH.dbd.CH H
51 25 H 0 CH.sub.2CH.sub.2 H 52 26 H 0 CH.sub.2CH.sub.2 H 53 27
6-Cl 0 CH.dbd.CH H 54 28 2-CH.sub.3 0 CH.sub.2CH.sub.2 H 55 29 H 0
CH.dbd.CH H 56 30 H 0 CH.dbd.CH H 57 31 H 0 CH.dbd.CH H 58 32 H 0
CH.sub.2CH.sub.2CH.sub.2 H 59 33 H 0 CH.sub.2CH.sub.2 H 60 34 H 0
CH.dbd.CH H 61 35 H 0 CH.sub.2 H 62 36 H 0 CH.sub.2CH.sub.2CH.sub.2
H 63 37 H 0 CH.sub.2CH.sub.2 H 64 38 H 0 CH.sub.2CH.sub.2 H 65 39 H
0 CH.sub.2CH.sub.2 H 66 40 H 0 CH.sub.2CH.sub.2 H 67 41 H 0
CH.sub.2CH.sub.2 H 68 42 H 0 CH.dbd.CH H 69 43 H 0
CH.sub.2CH.sub.2CH.sub.2 H 70 44 H 0 CH.sub.2CH.sub.2 H 71 45 H 1
CH.sub.2CH.sub.2 H 72 46 H 0 CH.dbd.CH H 73 47 H 1 CH.dbd.CH H 74
48 2-Cl 0 CH.dbd.CH H 75 49 2-F 0 CH.dbd.CH H 76 50 5-F 0 CH.dbd.CH
H 77 51 6-CH.sub.2O 0 CH.dbd.CH H 78 52 H 0 79 H 80 53 H 0
CH.dbd.CH CH.sub.3 81 54 H 0 CH.sub.2CH.sub.2 H 82 55 H 0 CH.dbd.CH
H 83 56 H 0 CH.dbd.CH H 84 57 H 0 CH.dbd.CH H 85 58 H 0 CH.dbd.CH H
86 59 H 0 CH.sub.2CH.sub.2 H 87 60 H 0 CH.dbd.CH H 88 61 H 0
CH.dbd.CH H 89 62 H 0 CH.sub.2CH.sub.2 H 90 63 H 0 CH.dbd.CH H 91
64 H 0 CH.dbd.CH H 92 65 H 0 CH.sub.2CH.sub.2CH.sub.2CH- .sub.2 H
93 66 H 0 CH.sub.2CH.sub.2 H 94 67 H 0 95 H 96 68 H 0
CH.sub.2CH.sub.2 H 97 69 H 0 CH.sub.2CH.sub.2CH.sub.2 H 98 70 H 0
CH.sub.2CH.sub.2 H 99 71 H 0 CH.dbd.CH H 100 72 H 0
CH.sub.2CH.sub.2 H 101 73 H 0 CH.dbd.CH H 102 74 H 0
CH.sub.2CH.sub.2 H 103 75 H 0 CH.dbd.CH H 104 76 H 0
CH.sub.2CH.sub.2 H 105 77 H 0 CH.dbd.CH H 106 78 H 0 CH.dbd.CH H
107 79 H 0 CH.dbd.CH H 108 80 H 0 CH.sub.2CH.sub.2 H 109 81 H 0
CH.dbd.CH H 110 82 H 0 CH.sub.2CH.sub.2 H 111 83 H 0
CH.sub.2CH.sub.2 H 112 84 H 0 CH.dbd.CH H 113 85 H 0
CH.sub.2CH.sub.2 H 114 86 H 0 CH.dbd.CH H 115 87 H 0
CH.dbd.CH--CH.dbd.CH H 116 88 H 0 CH.sub.2CH.sub.2 H 117 89 H 0
CH.dbd.CH H 118 90 H 0 CH.sub.2 H 119 91 H 0 CH.sub.2CH.sub.2 H 120
92 H 1 CH.sub.2CH.sub.2 H 121 93 2-F 0 CH.sub.2CH.sub.2 H 122 94
6-CH.sub.3 0 CH.sub.2CH.sub.2 H 123 95 H 0 CH.dbd.CH H 124 96 H 0
CH.sub.2CH.sub.2 H 125 97 H 0 CH.dbd.CH H 126 98 H 0
CH.sub.2CH.sub.2 H 127 99 H 0 CH.dbd.CH H 128 100 H 0
CH.sub.2CH.sub.2 H 129 101 H 1 CH.sub.2CH.sub.2 H 130 102 2-OH 0
CH.sub.2CH.sub.2 H 131 103 6-CH.sub.3O 0 CH.sub.2CH.sub.2 H 132 104
0 CH.dbd.CH H 133 105 1 CH.dbd.CH H 134 106 2-OH 0 CH.dbd.CH H 135
107 2-F 0 CH.dbd.CH H 136 108 5-F 0 CH.dbd.CH H 137 109 6-F 0
CH.dbd.CH H 138 110 2-Cl 0 CH.dbd.CH H 139 111 6-C.sub.2H.sub.5S 0
CH.dbd.CH H 140 112 6-C.sub.6H.sub.5O 0 C.dbd.CH H 141 113 H 0 142
H 143 114 H 0 144 H 145 115 H 0 146 H 147 116 H 0 148 H 149 117 H 0
150 H 151 118 H 0 152 H 153 119 H 0 154 H 155 120 H 0
CH.sub.2CF.sub.2 H 156 121 H 0 CH.dbd.CH CH.sub.3 157 122 H 0
CH.sub.2CH.sub.2 C.sub.2H.sub.5 158 123 H 0 CH.dbd.CH
C.sub.2H.sub.5 159 124 H 0 CH.dbd.CH 160 161 125 H 0
CH.sub.2CH.sub.2 OH 162 126 H 0 CH.dbd.CH OH 163 127 H 0 164 H 165
128 H 0 C.ident.C H 166 129 H 0 OCH.sub.2 H 167 130 H 0
SCH.sub.2CH.sub.2 H 168 131 H 0 CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H
169 132 H 0 CH.dbd.CH--CH.dbd.CH H 170 133 H 0
CH.sub.2NHCH.sub.2CH.sub.2 H 171 134 H 0 172 H 173 135 H 0 174 H
175 136 H 0 CH.dbd.CH H 176 137 H 0
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 177 138 H 0 CH.sub.2CH.sub.2 H
178 139 H 0 CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 179 140 H 0
CH.sub.2CH.sub.2CH.sub.2 H 180 141 H 0
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 181 142 H 0 CH.sub.2CH.sub.2 H
182 143 H 0 CH.dbd.CH H 183 144 H 0
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 184 145 H 0
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 185 146 H 0 CH.dbd.CH H 186 147
H 0 CH.dbd.CH H 187 148 H 0 CH.dbd.CH H 188 149 H 0 OCH.sub.2 H 189
150 H 0 CH.sub.2CH.sub.2 H 190 151 H 0 CH.sub.2 H 191 152 H 0
CH.dbd.CH H 192 153 H 0 CH.sub.2CH.sub.2 H 193 154 H 0 CH.dbd.CH H
194 155 H 0 CH.sub.2CH.sub.2 H 195 156 H 0 CH.dbd.CH H 196 157 H 0
CH.sub.2CH.sub.2 H 197 158 H 0 CH.dbd.CH H 198 159 H 0 CH.dbd.CH H
199 160 H 0 CH.dbd.CH H 200 161 H 0 CH.sub.2CH.sub.2 H 201 162 H 0
CH.sub.2CH.sub.2 H 202 163 H 0 CH.dbd.CH H 203 164 H 0
CH.sub.2CH.sub.2 H 204 165 H 0 CH.dbd.CH H 205 166 H 0
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 206 167 H 0 CH.sub.2CH.sub.2 H
207 168 H 0 CH.sub.2CH.sub.2 H 208 169 H 0 CH.dbd.CH H 209 170 H 0
CH.sub.2CHF H 210 171 H 0 CH.dbd.CH H 211 172 H 1 CH.dbd.CH H 212
173 H 0 CH.dbd.CH CH.sub.3 213 174 H 0 CH.dbd.CH H 214 175 H 0
CH.sub.2CH.sub.2 H 215 176 H 0 CH.sub.2CH.sub.2 H 216 177 H 0
CH.dbd.CH H 217 178 H 0 CH.dbd.CH H 218 179 H 0 CH.dbd.CH H 219 180
H 0 220 H 221 181 H 0 CH.sub.2CH.sub.2 H 222 182 H 0
CH.sub.2CH.sub.2 H 223 183 H 0 CH.dbd.CH H 224 184 H 0
CH.sub.2CH.sub.2CH.sub.2 H 225 185 H 0 CH.sub.2CH.sub.2 H 226 186 H
0 CH.dbd.CH H 227 187 H 0 CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 228
188 H 0 CH.dbd.CH H 229 189 H 0 CH.sub.2CH.sub.2 H 230 190 H 0
CH.dbd.CH H 231 191 H 0 CH.sub.2CH.sub.2 H 232 192 H 0 CH.dbd.CH H
233 193 H 0 CH.sub.2CH.sub.2 H 234 194 H 0 CH.dbd.CH H 235 195 H 0
CH.sub.2CH.sub.2 H 236 196 H 0 CH.sub.2CH.sub.2 H 237 197 H 0
CH.dbd.CH H 238 198 H 0 CH.dbd.CH H 239 199 H 0 SCH.sub.2CH.sub.2 H
240 200 H 0 CH.dbd.CH H 241 201 H 0 CH.sub.2CH.sub.2 H 242 202 H 0
CH.sub.2CH.sub.2 H 243 203 H 0 CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H
244 204 H 0 CH.sub.2CH.sub.2 H 245 205 H 0 CH.dbd.CH H 246 206 H 0
CH.sub.2CH.sub.2 H 247 207 H 0 CH.dbd.CH H 248 208 H 0
CH.sub.2CH.sub.2CH.sub.2 H 249 209 H 0 CH.sub.2CH.sub.2 H 250 210 H
0 CH.dbd.CH H 251 211 H 0 CH.sub.2CH.sub.2 H 252 212 H 0 CH.dbd.CH
H 253 213 H 0 CH.dbd.CH H 254 214 H 0 CH.dbd.CH H 255 215 H 0
CH.sub.2 H 256 216 H 0 CH.dbd.CH H 257 217 H 0 CH.sub.2CH.sub.2 H
258 218 H 0 CH.sub.2CH.sub.2 H 259 219 H 0 CH.dbd.CH H 260 220 6-F
0 CH.dbd.CH H 261 221 H 0 CH.sub.2CH.sub.2 H 262 222 H 0 CH.dbd.CH
H 263 223 H 0 CH.sub.2CH.sub.2 H 264 224 H 0 CH.dbd.CH H 265 225 H
0 CH.dbd.CH H 266 226 H 0 CH.sub.2CH.sub.2 H 267 227 H 0 CH.dbd.CH
H 268 228 H 0 CH.dbd.CH H 269 229 H 0 CH.dbd.CH H 270 230 H 0
CH.sub.2CH.sub.2 H 271 231 H 0 CH.dbd.CH H 272 232 H 0
CH.sub.2CH.sub.2 H 273 233 H 0 CH.dbd.CH H 274 234 H 0 CH.dbd.CH H
275 235 H 0 CH.sub.2CH.sub.2 H 276 236 H 0 CH.sub.2CH.sub.2 H 277
237 H 0 CH.dbd.CH H 278 238 H 0 CH.sub.2CH.sub.2 H 279 239 H 0
CH.dbd.CH H 280 240 H 0 CH.sub.2CH.sub.2 H 281 241 H 0 CH.dbd.CH H
282 242 H 0 CH.dbd.CH H 283 243 H 0 CH.dbd.CH--CH.dbd.CH H 284 244
H 0 CH.sub.2CH.sub.2 H 285 245 H 0 CH.dbd.CH H 286 248 H 0
CH.dbd.CH--CH.dbd.CH H 287 247 H 0 CH.sub.2CH.sub.2 H 288 248 H 0
CH.dbd.CH H 289 249 H 0 CH.sub.2CH.sub.2CH.sub.2 H 290 250 H 0
CH.dbd.CH H 291 251 H 0 CH.sub.2CH.sub.2 H 292 252 H 0 CH.dbd.CH H
293 253 H 0 CH.dbd.CH--CH.dbd.CH H 294 254 H 0 CH.dbd.CH H 295 255
H 0 CH.sub.2CH.sub.2CH.sub.2 H 296 256 H 0 CH.sub.2CH.sub.2 H 297
257 H 0 CH.dbd.CH H 298 258 H 0 CH.sub.2CH.sub.2 H 299 259 H 0
CH.dbd.CH H 300 260 H 0 CH.dbd.CH--CH.dbd.CH H 301 261 H 0
CH.sub.2CH.sub.2 H 302 262 H 0 CH.dbd.CH H 303 263 H 0
CH.sub.2CH.sub.2 H 304 264 H 0 CH.sub.2CH.sub.2 H 305 265 H 0
CH.dbd.CH H 306 266 H 0 CH.sub.2CH.sub.2 H 307 267 H 0
CH.sub.2CH.sub.2 H 308 268 H 0 CH.dbd.CH H 309 269 H 0
CH.sub.2CH.sub.2 H 310 270 H 0 CH.sub.2CH.sub.2 H 311 271 H 0
CH.dbd.CH H 312 272 H 0 CH.sub.2CH.sub.2 H 313 273 H 0
CH.dbd.CH--CH.dbd.CH H 314 274 H 0 CH.sub.2CH.sub.2 H 315 275 H 0
CH.sub.2CH.sub.2 H 316 276 H 0 CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H
317 277 H 0 CH.dbd.CH H 318 278 H 0 CH.sub.2CH.sub.2 H 319 279 H 0
CH.dbd.CH H 320 280 H 0 CH.sub.2CH.sub.2 H 321 281 H 0
CH.sub.2CH.sub.2 H 322 282 H 0 CH.dbd.CH H 323 283 H 0 CH.dbd.CH H
324 284 H 0 CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 325 285 H 0
CH.sub.2CH.sub.2 H 326 286 H 0 CH.dbd.CH H 327 287 H 0
CH.sub.2CH.sub.2 H 328 288 H 0 CH.dbd.CH H 329 289 H 0
CH.sub.2CH.sub.2 H 330 290 H 0 CH.dbd.CH H 331 291 H 0
CH.dbd.CH--CH.dbd.CH H 332 292 H 0 CH.dbd.CH H 333 293 H 0
CH.dbd.CH H 334 294 H 0 CH.sub.2CH.sub.2 H 335 295 H 0 336 H 337
295 H 0 CH.sub.2CH.sub.2 H 338 297 H 0 CH.sub.2CH.sub.2 H 339 298 H
0 CH.dbd.CH H 340 299 H 0 CH.dbd.CH H 341 300 H 0 CH.sub.2CH.sub.2
H 342 301 H 0 CH.dbd.CH H 343 302 H 0 CH.sub.2CH.sub.2 H 344 303 H
0 CH.dbd.CH--CH.dbd.CH H 345 304 H 0 CH.sub.2CH.sub.2 H 346 305 H 0
CH.sub.2CH.sub.2 H 347 306 H 0 CH.dbd.CH H 348 307 H 0 CH.dbd.CH H
349 308 H 0 CH.sub.2CH.sub.2 H 350 309 H 0 CH.dbd.CH H 351 310 H 0
CH.dbd.CH H 352 311 H 0 CH.sub.2CH.sub.2 H 353 312 H 0
CH.sub.2CH.sub.2CH.sub.2CH- .sub.2 H 354 313 H 0 CH.sub.2CH.sub.2 H
355 314 H 0 CH.dbd.CH H 356 315 H 0 CH.dbd.CH H 357 316 H 0
CH.dbd.CH--CH.dbd.CH H 358 317 H 0 CH.sub.2CH.sub.2 H 359 318 H 0
C.ident.C H 360 319 H 0 CH.sub.2CH.sub.2CH.sub.2 H 361 320 H 0
CH.sub.2CH.sub.2 H 362 321 H 0 CH.dbd.CH H 363 322 H 0 CH.dbd.CH H
364 323 H 0 CH.dbd.CH H 365 324 H 0 CH.sub.2CH.sub.2 H 366 325 H 0
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 367 326 H 0 368 H 369 327 H 0
CHphd 2CH.sub.2 H 370 328 H 0 CH.sub.2CH.sub.2 H 371 329 H 0
CH.sub.2CH.sub.2CH.sub.2 H 372 330 H 0 CH.dbd.CH H 373 331 H 0
CH.dbd.CH H 374 332 H 0 CH.sub.2CH.sub.2 H 375 323 H 0
CH.sub.2CH.sub.2 H 376 334 H 0 OCH.sub.2 H 377 335 H 0
CH.sub.2CH.sub.2CH.sub.2 H 378 336 H 0 CH.sub.2CH.sub.2 H 379 337 H
0 CH.sub.2CH.sub.2 H 380 338 H 0 CH.dbd.CH H 381 339 H 0
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 H 382 340 H 0 CH.sub.2CH.sub.2 H
383 341 H 0 CH.sub.2CH.sub.2 H 384 342 H 0 CH.dbd.CH H 385 343 H 0
CH.sub.2CH.sub.2 H 386 344 H 0 CH.dbd.CH H 387 345 H 0
CH.sub.2CH.sub.2 H 388 346 H 0 389 H 390 347 H 0 CH.dbd.CH H 391
348 H 0 CH.sub.2CH.sub.2 H 392 349 H 0 CH.sub.2CH.sub.2CH.sub.2CH-
.sub.2 H 393 350 H 0 CH.dbd.CH H 394 351 H 0 CH.dbd.CH H 395 352 H
0 CH.sub.2CH.sub.2 H 396 353 H 0 CH.dbd.CH H 397 354 H 0
CH.sub.2CH.sub.2 H 398 355 H 0 CH.dbd.CH--CH.dbd.CH H 399 356 H 0
CH.sub.2CH.sub.2 H 400 357 H 0 CH.dbd.CH H 401 358 H 0
CH.sub.2CH.sub.2 H 402 359 H 0 CH.dbd.CH H 403 360 H 0 CH.dbd.CH H
404 361 H 0 CH.dbd.CH--CH.dbd.CH H 405 362 H 0 CH.dbd.CH--CH.dbd.CH
H 406 363 H 0 CH.dbd.CH H 407 364 H 0 408 H 409 365 H 0 C.ident.C H
410 366 H 0 (CH.sub.2).sub.2CH.dbd.CH H 411 367 H 0 CH.dbd.CH H 412
368 H 0 CH.dbd.CH--CH.dbd.CH H 413 359 H 0 CH.dbd.CH H 414 370 H 0
CH.dbd.CH H 415 371 H 0 CH.dbd.CH H 416 372 H 0
CH.dbd.CH--CH.dbd.CH H 417 373 H 0 CH.sub.2CH.sub.2 H 418 374 H 0
CH.sub.2CH.sub.2 H 419 375 H 0 CH.dbd.CH H 420 376 H 0 CH.dbd.CH H
421 377 H 0 CH.sub.2CH.sub.2 H 422 378 H 0 CH.dbd.CH H 423 379 H 0
CH.dbd.CH H 424 380 H 0 CH.dbd.CH--CH.dbd.CH H 425 381 H 0
CH.dbd.CH H 426 382 H 0 CH.dbd.CH H 427 383 H 0 CH.sub.2CH.sub.2 H
428 384 H 0 CH.dbd.CH H 429 385 H 0 CH.sub.2CH.sub.2 H 430 386 H 0
CH.dbd.CH H 431 387 H 0 CH.sub.2CH.sub.2 H 432 388 H 0
CH.sub.2CH.sub.2 H 433 389 H 0 CH.dbd.CH H 434 390 H 0 CH.dbd.CH H
435 391 H 0 CH.sub.2CH.sub.2 H 436 392 H 0 CH.dbd.CH H 437 393 H 0
CH.sub.2CH.sub.2 H 438 394 H 0 CH.sub.2CH.sub.2 H 439 395 H 0
CH.dbd.CH H 440 396 H 0
CH.sub.2CH.sub.2 H 441 397 H 0 CH.dbd.CH H 442
[0390] Various modes for synthesis of compounds used according to
the invention are described in the following for reasons of
simplifying reproducability.
[0391] Aside from a few exceptions, the optionally combined
compounds presently described and used according to the invention
are not previously described in the literature. A smaller portion
of these compounds overlaps various previously known generic
formulae that are very generally defined with respect to structure
and which were named at the beginning as prior art. The synthesis
methods for the production of the presently used compounds are
entirely known to the person skilled in the art either generally
from the relevant literature and/or from the prior art publications
named at the beginning; also see the literature information
referred to below. Consequently, the presently used compounds of
the synthesis encompassed by the defined generic formula are easily
accessible by analogous methods, as they are described, for
example, in the following.
[0392] Method (A):
[0393] Compounds of formula (I) are obtained by reacting carboxylic
acids of formula (II) 443
[0394] in which R.sup.1, R.sup.2, R.sup.3, A and k have the meaning
given above or their reactive derivatives are reacted with
compounds of formula (III) 444
[0395] wherein D, E, G and R.sup.4 have the above meanings.
[0396] Reactive derivatives of compound (II) can be present, for
example, as activated esters, anhydrides, acid halides, especially
acid chlorides, or simple low alkyl esters. Suitable acitivated
esters are, for example, p-nitrophenyl ester, 2,4,6-trichlorphenyl
ester, pentachlorophenyl ester, cyanomethyl ester, esters of
N-hydroxysuccinimide, of N-hydroxyphthalimides, of
1-hydroxybenzotriazol, of N-hydroxypiperidine, of 2-hydroxypyridine
or of 2-mercaptopyridine, etc. Anhydrides can be symmetric
anhydrides or mixed, as they are obtained, for example, with
pivaloyl chloride or with chloroformates. Aromatic (for example
chloroformic phenyl ester), araliphatic (for example chloroformic
benzyl ester) or aliphatic chloroformates (for example chloroformic
methyl ester and/or corresponding -ethyl or -isobutyl ester) can be
used for this.
[0397] Reaction of compounds (II) with compounds (III) can also be
carried out in the presence of condensation agents such as
dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,
N,N'-carbonyldiimidazol, 1-ethoxycarbonyl-2-ethoxy-1,2-dih-
ydroquinoline, etc. If carbodiimides are used as the condensation
agent, reagents such as N-hydroxysuccinimide, N-hydroxyphthalimide,
1-bydroxybenzotriazol, N-hydroxypiperidine, etc. can be
advantageously added.
[0398] Compounds of formula (III) can be used for reaction as free
bases as well as in the form of their acid addition salts. For
this, the salts of inorganic acids are to be preferred, i.e.
hydrochlorides, hydrobromides or sulfates.
[0399] Reaction of compounds (II) or their reactive derivatives
with compounds (III) are normally carried out in a suitable,
preferably inert solvent. As examples, aromatic hydrocarbons such
as benzene, toluol, xylene, halogenated hydrocarbons (for example
dichloromethane, chloroform, 1,2-dichloroethane,
trichloroethylene), ethers (for example diethyl ether,
tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate,
acetonitrile or polar aprotic solvents such as, for example,
dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone are to
be named. Pure solvents, as well as mixtures of two or more, can be
used.
[0400] The reaction is optionally carried out in the presence of an
auxiliary base. Suitable examples for this are alkali metal
carbonates (sodium carbonate, potassium carbonate), alkali metal
hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen
carbonate), or organic bases such as, for example, triethylamine,
ethyl diisopropylamine, tributylamine, N-methylmorpholine or
pyridine. A suitable excess of compound (III) can also be used as a
base. If compounds (III) are used in form of their acid addition
salts, then it is appropriate to consider the amount of auxiliary
base used as equivalent.
[0401] The reaction temperatures can--depending on reactivity of
the educts--vary in a wide range. Generally, the reaction is
carried out at temperatures between -40.degree. C. and 180.degree.
C., preferably between -10.degree. C. and 130.degree. C.,
especially at the boiling point of the solvent used.
[0402] The starting compounds (II) and (III) are known and/or can
be produced according to known methods in an analogous manner.
Moreover, the production of representative examples is further
described below.
[0403] Method (B)
[0404] Compounds of formula (I) can be produced by reaction of
compounds of formula (I), wherein G is hydrogen and which
themselves possess the above-named pharmacological activities such
as a cytostatic and/or immunomodulatory activity, as intermediate
products as well as end products, with a compound of formula
(V),
L-G (IV)
[0405] in which G has the meaning given above, with the exception
of hydrogen, and L is a suitable nucleofuge or reactive group. The
type of nucleofuge or reactive group L and the conditions of the
reaction are dependent of the nature of group G.
[0406] Method (B1)
[0407] Compounds of formula (I), in which G, with the exception of
hydrogen, has the meaning of (G1) according to the above definition
can, aside from method (a), also be produced by reacting compounds
of formula (I), wherein G is hydrogen, with a suitable alkylation
agent and/or arylation agent of formula (IV), wherein G is an
alkyl-, alkenyl-, alkinyl-, cycloalkyl-, aryl-, aralkyl-,
heteroaryl- or heteroaralkyl residue according to definition and
the leaving group L can be a reactive derivative of an alkohol, for
example, a halogen atom such as chlorine, bromine or iodine or a
sulfonic acid ester, i.e. for example a methanesulfonyloxy-,
trifluoromethanesulfonyloxy-, ethanesulfonyloxy-,
benzenesulfonyloxy-, p-toluolsulfonyloxy-,
p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy residue,
etc. A reactive group L can be a terminal epoxide group for
example.
[0408] The reaction of compounds (I), in which G is a hydrogen, and
(IV) is usually conducted in a suitably inert solvent. Such
solvents can be, for example, aromatic hydrocarbons (benzene,
toluol, xylene), ethers (for example tetrahydrofuran, dioxane,
glycol dimethyl ether), ethyl acetate, acetonitrile, ketones
(acetone, ethyl methyl ketone), polar protic solvents such as
alcohols (ethanol, isopropanol, butanol, glycol monomethyl ether)
or polar aprotic solvents such as, for example, dimethylsulfoxide,
dimethylformamide or N-methylpyrrolidone. Pure solvents as well as
mixtures of two or more can also be used. Preferably, the reactions
are carried out in the presence of bases, whereby said bases can be
used as in method (a) above. If chlorides or bromides are used as
compound (IV), the reaction can be accelerated by the addition of
alkali metal iodides (sodium iodide, potassium iodide). The
reaction temperatures can vary between 0.degree. C. and 180.degree.
C. depending on the reactivity of the educts, but preferably lie
between 20.degree. C. and 130.degree. C.
[0409] Method (B2)
[0410] Compounds of formula (I), in which G represents an acyl
residue, a carbamoyl residue, a sulfonyl residue or a phosphinoyl
residue according to the above definition, can also be produced,
aside from the above method (a), by reacting compounds of formula
(I), in which G is hydrogen, with a carboxylic acid, carbamic acid,
sulfonic acid and/or phosphinic acid of formula (V), in which G is
an acyl residue, carbamoyl residue, sulfonyl residue or phosphinoyl
residue according to definition,
HO-G (V)
[0411] or their derivatives capable of reaction. Preferred
derivatives of carboxylic acids and/or sulfonic acids (V) which are
capable of reaction are symmetric or unsymmetric carboxylic acid
anhydrides and/or sulfonic acid anhydrides or acyl- and/or sulfonyl
halides, especially acyl- and/or sulfonyl chlorides. Preferably,
derivatives of carbamates and/or phosphinic acids which are capable
of reaction are the carbamoyl halides and/or phosphinyl halides,
especially carbanyl- and/or phosphinyl chlorides. The reaction of
the acids (V) and/or their reactive derivatives with compounds (I),
in which G is hydrogen, preferably occurs in the presence of
auxiliary bases in solvents and under conditions as they are
described in method (A).
[0412] Method (B3)
[0413] Compounds of formula (I), in which G represents a carbamoyl
residue according to the definition G2 with r=0, i.e. the group
445
[0414] can also be produced, aside from the methods (A) and (B2),
by reacting compounds of formula (I), in which C is hydrogen with a
carbonyl group transmitter to an intermediate product and
subsequently reacting this directly with a primary or secondary
amine with the formula (VI)
H--NR.sup.13R.sup.15 (VI)
[0415] in which R.sup.13 and R.sup.15 and/or the group
--NR.sup.13R.sup.15 have the meanings according to the above
definitions without having to purify or isolate the intermediate
product. Trichloromethylcarbonate (triphosgene) and
carbonyldiimidazol have been proven as particularly reactive
carbonyl group transmitters. The reaction of compounds of formula
(I), wherein G is hydrogen, with triphosgene and/or
carbonyldiimidazol are typically conducted in an absolute, inert
solvent in the presence of a tertiary organic amine as an auxiliary
base in such a manner that the solution of compounds (I) and the
auxiliary base are slowly poured into a solution of an equivalent
amount of carbonyl group transmitter. Thereby, the reaction
requires molar ratios of 1:1 for the reaction of compound (I) and
carbonyldiimidazol, and, in contrast, a ratio of 1:0.35 for the use
of triphosgene. After complete reaction of the components to the
intermediate product, compound (VI) is added in stochiometric
arnounts or in excess as a solution or a solid and the reaction is
typically completed at elevated temperature. Suitable inert
solvents are, for example hydrocarbons such as hexane, heptane,
benzene, toluol, xylene, chlorinated hydrocarbons (for example
dichloromethane, chloroform, 1,2-dichloroethane,
trichloroethylene), ethers (for example diethyl ether,
tetrahydrofuran, dioxane), esters such as ethyl acetate, butyl
acetate, acetonitrile or polar aprodic solvents such as formamide
or dimethylformamide. Pure solvents as well as mixtures can be used
diversely. Sometimes it is of advantage to carry out the first
partial reaction at low temperature in a low-viscosity,
highly-volatile solvent and to remove the solvent after formation
of the intermediate and replace it by a higher boiling solvent.
Amines such as for example triethylamine, ethyl diusopropylamine,
tributylamine, N-methylmorpholine or pyridine are suitable as
auxiliary bases. If compounds (I) or (VI) are used as salts, the
amount of the auxiliary base is increased accordingly. The reaction
temperatures can lie in between -40.degree. C. and 50.degree. C.
for the first partial reaction, preferably at 0.degree. C. bis
30.degree. C., and between 0.degree. C. and 150.degree. C. for the
second partial reaction, preferably at 20.degree. C. bis
120.degree. C.
[0416] Method (B4)
[0417] Compounds of formula (I), in which G represents a carbamoyl
residue according to the definition G2 with r=0 and
R.sup.15=hydrogen, i.e. a group 446
[0418] can also be produced, aside from methods A, B2 and B3, by
reacting the compounds of formula (I) in which G is hydrogen, with
an isocyanate of formula (VII) in which R.sup.13 has the meaning
according to the above definition
O.dbd.C--N--R.sup.13 (VII)
[0419] Reaction of the compounds of formula (I), in which G is
hydrogen, with the isocyanates of formula (VII) are conducted
thereby in an absolute, inert solvent which can be a hydrocarbon
such as pentane, hexane, heptane, benzene, toluol, or xylene,
chlorinated hydrocarbons (such as dichloromethane, chloroform,
1,2-dichloroethane, trichloroethylene), ethers (for example,
diethyl ether, tetrahydrofuran, dioxane), esters such as ethyl
acetate, butyl acetate, or polar aprotic solvents such as formamide
or dimethylformamide. Mixtures of various solvents can also be
used. Thereby, the reaction temperatures can vary in the region
from -20.degree. C. to 150.degree. C., but preferably lie at
20.degree. C. to 100.degree. C.
[0420] The above-named intermediate products in the form of
compounds according to formula (I), wherein G is hydrogen, which
have the above-mentioned activities, such as for example a
cytostatic activity in an analogous way to the end products
themselves, are suitable for the production of a multitude of end
products through the synthesis methods B1-B4.
[0421] They themselves can, in principle, be produced according to
method A by reacting a carboxylic acid of formula (II) with amines
of formula (III) in which G is hydrogen as described above.
However, since the compounds of formula (III) with hydrogen as G
represent .alpha.,.omega.-diamines, the formation of product
mixtures is always to be expected in their reaction with carboxylic
acids (II) or their reactive derivatives making a subsequent
separation necessary.
[0422] In contrast, compounds of formula (I), in which G is
hydrogen, are essentially more advantageously produced from other
compounds of formula (I), in which G is a selectively cleavable
group under mild conditions, i.e. corresponds to a nitrogen
protective group.
[0423] Among the compounds according to formula (I) with tumor
growth inhibiting properties, compounds are particularly suitable
for this in which G represents a benzyl group, a 4-methoxybenzyl
group, a diphenylmethyl group, a triphenylmethyl group, a
benzyloxycarbonyl group, a methoxy- and/or ethoxycarbonyl group, a
tertbutoxycarbonyl group, an allyloxycarbonyl group or a
trifluoroacetyl group. For example, compounds according to formula
(I) with benzyl, diphenylmethyl, triphenylmethyl or
benzyloxycarbonyl groups can already be catalytically transformed
into the compounds of formula (I) with hydrogen as G at room
temperature under mild conditions with elementary hydrogen or by
transfer hydration. Compounds of formula (I) with a
4-methoxylbenzyl group are transformed into compounds of formula
(I) with hydrogen as G by selective oxidation with
ammonium-cer(IV)-nitrate. The cleavage of simple alkoxycarbonyl
groups such as the methoxy- or ethoxycarbonyl group as well as the
trifluoroacetyl group as G in compounds of formula (I) succeed by
alkali hydrolysis under mild conditions without cleaving the A and
D linked amide function. This is suitably valid for the cleavage of
the triphenylmethyl group and the tert-butoxycarbonyl group as G in
compounds of formula (I), which occurs in acidic medium under mild
conditions. Finally, compounds of formula (I) with an
allyloxycarbonyl group as G can be converted into such with
hydrogen as G in neutral medium with palladium catalyst. All these
methods are fully familiar to the person skilled in the art, and
are furthermore also documented in monographs (see for example
Greene, Wuts, Protective Groups in Organic Synthesis, New York,
1991).
[0424] Method C
[0425] Compounds of formula (I), in which R.sup.4 is an alkyl,
alkenyl, alkinyl or cycloalkyl residue according to the above
definition can also be produced, aside from the methods A and B, by
reacting compounds of formula (I), in which R.sup.4 is hydrogen,
with a suitable alkylation agent of formula (VIII)
L-R.sup.4 (VIII)
[0426] in which R.sup.4 is an alkyl, alkenyl, alkinyl or cycloalkyl
residue according to the above definition and L is a suitable
nucleofuge, i.e. for example a halogen atom such as chlorine,
bromine or iodine or a sulfonic acid ester of an alcohol. Preferred
sulfonic acid esters (VIII) contain a methylsulfonyloxy residue,
trifluoromethanesulfonyloxy-, p-toluolsulfonyloxy-,
p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy residue as
L. As an amide alkylation in the presence of tertiary amino groups,
this reaction requires the use of strong auxiliary bases such as
potassium-tert-butylate, sodium hydride, potassium hydride or butyl
lithium in aprotic, inert solvents. Such solvents can be for
example aliphatic or aromatic hydrocarbons (pentane, hexane,
heptane, benzene, toluol), ethers (for example, tetrahydrofuran,
dioxane) or polar solvents such as dimethylsulfoxide,
dimethylformamide or N-methylpyrrolidone. Depending on the
reactivity of the educts, the reaction temperatures can lie between
-40.degree. C. and 140.degree. C. preferably between -20.degree. C.
and 80.degree. C.
[0427] Method D
[0428] Compounds of formula (I) in which A is a saturated alkylene
group can also be produced, aside from methods A, B and C, by
hydrating compounds of formula (I) in which A is an unsaturated
group according to the above definition, i.e. an alkenylene group
or alkadienyl group with elementary hydrogen in the presence of a
suitable catalyst. This method is also applicable when the
compounds of formula (I) with an unsaturated group A in the
molecule simultaneously contain a principally hydrogenolytically
cleavable group B, i.e.--as already mentioned above--a benzyl
group, a diphenylmethyl or triphenylmethyl group. In the selection
of the conditions, especially the solvent, the temperature and the
acid additive in the reaction mixture, the reaction can be
controlably driven either to a selective satuation of the C--C
multiple bond(s) in the structural element A or to a simultaneous
cleavage of the benzyl, diphenylmethyl or triphenylmethyl residue G
under formation of the compounds of formula (I) with hydrogen as
G.
[0429] The hydration is preferably carried out in barely polar,
aprotic solvents for selective hydration of one or more C--C
multiple bonds of group A in the compounds of formula (I) according
to the invention while attaining a simultaneously present
hydrogenolytically cleavable benzyl, diphenylmnethyl or
triphenylmethyl residue as the structural element G. Esters such as
ethyl acetate, propyl acetate, butyl acetate or ethers such as
tetrahydrofuran, dioxane or ethylene glycol dimethyl ether can be
used. Compounds of formula (I) to be hydrated can be present as a
free base or entirely or partially in the form of a salt by
addition of a sub-maximal to a maximal stochiometric amount of a
strong acid, preferably a mineral acid. As a catalyst, palladium Is
suitable in various proportional amounts from 1, 3, 5 or 10% on
solid supports such as activated carbon, activated aluminum oxide
or calcium carbonate. The hydration is carried out under normal
pressure and at a temperature of 10 to maximally 30.degree. C.,
preferably at 20 to 25.degree. C. and interrupted after consumption
of the amount of hydrogen calculated for the saturation of the
multiple bonds.
[0430] In contrast, for simultaneous cleavage of the multiple bonds
in A and the cleavage of a benzyl, diphenylmethyl or
triphenylmethyl group as G in the compound of formula (I), polar,
aprotic solvents are used such as methanol, ethanol, isopropanol,
methoxyethanol or water or mixtures thereof, whereby a considerable
excess of a strong acid compared to the stochiometric salt
formation, preferably a mineral acid such as concentrated
hydrochloric acid or sulfuric acid is simultaneously added. The
molecular ratio of substrate/acid can lie in the range of 1:2 to
1:10 thereby, preferably between 1:3 and 1:5. The same catalysts
which are mentioned above in connection with the selective
hydration are suitable as catalysts. The hydration is carried out
under normal pressure or slightly increased hydrogen pressure of 2
to 3 bar, preferably under normal pressure, until the termination
of the uptake of hydrogen. Depending on uptake speed, the reaction
temperature can vary between 10 and 50, 70 or 80.degree. C. as a
function of the boiling point of the solvent and/or solvent mixture
and employed pressure. If, for example, the reaction is carried out
in ethanol or ethanol/water under normal pressure, the reaction
temperature preferably lies between 40 to 60.degree. C.
[0431] The compounds of formula (I) produced according to the
method (A), (B1) to (B4), (C) or (D) can be isolated and purified
in a known manner, for example by subjecting the residue after
distillation of the solvent to partition, extraction,
re-precipitation or recrystallization or another purification
method. For this, column chromatography on a suitable support or
preparative, middle or high pressure liquid chromatography are
preferred for this.
[0432] The compounds (I) are first normally obtained in form of
their free bases or their hydrates or solvates, depending on the
type of isolation and purification. Their addition salts with
pharmaceutically suitable acids are obtained in a typical manner by
converting the base with the desired acid in a suitable solvent.
Depending on the number of basic centers of compound (1), one or
more equivalent acids per mole of base can be bound.
[0433] Suitable solvents are, for example, chlorinated hydrocarbons
such as dichloromethane or chloroform; ethers such as diethyl
ether, dioxane or tetrahydrofuran; acetonitrile; ketones such as
acetone or ethyl methyl ketone; esters such as methyl acetate or
ethyl acetate or low molecular alcohols such as methanol, ethanol
or isopropanol; and water. Pure solvents as well as mixtures of two
or three solvents can also be used. The salts can be isolated by
crystallization, precipitation or the evaporation of the solvent.
Thereby, they optionally accumulate as hydrates or solvates.
[0434] The bases can be recovered from the salts by alkalization,
for example with aqueous ammonia solution, alkali carbonate or
diluted sodium hydroxide solution, The following listed compounds
and/or their pharmaceutically acceptable salts, if not already
concretely labelled as such, are particularly preferred.
[0435]
N-[2-(1-benzylpiperidin-4-yl)-ethyl]-3-(pyridin-3-yl)-propionamide,
[0436]
N-{2-[1-(2-phenylethyl)-piperidin-4-yl]-ethyl}-3-(pyridin-3-yl)prop-
ionamide
[0437]
N-{2-[1-(4-phenylbutyl)-piperidin-4-yl]-ethyl}-3-(pyridin-3-yl)-pro-
pionamide
[0438]
N-{2-[1-(4-hydroxyphenylbutyl)piperidin-4-yl]-ethyl}-3-(pyridin-3-y-
l)-propionamide
[0439]
N-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-3-(pyridin-3-yl)-propi-
onamide,
[0440]
N-[3-(1-diphenylmethylpiperidin-4-yl)-propyl]-3-(pyridin-3-yl)-prop-
ionamide,
[0441]
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-pyridin-3-yl)-propio-
namide,
[0442]
N-[2-(1-benzylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,
[0443]
N-{4-[1-(2-phenylethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acr-
ylamide
[0444]
N-{4-[1-(4-biphenylylmethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl-
)-acrylamide
[0445]
N-{4-[1-(1-naphthylmethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)--
acrylamide
[0446]
N-{4-[1-(9-anthrymethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-ac-
rylamide
[0447]
N-{4-[1-(Cyclohexylphenylmethyl)-piperidin-4-yl]-butyl}-3-(pyridin--
3-yl)-acrylamide
[0448]
N-{4-[1-(10,11-dihydro5H-dienzo[ad]cycloheptene-5-yl)-piperidin-4-y-
l]-butyl}-3-(pyridin-3-yl)-acrylamide
[0449]
N-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-3-(pyridin-3-yl)-acryl-
amide,
[0450]
N-[3-(1-diphenylmethylpiperidin-4-yl)-propyl]-3-(pyridin-3-yl)-acry-
lamide,
[0451]
N-[5-(1-diphenylmethylpiperidin-4-yl)-pentyl]-3-pyridin-3-yl)-acryl-
amide,
[0452]
N-[6-(1-diphenylmethylpiperidin-4-yl)-hexyl]-3-(pyridin-3-yl)-acryl-
amide,
[0453]
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-p-
entadiene acid amide,
[0454]
N-(4-{1-[bis-(4-fluorophenyl)-methyl]-piperidin-4-yl}-butyl)-3-(pyr-
idin-3-yl)-acrylamide,
[0455]
N-(4-{1-[bis-(2-chlorophenyl)-methyl]-piperidin-4-yl}-butyl)-3-(pyr-
idin-3-yl)-acrylamide,
[0456]
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(2-fluoropyridin-3-y-
l)-acrylamide,
[0457]
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(6-fluoropyridin-3-y-
l)-acrylamide,
[0458]
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acryl-
amide,
[0459]
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acryl-
amide dihydrochloride or,
[0460]
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acryl-
amide methanesulfonate,
[0461] For a better understanding of the use according to the
invention and reproducability of the compounds used, a series of
synthetic examples is described in the following:
SYNTHETIC EXAMPLES
For the End Products of the Invention According to Formula (I)
[0462] In the following production examples for the end products,
the abbreviations stand for the following terms:
[0463] MP=melting point,
[0464] RT=room temperature,
[0465] THF=tetrahydrofuran,
[0466] DMF=dimethylformamide,
[0467] CDI=carbonyldlimidazol,
[0468] abs.=absolute,
[0469] EDC=N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide
hydrochloride,
[0470] HOBT=1-hydroxybenzotriazol,
[0471] TEA=triethylamine.
[0472] .sup.1H-NMR-Spectrum=proton resonance spectrum, taken at 100
MHz. The chemical shifts are given in ppm against TMS as a standard
(.delta.=0.0), whereby
[0473] s=singlet,
[0474] d=doublet,
[0475] t=triplet,
[0476] dt=doublet-triplet,
[0477] m=multiplet,
[0478] ar=aromatic,
[0479] py=pyridine.
Example 1
[0480]
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-N-ethyl-3-(pyridin-3-y-
l)-acrylamide (Substance 123)
[0481] 10 g (22.0 mmol)
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(py-
ridin-3-yl)-acrylamide (substance 104) are dissolved in 100 ml THF
and added to 0.73 g (24.3 mmol) 80% NaH (heavy foaming) and stirred
20 minutes at RT. 2.1 ml (26.4 mmol) ethyl iodine are added
dropwise and the mixture is stirred five hours at RT. 0.1 g
tetrabutyl ammonium iodine are added and the batch is further
stirred at RT overnight. Subsequently, 0.1 g (3 mmol) 80% NaH are
added and this is heated at 50.degree. C. for one hour under
stirring. The batch is carefully hydrolyzed with 50 ml water after
cooling to RT. The aqueous phase is extracted with 100 ml
dichloromethane and the combined organic phases are washed with 50
ml water. The organic phase is concentrated in vacuum and the
residue is chromatographically pre-purified twice over silica gel
with CHCl.sub.3/CH.sub.3OH (95/5 to 90/10 and 98/2 to 95/5),
subsequently further purified by flash chromatography with
CHCl.sub.3/CH.sub.3OH (100/0 to 98/2) and crystallized three times
from 20 ml 1-chlorobutane, 10 ml acetonitrile/diisopropyl ether
(1/1) and 8 ml isopropanol/diIsopropyl ether (1/1). Yellow crystals
with a MP of 115-117.degree. C. were recovered; yield: 1.1 g
(10%)
2 C.sub.32H.sub.39N.sub.3O (481.7) IR-Spectrum (KBr): .nu.(C.dbd.O)
1640 cm.sup.-1 .nu.(C.dbd.C) 1600 cm.sup.-1 .sup.1H-NMR-Spectrum
(CDCl.sub.3): 0.90-1.95(16H, m, piperidine,
piperidine-(CH.sub.2).sub.3CH.sub.3) 2.70-3.00(2H, m, piperidine)
3.20-3.70(4H, m, CONCH.sub.2, J 4.21(1H, s, Ar.sub.2CH) 6.89(1H, d,
CH.dbd.CHCO, J=15.5Hz) 7.00-7.50(11H, m, ar, py) 7.69-7.60(1H, d,
CH.dbd.CHCO, J=15.5Hz) 7.70-7.95(1H, m, py) 8.50-8.65(1H, m, py)
8.70-8.85(1H, m, py)
Example 2
[0482]
N-[4-(1-diphenylmethylpiperidin-4-yl)butyl]-3-(pyridin-3-yl)-acryla-
mide (Substance 104)
[0483] 2.0 g (13.6 mmol) 3-(pyridin-3-yl)-acrylic acid are
suspended in 60 ml abs. dichloromethane and, after addition of
three drops of pyridine, cooled to ca. 0.degree. C. in an ice bath
under moisture exclusion. 1.8 ml (18.6 mmol) oxalyl chloride are
added dropwise and the mixture is stirred at RT overnight.
Subsequently, the solvent and excess oxalyl chloride is distilled
off in a rotary evaporator. In order to completely remove the
oxalyl chloride, the residue is dried further for two hours under
high-vacuum. The acid chloride obtained in this manner is suspended
in 50 ml abs. dichloromethane and cooled to ca. 0.degree. C. in an
ice bath under moisture exclusion. 4.0 g (12.4 mmol)
4-(1-diphenylmethylpiper- idin-4-yl)-butylamine are dissolved in 30
ml abs. dichloromethane and added dropwise to this suspension.
After complete addition, the ice bath is removed and the reaction
mixture is stirred for a further two hours at RT. The mixture is
subsequently washed with 10% sodium hydroxide solution. The aqueous
phase is extracted with acetic acid ethyl ether. The combined
organic phases are dried over sodium sulfate and the solvent is
removed under vacuum. The residue is crystallized once from 15 ml
isopropanol and then twice from acetic acid ethyl ester. Colorless
crystals with a MP of 156.degree. C. were recovered, yield: 1.6 g
(28%)
3 C.sub.30H.sub.35N.sub.3O (453.6) IR-Spectrum (KBr): .nu.(NH) 3310
cm.sup.-1 .nu.(C.dbd.O) 1660, 1545 cm.sup.-1 .nu.(C.dbd.C) 1620
cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 0.90-2.20(13H, m,
piperidine, piperidine-(CH.sub.2).sub.3) 2.65-3.05(2H, m,
piperidine) 3.20-3.60(2H, m, CONCH.sub.2, J 4.21(1H, s, Ar.sub.2CH)
5.75-6.15(1H, m, NH) 6.45(1H, d, CH.dbd.CHCO, J=15.6)
6.90-8.00(13H, m, ar, py, CH.dbd.CHCO) 8.45-8.70(1H, m, py)
8.70-8.90(1H, m, py)
Example 3
[0484]
N-(4-{1-[bis-(4-fluorophenyl)-methyl]-piperidin-4-yl}-butyl)-3-(pyr-
idin-3-yl)-acrylamide (substance 171)
[0485] 3.7 g (24.5 mmol) 3-(3-pyridyl)-acrylic acid are suspended
in 100 ml abs. dichloromethane and, after addition of three drops
of pyridine, cooled to cA 0.degree. C. in an ice bath under
moisture exclusion. 2.8 ml (22.1 mmol) oxalyl chloride are added
dropwise and the mixture is stirred at RT overnight Subsequently,
the solvent and excess oxalyl chloride is distilled off in a rotary
evaporator. In order to completely remove the oxalyl chloride, the
residue is dried further for 2 hours under high-vacuum. The acid
chloride obtained in this manner is suspended in 50 ml abs.
dichloromethane and cooled to ca. 0.degree. C. in an ice bath under
moisture exclusion. 8.0 g (22.3 mmol)
4-[1-bis-(4-fluorophenyl)-met- hyl-piperidin-4-yl]-butylamine are
dissolved in 50 ml abs. dichloromethane and added dropwise to this
suspension. After complete addition, the ice bath is removed and
the reaction mixture is stirred for a further two hours at RT. The
mixture is subsequently distributed between 10% sodium hydroxide
solution and dichlorornethane, and the aqueous phase is extracted a
further three times with dichloromethane. The combined organic
phases are washed with 100 ml water, dried over sodium sulfate and
the solvent is removed under vacuum. The residue is
chromatographically purified over silica gel with
CHCl.sub.3/CH.sub.3OH (99.5/0.5 to 97/3) and crystallized from 30
ml acetic acid ethyl ester after drawing off the solvent. Colorless
crystals with a MP of 108.degree. C. were recovered; yield 3,5 g
(34%).
4 C.sub.30H.sub.33F.sub.2N.sub.3O (489.6) IR-Spectrum (KBr):
.nu.(NH) 3320 cm.sup.-1 .nu.(C.dbd.O) 1655, 1540 cm.sup.-1
.nu.(C.dbd.C) 1620 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
1.00-2.00(13H, m, piperidine, piperidine-(CH.sub.2).sub.3)
2.60-2.95(2H, m, piperidine) 3.38(2H, dt, CONHCH.sub.2, J=6.6Hz, J=
12.7Hz) 4.20(1H, s, Ar.sub.2CH) 5.85-6.10(1H, m, NH) 6.47(1H, d,
CH.dbd.CHCO, J=15.7Hz) 6.80-7.50(9H, m, ar, py) 7.65-7.90(1H, m,
py) 8.45-8.65(1H, m, py) 8.65-8.85(1H, m, py)
Example 4
[0486]
N-{4-[1-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-yl)-piperidin--
4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide (substance 219)
[0487] Production occurred analogously to Example 3.
[0488] Batch size: 2.6 g (17.6 mmol) 3-(3-pyridyl)-acrylic acid,
2.6 g (20.8 mmol) oxalyl chloride and 5.57 g (16.0 mmol)
4-[1-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-yl)-piperidin-4-yl]-but-
ylamine.
[0489] In the work up, the mixture is concentrated under vacuum and
subsequently distributed between 100 ml 10% NaOH and 300 ml acetic
acid ethyl ester. The aqueous phase is extracted again with 50 ml
acetic acid ethyl ester and the combined organic phases are washed
with 50 ml water, dried over sodium sulfate and the solvent is
removed under vacuum. The residue is chromatographically purified
over silica gel with CHCl.sub.3/CH.sub.3OH (97/3) and crystallized
twice from 40 ml and 30 ml acetonitrile after drawing off the
solvent. Colorless crystals with a MP of 125-127.degree. C. were
recovered; yield 2.3 g (30%).
5 C.sub.32H.sub.37F.sub.2N.sub.3O (479.6) IR-Spectrum (KBr):
.nu.(NH) 3300 cm.sup.-1 .nu.(C.dbd.O) 1655, 1540 cm.sup.-1
.nu.(C.dbd.C) 1620 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
0.90-2.00(13H, m, piperidine, piperidine-(CH.sub.2).sub.3)
2.55-3.00(4H, m, piperidine, ar --CH--CH-ar) 3.36(2H, dt,
CONHCH.sub.2, J=6.6Hz, J= 12.7Hz) 3.90(1H, s, Ar.sub.2CH)
5.60-5.85(1H, m NH) 6.43(1H, d, CH.dbd.CHCO, J=15.7Hz)
6.90-7.40(9H, m, ar, py) 7.60(1H, d, CH.dbd.CHCO, J=15.6Hz)
7.65-7.90(1H, m, py) 8.50-8.65(1H, m, py) 8.70-8.80(1H, m, py)
Example 5
[0490]
N-[4(1-benzylpiperidin-4-yl)butyl]-3-(pyridin-3-yl)-acrylamide
(Substance 46)
[0491] 6.5 g (18.0 mmol)
N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acr- ylamide
dihydrochloride (substance 22) are suspended in 80 ml acetone added
to 9.9 g (72.0 mmol) potassium carbonate. A solution of 3.4 g (19.8
mmol) benzyl bromide in 10 ml acetone is added dropwise to this
mixture at RT and stirred overnight. Subsequently, the suspension
is filtered and the filtrate is concentrated under vacuum. The
residue is taken up in 100 ml CHCl.sub.3 and washed with 30 ml
water. The organic phase is dried over sodium sulfate and the
solvent is removed under vacuum. The residue is chromatographically
purified over silica gel with CHCl.sub.3/CH.sub.3OH (95/5 to 90/10)
and crystallized from 15 ml acetonitrile after drawing off the
solvent. Beige colored crystals with a MP of 88-90.degree. C. were
recovered; yield: 1.1 g (16%)
6 C.sub.24H.sub.31N.sub.3O (377.5) IR-Spectrum (KBr): .nu.(NH) 3320
cm.sup.-1 .nu.(C.dbd.O) 1655, 1530 cm.sup.-1 .nu.(C.dbd.C) 1620
cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 1.00-2.10(13H, m,
piperidine, piperidine-(CH.sub.2).sub.3) 2.70-3.00(2H, m,
piperidine) 3.20-3.55(4H, m, CONHCH.sub.2, ar, CH.sub.2)
5.65-6.00(1H, m, NH) 6.45(1H, d, CH.dbd.CHCO, J=15.6Hz) 3.36(2H,
dt, CONHCH.sub.2, J=6.6Hz, J= 12.7Hz) 7.10-7.40(6H, m, ar, py)
7.62(1H, d, CH.dbd.CHCO, J=15.6Hz) 5.60-5.85(1H, m, NH) 6.43(1H, d,
CH.dbd.CHCO, J=15.7Hz) 7.65-7.90(1H, m, py) 8.45-8.65(1H, m, py)
8.65-8.85(1H, m, py)
Example 6
[0492]
N-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-3-(pyridin-3-yl)-acryl-
amide (Substance 95)
[0493] Production occurred analogously to Example 3.
[0494] Batch size: 2.3 g (15.5 mmol) 3-(3-pyridyl)-acrylic acid,
2.7 g (21.3 mmol) oxalyl chloride and 4.1 g (13.9 mmol)
2-(1-diphenylmethylpipe- ridine-4-yl)-ethylamine in 60 ml abs.
dichlormethane.
[0495] In the work up, the mixture is concentrated under vacuum and
subsequently dispersed between 100 ml 10% NaOH and 300 ml acetic
acid ethyl ester. The aqueous phase is extracted again with 50 ml
acetic acid ethyl ester and the combined organic phases are washed
with 50 ml water, dried over sodium sulfate and the solvent is
removed under vacuum. The residue is chromatographically
pre-purified over silica gel with CHCl.sub.3/CH.sub.3OH (95/5) and
subsequently purified by flash-chromatography with
CHCl.sub.3/CH.sub.3OH (100/0 to 94/6), After drawing off the
solvent, this is crystallized from 19 ml acetic acid ethyl
ester/petroleum ether. Colorless crystals with a MP of
141-143.degree. C. were recovered; yield 0.6 g (10%).
7 C.sub.28H.sub.31N.sub.3O (425.6) IR-Spectrum (KBr): .nu.(NH) 3820
cm.sup.-1 .nu.(C.dbd.O) 1660, 1550 cm.sup.-1 .nu.(C.dbd.C) 1620
cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 1.05-2.00(9H, m,
piperidine, piperidine-CH.sub.2) 2.70-3.00(2H, m, piperidine)
3.41(2H, dt, CONHCH.sub.2, J=6.6Hz, J= 12.7Hz) 4.23(1H, s,
Ar.sub.2CH) 5.55-5.80(1H, m, NH) 6.43(1H, d, CH.dbd.CHCO, J=15.6Hz)
7.00-7.55(11H, m, ar, py) 7.61(1H, d, CH.dbd.CHCO, J=15.6Hz)
7.60-7.90(1H, m, py) 8.55-8.65(1H, m, py) 8.65-8.80(1H, m, py)
Example 7
[0496]
N-{4-[1-(9-anthryl)-methylpiperidin-4-yl]-butyl}-3-(pyridin-3-yl)-a-
crylamide (Substance 81)
[0497] 5.4 g (15.0 mmol)
N-[4-piperidin-4-ylfibutyl]-3-(pyridin-3-yl)-acry- lamide
dichloride (substance 22) were suspended in 80 ml dichloromethane
and added to 5.1 g (50.0 mmol) TEA. To this mixture, a solution of
3.7 g (16.5 mol) (9-anthyl)-methylchloride in dichloromethane is
added at RT and stirred overnight. Subsequently, the mixture is
washed twice, each with 100 ml water. The organic phase is dried
over sodium sulfate and the solvent is removed under vacuum. The
residue is chromatographically purified over silica gel with
CHCl.sub.3/CH.sub.3OH (95/5 to 94/6) and crystallized first from
100 ml ethanol and then from 83 ml ethanol/diisopropyl ether (75/8)
after drawing off the solvent. Yellow crystals with a MP of
162-164.degree. C. were recovered; yield: 1.8 g (25%)
8 C.sub.32H.sub.35N.sub.3O (477.6) IR-Spectrum (KBr): .nu.(NH) 3360
cm.sup.-1 .nu.(C.dbd.O) 1680, 1560 cm.sup.-1 .nu.(C.dbd.C) 1640
cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 0.90-1.80(11H, m,
piperidine, piperidine-CH.sub.2).sub.3) 2.05-2.40(2H, m,
piperidine) 2.80-3.15(2H, m, piperidine) 3.20-3.55(2H, m,
CONHCH.sub.2) 4.45(1H, s, Ar.sub.2CH) 5.60-5.90(1H, m, NH) 6.42(1H,
d, CH.dbd.CHCO, J=15.6Hz) 7.20-8.20(10H, m, ar, py, CH.dbd.CHCO)
8.40-8.90(4H, m, ar, py)
Example 8
[0498]
N-{4-[1-(cyclohexylphenylmethyl)-piperidin-4-yl]-butyl}-3-(pyridin--
3-yl)-acrylamide (Substance 84)
[0499] 4.5 g (17.7 mmol) (bromcyclohexylphenyl)-methane, 5.6 g
(15.5 mmol)
N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide
dihydrochloride (substance 22), 8.5 g (61.8 mmol) potassium
carbonate and 2.8 g (16.9 mmol) sodium iodide are stirred in 200 ml
DMF 18 hours at ca. 75.degree. C. After cooling, the mixtuure is
filtered over a diatomaceous earth layer and the filtrate is
concentrated under vacuum. The residue is taken up in 200 ml
CHCl.sub.3 and washed twice with 60 ml and 30 ml water. The organic
phase is dried over a sodium sulfate and the solvent is removed
under vacuum. The residue is chromatographically purified over a
silica gel with CHCl.sub.3/CH.sub.3OH (96/4 bis 92/8) and
crystallized three times, each from 40 ml acetonitrile and once at
the conclusion from 50 ml acetonitrile. Colorless crystals with a
MP of 143-145.degree. C. were recovered; yield 0,58 g (8%).
9 C.sub.30H.sub.41N.sub.3O (459.7) IR-Spectrum (KBr): .nu.(NH) 3330
cm.sup.-1 .nu.(C.dbd.O) 1680, 1570 cm.sup.-1 .nu.(C.dbd.C) 1640
cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 0.50-2.20(24H, m,
piperidine, piperidine-CH.sub.2).sub.3, cyclohexane) 2.55-2.90(2H,
m, piperidine) 3.08(1H, d, Ar--CH, J=9.2Hz) 3.35(2H, dt,
CONHCH.sub.2, J=6.5Hz, J= 12.7Hz) 5.70-6.05(1H, m, NH) 6.45(1H, d,
CH.dbd.CHCO, J=15.6Hz) 7.00-7.50(6H, m, ar, py) 7.60(1H, d,
CH.dbd.CHCO, J=15.6Hz) 7.60-7.90(1H, m, py) 8.45-8.65(1H, m, py)
8.65-8.85(1H, m, py)
Example 9
[0500]
N-(4-{1-[bis-(2-chlorphenyl)-methyl]-piperidin-4-yl}-butyl)-3-(pyri-
din-3-yl)-acrylamid (Substance 186)
[0501] Production occurred analogously to Example 3.
[0502] Batch size: 1.6 g (10.7 mmol) 3-(3-pyridyl)acrylic acid, 1.9
g (15.0 mmol) oxalyl chloride and 3.9 g (10.0 mmol)
4-{1-[bis-(2-chlorophen- yl)-methyl]-piperidine-4-y)}-butylamine.
In the purification, chromatographic purification is done twice
over silica gel with CHCl.sub.3/CH.sub.3OH (97/3 and 97/3 to 95/5)
and crystallization is from 25 ml acetic acid after drawing off the
solvent. Colorless crystals with a MP of 129-131.degree. C. were
recovered; yield 0.6 g (11%).
10 C.sub.30H.sub.33Cl.sub.2N.sub.3O (522.5) IR-Spectrum (KBr):
.nu.(NH) 3240 cm.sup.-1 .nu.(C.dbd.O) 1655, 1560 cm.sup.-1
.nu.(C.dbd.C) 1620 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
0.90-1.95(11H, m, piperidine, piperidine-CH.sub.2).sub.3)
1.90-2.40(2H, m, piperidine) 2.55-3.00(2H, m, piperidine) 3.38(2H,
dt, CONCH.sub.2 J=6.5Hz, J= 12.4Hz) 5.31(1H, s, Ar.sub.2CH)
5.55-5.90(1H, m, NH) 6.44(1H, d, CH.dbd.CHCO, J=15.6Hz)
6.90-8.00(11H, m, ar, py, CH.dbd.CHCO) 8.55-8.70(1H, m, py)
8.70-8.95(1H, m, py)
Example 10
[0503]
N-[3-(1-diphenylmethylpiperidin-4-yl)-propyl]-3-(pyridin-3-yl)-acry-
lamide (substance 97)
[0504] Production occurred analogously to Example 3.
[0505] Batch size: 3.9 g (26.1 mmol) 3-(3-pyridyl)-acrylic acid,
4.1 g (47.4 mmol) oxalyl chloride and 7.38 (23.7 mmol)
3-(1-diphenylmethylpiper- idine-4-yl)-propylamine.
[0506] In the purification, crystallization is done first from
1-chlorobutane and subsequently once from acetic acid. Colorless
crystals with a MP of 110-113.degree. C. were recovered; yield 6.2
g (60%).
11 C.sub.29H.sub.33N.sub.3O (439.6) IR-Spectrum (KBr): .nu.(NH)
3240 cm.sup.-1 .nu.(C.dbd.O) 1650, 1555 cm.sup.-1 .nu.(C.dbd.C)
1605 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 0.90-2.25(11H, m,
piperidine, piperidine-CH.sub.2).sub.3) 2.70-3.05(2H, m,
piperidine) 3.36(2H, dt, CONCH.sub.2 J=6.5Hz, J= 12.8Hz) 4.21(1H,
s, Ar.sub.2CH) 5.85-6.20(1H, m, NH) 6.46(1H, d, CH.dbd.CHCO,
J=15.7Hz) 6.90-7.70(11H, m, ar, py) 7.60(1H, d, CH.dbd.CHCO,
J=15.7Hz) 7.60-7.90(1H, m, py) 8.45-8.65(1H, m, py) 8.65-8.85(1H,
m, py)
Example 11
[0507]
N-[3-(1-diphenylmethylpiperidin-4-yl)propyl]-3-(pyridin-3-yl)-propi-
onamide (substance 96)
[0508] 3.0 g (6.8 mmol)
N-[3-(1-diphenylmethylpiperidin-4-yl)-propyl]-3-(p-
yridin-3-yl)-acrylamide (substance 97) are suspended in 60 ml THF
and added to 5 drops concentrated hydrochloric acid and 0.35 g
palladium (5%) on activated carbon. The mixture is stirred at RT
under hydrogen atmosphere until consumption of the theoretical
amount of hydrogen to be taken up. The suspension is filtered from
the catalyst and the solvent is removed under vacuum. The residue
is chromatographically purified over a silica gel with
CHCl/CH.sub.3OH/NH.sub.4OH (85/15/2) and crystallized twice after
drawing off the solvent. Colorless crystals with a MP of
109-110.degree. C. were recovered; yield 1.7 g (56%).
12 C.sub.29H.sub.35N.sub.3O.sub.2 (441.6) IR-Spectrum (KBr):
.nu.(NH) 3230 cm.sup.-1 .nu.(C.dbd.O) 1620, 1555 cm.sup.-1
.sup.1H-NMR-Spectrum (CDCl.sub.3): 1.00-2.00(11H, m, piperidine,
piperidine-CH.sub.2).sub.2) 2.44(2H, t, CO--CH.sub.2, J=7.4Hz)
2.75-3.15(4H, m, piperidine, py-CH.sub.2) 3.15(2H, dt, CONCH.sub.2
J=6.7Hz, J= 13.0Hz) 4.21(1H, s, Ar.sub.2CH) 5.30-5.60(1H, m, NH)
7.00-7.70(12H, m, Ar, pyridine 6.90-7.70(11H, m, ar, py)
8.35-8.55(2H, m, pyridine)
Example 12
[0509]
N-[4(1-diphenylmethylpiperidin-4-yl)-butyl]-2-(pyridin-3-yloxy)-ace-
tamide (substance 129)
[0510] 5.0 g (32.6 mmol) 3-pyridyloxyacetic acid and 3.95 g (39.1
mmol) TEA are suspended in 200 ml abs. dichloromethane and cooled
to ca. 0.degree. C. under moisture exclusion. 6.34 g (41.3 mmol)
88% HOBT and 7.49 g (39.1 mmol) EDC are added and the mixture is
stirred 30 min under ice cooling. 11.56 g (35.9 mmol)
N-4-(1-diphenylmethylpiperidine-4-yl)-bu- tylamine are dissolved in
50 ml abs. dichloromethane and added dropwise under ice cooling.
The mixture is stirred without further cooling at RT overnight.
Subsequently, the batch is washed once with 50 ml 1M NaOH and twice
each with 70 ml water. The organic phase is dried over sodium
sulfate and the solvent is removed under vacuum. The resinous
residue is chromatographically purified over silica gel with
CHCl.sub.3/CH.sub.3OH (95/5 to 90/10) and crystallized from 30 ml
acetic acid ethyl ester after drawing off the solvent. Colorless
crystals with a MP of 103-105.degree. C. were recovered; yield 3.45
g (23%).
13 C.sub.29H.sub.35N.sub.3O.sub.2 (457.6) IR-Spectrum (KBr):
.nu.(NH) 3360 cm.sup.-1 .nu.(C.dbd.O) 1660, 1545 cm.sup.-1
.sup.1H-NMR-Spectrum (CDCl.sub.3): 0.95-2.05(13H, m, piperidine,
piperidine-CH.sub.2).sub.3) 2.70-3.00(2H, m, piperidine) 3.34(2H,
dt, CONHCH.sub.2, J=6.5Hz, J= 12.9Hz) 4.21(1H, s, Ar.sub.2CH)
4.51(2H, s, COCH.sub.2O) 6.40-6.70(1H, m, NH) 7.00-7.60(12H, m, Ar,
py) 8.20-8.45(2H, m, py)
Example 13
[0511]
N-[5(1-diphenylmethylpiperidin-4-yl)-pentyl]-3-pyridin-3-yl)-propio-
namide (Substance 142)
[0512] 2.47 g (16.3 mmol) 3-(3-pyridyl)priopionic acid are
suspended in 40 ml abs. dichloromethane and, after addition of
three drops of pyridine, cooled to ca. 0.degree. C. in an ice bath
under moisture exclusion. 1.90 ml (22.3 mmol) oxalyl chloride are
added slowly and the mixture is first stirred under ice cooling for
30 minutes and then at RT overnight. Subsequently, the solvent and
excess oxalyl chloride is distilled off in a rotary evaporator. In
order to completely remove the oxalyl chloride, the colorless
residue is further dried for two hours under high-vacuum. The acid
chloride obtained in this manner is suspended in 50 ml abs.
dichloromethane and cooled to ca. 0.degree. C. in an ice bath under
moisture exclusion without further purification. 5.0 g (14.8 mmol)
5-(1-diphenylmethylpiperidin-4-yl)-pentylamine are dissolved in 40
ml abs. dichloromethane and added dropwise to this suspension.
After complete addition, the ice bath is removed and the reaction
mixture is stirred for a further two hours at RT. The mixture is
subsequently concentrated, taken up in 10% sodium hydroxide
solution and extracted three times with acetic acid ethyl ester.
The combined organic phases are washed with a saturated NaCl
solution, dried over sodium sulfate and the solvent is removed in a
vacuum. The residue is chromatographically purified over silica gel
with CHCl.sub.3CH.sub.3OH (96/4) and crystallized from 40 ml
acetonitrile after drawing off the solvent. Colorless crystals with
a MP of 112-114.degree. C. were recovered; yield: 3.5 g (50%)
14 C.sub.31H.sub.39N.sub.3O (469.7) IR-Spectrum (KBr): .nu.(NH)
3260 cm.sup.-1 .nu.(C.dbd.O) 1635, 1550 cm.sup.-1
.sup.1H-NMR-Spectrum (CDCl.sub.3): 0.90-2.00(15H, m, piperidine,
piperidine-CH.sub.2).sub.4) 2.40(2H, t, CH--CH.sub.2, J=7.5)
2.70-3.10(4H, m, piperidine, py, CH.sub.2) 3.19(2H, dt,
CONHCH.sub.2, J=6.6Hz, J= 12.6Hz) 4.21(1H, s, Ar.sub.2CH)
5.30-5.60(1H, m, NH) 7.00-7.75(12H, m, Ar, py) 8.35-8.65(2H, m,
py)
Example 14
[0513]
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-propi-
onamide (substance 100)
[0514] 21.6 g (131 mmol) 3-(3-pyridyl)-propionic acid methyl ester,
35.1 g ml (109 mmol) 4-(1-diphenylmethylpiperidine-4-yl)butylamine
and 9.8 g (54.5 mmol) 30% sodium methylate solution in methanol are
heated to boiling in 480 ml toluene for five hours. Subsequently,
30 ml of solvent are distilled; thereby, sodium methylate
precipitates and the temperature of the suspension increases to
102.degree. C. under heavy foaming. The mixture is cooled to
70-80.degree. C. and extracted twice with 45 ml and 30 ml of water.
The organic phase is azeotropically dried on a moisture separator
and cooled to ca. 0.degree. C. The resulting precipitate is
filtered off and crystallized from 190 ml toluol. Colorless
crystals with a MP of 139.degree. C. were recovered; yield 46.3 g
(93%).
15 C.sub.30H.sub.37N.sub.3O (455.6) IR-Spectrum (KBr): .nu.(NH)
3250 cm.sup.-1 .nu.(C.dbd.O) 1630, 1570 cm.sup.-1
.sup.1H-NMR-Spectrum (CDCl.sub.3): 1.00-2.10(13H, m, piperidine,
piperidine-CH.sub.2).sub.3) 2.43(2H, t, CO--CH.sub.2, J=7.4Hz)
2.70-3.10(4H, m, py-CH.sub.2) 3.12(2H, dt, CONHCH.sub.2, J=6.5Hz,
J= 12.5Hz) 4.21(1H, s, Ar.sub.2CH) 5.45-5.75(1H, m, NH)
7.05-7.60(12H, m, Ar, py) 8.30-8.60(2H, m, py)
Example 15
[0515]
N-{4-[1-(6,11-dihydrodibenzo[b,e]-oxepin-11-yl)-piperidineyl]-butyl-
}-3-(pyridin-3-yl)-propionamide (substance 230)
[0516] 3.46 g (15 mmol) 11-chloro-6,11-dihydrodibenzo[b,e]oxepine
are dissolved in 90 ml abs. dichloromethane and 5.43 g (15 mmol)
N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide
dihydrochloride are added. 5.0 g (49.5 mmol) TEA are dissolved in
20 ml abs. dichloromethane and added dropwise under ice cooling.
The mixture is stirred without further cooling for two days at RT.
Subsequently, the batch is washed twice, each with 50 ml water. The
organic phase is dried over silica gel with CHCl.sub.3/CH.sub.3OH
(95/5) and crystallized twice at first, each from 10 ml
1-chlorobutane, and subsequently crystallized once from 10 ml
acetic acid. Colorless crystals with a MP of 110-112.degree. C.
were isolated, yield 0.2 g (3%/O).
16 C.sub.31H.sub.37Cl.sub.2N.sub.3O.sub.2 (483.6) IR-Spectrum
(KBr): .nu.(NH) 3240 cm.sup.-1 .nu.(C.dbd.O) 1630, 1570 cm.sup.-1
.sup.1H-NMR-Spectrum (CDCl.sub.3): 0.80-2.00(13H, m, piperidine,
piperidine-CH.sub.2).sub.3) 2.43(2H, t, CO--CH.sub.2, J=7.5Hz)
2.55-3.30(6H, m, piperidine, py-CH.sub.2, CONHCH.sub.2) 3.83(1H, s,
Ar.sub.2CH) 4.68(1H, d, O--CH, J=11.3Hz) 5.25-5.55(1H, m, NH
6.65-7.65(11H, m, Ar, py, O--CH) 8.35-8.60(2H, m, py)
Example 16
[0517]
N-{4-[1-(9H-fluorene)piperidine-4-yl]-butyl}-3-(pyridin-3-yl)-propi-
onamide (substance 209)
[0518] 8.0 g (27.7 mmol)
N-(4-piperidin-4-yl-butyl)-3-pyridin-3-yl)-propio- namide and 5.6 g
(55.3 mmol) TEA are present in 100 ml acetonitrile and cooled to
ca. 0.degree. C. under moisture exclusion. 6.8 g (27.7 mmol)
9-bromofluorene are added in solid form and the mixture is stirred
for 2 days at ca. 65.degree. C. and for two days at RT.
Subsequently, the solvent is drawn off under vacuum to a large
extent and the residue is dispersed between CHCl.sub.3 and 10%
NaOH. The organic phase is washed twice with water and dried over
sodium sulfate. After the removal of the solvent, the residue is
chromatographically purified over silica gel with
CHCl.sub.3/CH.sub.3OH (98/2 to 94/6) and crystallized from 30 ml
acetonitrile after drawing off the solvent. Colorless crystals with
a MP of 131-132.degree. C. were recovered; yield 2.5 g (20%).
17 C.sub.30H.sub.35N.sub.3O (453.6) IR-Spectrum (KBr): .nu.(NH)
3300 cm.sup.-1 .nu.(C.dbd.O) 1630, 1530 cm.sup.-1
.sup.1H-NMR-Spectrum (CDCl.sub.3): 0.95-1.80(11H, m, piperidine,
piperidine-CH.sub.2).sub.3) 2.25-2.80(6H, m, piperidine,
CO--CH.sub.2) 2.97(2H, t, py-CH.sub.2, J=7.5Hz) 3.19(2H, dt,
CONHCH.sub.2, J=6.5Hz, J= 12.5Hz) 4.82(1H, s, ArCH) 5.25-5.55(1H,
m, NH) 7.10-7.80(10H, m, Ar, py,) 8.35-8.55(2H, m, py)
Example 17
[0519]
N-{4-[1-(2-naphthylsulfonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl-
)-propionamide (substance 337)
[0520] 3.5 g (12 mmol)
N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propion- amide and 6.7
g (48.1 mmol) TEA are present in 100 ml abs. dichloromethane and
cooled to ca. 0.degree. C. under moisture exclusion. 3.0 g (13.2
mmol) naphthaline-2-sulfonic acid chloride are dissolved in 40 ml
abs. dichloromethane and added dropwise. The mixture is stirred
without further cooling at RT overnight. Subsequently, the batch is
washed twice, each with 80 ml water The organic phase is dried over
sodium sulfate and the solvent is removed under vacuum. The residue
is chromatographically purified over silica gel with
CHCl.sub.3/CH.sub.3OH (97/3) and crystallized from acetic acid
ethyl ester after drawing off the solvent. Colorless crystals with
a MP of 103-105.degree. C. were recovered; yield 2.87 g (50%).
18 C.sub.27H.sub.33N.sub.3O.sub.3S (479.6) IR-Spectrum (KBr):
.nu.(NH) 3320 cm.sup.-1 .nu.(C.dbd.O) 1645, 1530 cm.sup.-1
.sup.1H-NMR-Spectrum (CDCl.sub.3): 0.90-1.90(11H, m, piperidine,
piperidine-CH.sub.2).sub.3) 2.05-2.40(2H, m, piperidine) 2.42(2H,
t, CO--CH.sub.2, J=7.4Hz) 2.80-3.30(4H, t, dt, Py-CH.sub.2,
J=7.4Hz, CONHCH.sub.2) 3.70-4.00(2H, m, piperidine) 5.40-5.70(1H,
m, NH) 7.10-8.15(8H, m, Ar, Py,) 8.25-8.55(3H, m, Ar, Py)
Example 18
[0521]
N-{4-[1-(naphthylaminocarbonyl)-piperidin-4-yl]-butyl}-3(pyridin-yl-
)-propionamide (substance 305)
[0522] 2.6 g (17.7 mmol)1-naphthyl isocyanate are dissolved in 15
ml abs. THF and cooled to 0.degree. C. under moisture exclusion.
5.1 g (17.7 mmol)
N-(4-piperidine-4-yl-butyl)-3-(pyridine-3-yl)-propionamide are
dissolved in 35 ml abs. THF and added dropwise under ice cooling.
The mixture is stirred without further cooling at RT overnight.
Subsequently, the solution is drawn off under vacuum to a large
extent and the residue is chromatographically purified over silica
gel with CHCl.sub.3CH.sub.3OH (90/10) and further purified by
flash-chromatography with CHCl.sub.3/CH.sub.3OH (95/5 to 90/10).
After drawing off the solvent, crystallization occurs from
isopropanol/diisopropanol. Colorless crystals with a MP of
143-144.degree. C. were recovered; yield 0.77 g (9%).
19 C.sub.28H.sub.34N.sub.4O.sub.2 (458.6) IR-Spectrum (KBr):
.nu.(NH) 3240 cm.sup.-1 .nu.(C.dbd.O) 1630, 1560 cm.sup.-1
.sup.1H-NMR-Spectrum (CDCl.sub.3): 0.95-1.95(11H, m, piperidine,
piperidine-CH.sub.2).sub.3) 2.40(2H, t, CO--CH.sub.2, J=7.4Hz)
2.75-3.40(6H, m, piperidine, Py-CH.sub.2, CONHCH.sub.2)
4.00-4.30(2H, m, piperidine) 5.55-5.85(1H, m, NH) 6.77(1H, s, NH)
7.10-8.00(9H, m, Ar, Py,) 8.35-8.55(2H, m, Ar, Py)
Example 19
[0523]
N-{4-[1-(2-naphthoyl)piperidin-4-yl]-butyl}-(pyridin-3-yl)-propiona-
mide (substance 274)
[0524] 6.0 g (20.7 mmol)
N-(4-piperidine-4-yl-butyl)-3-(pyridine-3-yl)-pro- pionamide and
2.1 g (20.7 mmol) TEA are dissolved in 30 ml abs. dichloromethane
and cooled to ca. 0.degree. C. under moisture extraction. 3.95 g
(20.7 mmol) 2-naphthoylchloride are dissolved in 40 ml abs.
dichloromethane and added dropwise under ice cooling. The mixture
is stirred without further cooling at RT overnight. Subsequently,
the batch is made basic by the addition of 10% sodium hydroxide
solution and washed twice with a small amount of water. The organic
phase is dried over sodium sulfate and the solvent is removed under
vacuum. The resinous residue is chromatographically purified with
CHCl.sub.3/CH.sub.3OH (96/4). Yield of colorless resin: 5.4 g
(59%).
20 C.sub.28H.sub.33N.sub.3O.sub.2 (443.6) IR-Spectrum (KBr): n(NH)
3300 cm.sup.-1 n(C.dbd.O) 1630, 1540 cm.sup.-1 .sup.1H-NMR-Spectrum
(CDCl.sub.3): 1.00-2.05(11H, m, piperidin,
piperidine-(CH.sub.2).sub.3) 2.55(2H, t, CH--CH.sub.2, J=7.5Hz)
2.70-3.45(6H, m, piperidine, Py-CH.sub.2, CONHCH.sub.2)
3.65-4.15(1H, m, piperidin) 4.50-5.05(1H, m, piperidine)
5.60-5.85(1H, m, NH) 7.20-7.35(1H, m, Py) 7.50-7.75(4H, m, Ar, Py)
7.85-8.10(4H, m, Ar) 8.40-8.65(2H, m, Py)
Example 20/1
[0525] N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide
(substance 21)
[0526] 100 g (219.5 mmol)
N-[4-(1-diphenylmethylpiperidine-4-yl)-butyl]-3--
(pyridine-3-yl)-propionamide (substance 100) are dissolved in 500
ml ethanol and mixed with 8.0 g palladium (5%) on activated carbon
(moistened with 40 ml water) and 25 ml conc. hydrochloric acid. The
mixture is heated to ca. 45.degree. C. and stirred under hydrogen
atomosphere until consumption of the theoretical amount of hydrogen
to be taken up (ca five hours). After cooling, the catalyst is
filtered and the solvent is removed under vacuum. The residue is
taken up in 200 ml water and washed three times with a total of 200
ml CHCl.sub.3. The organic phases are discarded and the aqueous
phase is made alkaline with 11 g sodium hydroxide and extracted
three times, each with 100 ml CHCl.sub.3. After washing the organic
phase with 30 ml water, the solvent is removed under vacuum. The
oily residue is filtered over silica gel with
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH (80/20/2). Yield of the gradually
hardening resin: 53.0 g (83%).
[0527] For spectroscopic data, see Example 20/2.
Example 20/2
[0528] N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide
(substance 21)
[0529] 100 g (219.5 mmol)
N-[4-(1-diphenylmethylpiperidine-4-yl)-butyl]-3--
(pyridine-3-yl)-acrylamide (Substance 104) are dissolved in 500 ml
ethanol and mixed with 8.0 g palladium (5%) on activated carbon
(moistened with 40 ml water) and 25 ml conc. hydrochloric acid. The
mixture is heated to ca 45.degree. C. and stirred under hydrogen
atomosphere until consumption of the theoretical amount of hydrogen
to be taken up (ca. 1 day). After cooling, the catalyst is filtered
and the solvent is removed under vacuum. The residue is taken up in
400 ml water and washed twice, each with 100 ml toluol. The organic
phases are discarded and the aqueous phase is made alkaline with
400 ml 4M-sodium hydroxide solution and extracted three times each
with 200 ml dichloromethane. The combined organic phases are dried
over sodium sulfate and the solvent is removed under vacuum. The
wax-like residue is filtered over silica gel with
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH (90/9/1). Yield: 58.3 g (91%).
C.sub.29H.sub.33N.sub.3O.sub.2 (443.6)
21 IR-Spectrum (KBr): .nu.(NH) 3300 cm.sup.-1 .nu.(C.dbd.O) 1630,
1540 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 0.90-1.80(12H, m,
piperidin, NH piperidine-(CH.sub.2).sub.3) 2.35-2.75(4H, m,
CO--CH.sub.2, piperidine) 2.80-3.35(6H, m, piperidine, Py-CH.sub.2,
CONHCH.sub.2) 6.05-6.40(1H, m, NH) 7.10-7.35(1H, m, Py)
7.40-7.60(1H, m, Py) 7.20-7.35(1H, m, Py) 8.30-8.55(2H, m, Py)
Example 21
[0530]
N-{4-[1-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-piperidine-4-yl]-bu-
tyl}-3-(pyridin-3-yl)-acrylamide (substance 230)
[0531] 7.02 g (21.5 mmol)
N-[4-piperidine-4-yl)-butyl]-3-(pyridine-3-yl)-a- crylamide
dihydrochloride (substance 22 as dihydrochloride) are suspended in
100 ml abs. dichloromethane and mixed with 7.08 g (70.0 mmol) TEA.
The mixture is cooled to ca. 0.degree. C. under moisture exclusion
and a solution of 5.30 g (21.5 mmol)
11-chloro-6,1-dihydrodibenzo[b,e]thiepine in 10 ml abs.
dichloromethane is added dropwise. The mixture is stirred without
further cooling for 24 hours at RT. Subsequently, the batch is
washed with 50 ml 10% sodium hydroxide solution and 30 ml water.
The organic phase is dried over sodium sulfate and the solution is
removed under vacuum. The red-brown residue is chromatographically
purified three times over silica gel with CHCl.sub.31CH.sub.3OH
(100/0, 97/3 and 96/4 to 94/6). Subsequently, further purification
occurs by means of MPLC with CHCl.sub.3/CH.sub.3OH (98/2). yield:
0.5 g (5%) of a brittle vitreous solid with a MP of 89-91.degree.
C.
22 C.sub.31H.sub.35Cl.sub.2N.sub.3OS (497.7) IR-Spectrum (KBr):
.nu.(NH) 3280 cm.sup.-1 .nu.(C.dbd.O) 1660, 1550 cm.sup.-1
.nu.(C.dbd.C) 1620 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
0.90-2.00(13H, m, piperidine, piperidine-CH.sub.2).sub.3)
2.55-2.95(2H, m, piperidine) 3.20-3.60(3H, m, CONHCH.sub.2,
SCH.sub.2) 4.03(1H, s, Ar.sub.2CH) 6.10-6.35(1H, m, NH)
5.95-6.30(1H, m, SCH.sub.2) 6.44(1H, d, CH.dbd.CHO J=15.7Hz)
4.68(1H, d, O--CH, J=11.3Hz) 6.85-7.40(9H, m, Ar, Py) 8.50-8.65(1H,
m, Py) 8.65-8.80(1H, m, Py)
Example 22
[0532]
N-[4(1-diphenylmethylpiperidine-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-p-
entadienoic Acid Imide (Substance 132)
[0533] 3.85 g (22.0 mmol) 5-(3-pyridyl)-2,4-pentadieneoic acid are
suspended in 90 ml abs. dichloromethane and, after addition of
three drops of pyridine, cooled to ca. 0.degree. C. in an ice bath
under moisture exclusion. 3.8 g (30,0 mmol) oxalyl chloride are
added dropwise and the mixture is stirred at RT overnight.
Subsequently, the solvent and excess oxalyl chloride are distilled
off on a rotary evaporator. In order to completely remove the
oxalyl chloride, the residue is dried for a further two hours under
high-vacuum. The acid chloride obtained in this manner is suspended
in 50 ml abs. dichloromethane and cooled to ca. 0.degree. C. 6.44 g
(20.0 mmol) 4.(1-diphenylmethylpiperidine-4-yl)-butyl- amine are
dissolved in 40 ml abs. dichloromethane and added dropwise to the
suspension. After complete addition, the ice bath is removed and
the reaction is stirred for a further two hours at RT. The mixture
is subsequently washed with 10% sodium hydroxide solution. The
organic phase is washed twice, each with 40 ml water, dried over
sodium sulfate and the solution is removed under vacuum. The
residue is chromatographically purified three times over silica gel
with CHCl.sub.3CH.sub.3OH (98/2 to 95/5) and crystallized twice
from 250 ml acetonitrile after removal of the solvent Beige-colored
crystals with a MP of 164-166.degree. C. are isolated; yield: 4.7 g
(49%)
23 C.sub.32H.sub.37N.sub.3O (479.6) IR-Spectrum (KBr): .nu.(NH)
3280 cm.sup.-1 .nu.(C.dbd.O) 1650, 1550 cm.sup.-1 .nu.(C.dbd.C)
1600 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 1.00-2.00(13H, m,
piperidine, piperidine-CH.sub.2).sub.3) 2.70-3.00(2H, m,
piperidine) 3.34(2H, dt, CONHCH.sub.2, J=6.6Hz, J=12.8Hz) 4.21(1H,
s, Ar.sub.2CH) 5.50-5.75(1H, m, NH) 6.44(1H, d, CH.dbd.CH J=14.7Hz)
6.75-6.95(2H, m, CH.dbd.CH) 7.05-7.50(12H, m, Ar, Py, CH.dbd.CH)
7.65-7.85(1H, m, Py) 8.45-8.55(1H, m, Py) 8.60-8.75(1H, m, Py)
Example 23
[0534]
N-[4-(1-benzoylpiperidine-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide
(Substance 259)
[0535] 5.1 g (36.2 mmol) benzoyl chloride are dissolved in 150 ml
abs. dichloromethane and cooled to ca. 0.degree. C. under moisture
exclusion. 10.4 g (36.2 mmol)
N-[4-piperidine-4-yl)-butyl]-3-(pyridin-3-yl)-acrylami- de
(Substance 22) are dissolved in 50 ml abs. dichloromethane and
added dropwise under ice cooling. The mixture is stirred without
further cooling at RT overnight. Subsequently, the suspension is
added to 60 ml sodium hydroxide solution and extracted twice, each
with 80 ml dichloromethane. The combined organic phases are washed
twice, each with 60 ml water, dried over sodium sulfate and the
solution is removed under vacuum. The residue is
chromatographically purified three times over silica gel with
CHCl.sub.3/CH.sub.3OH (97/3 to 95/5) and crystallized from 75 ml
acetonitrile. Colorless crystals with a MP of 100-102.degree. C.
were recovered; yield: 9.8 g(69%).
24 C.sub.24H.sub.29N.sub.3O.sub.2 (391.5) IR-Spectrum (KBr):
.nu.(NH) 3280 cm.sup.-1 .nu.(C.dbd.O) 1670, 1545 cm.sup.-1
.nu.(C.dbd.C) 1630 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
0.80-2.00(11H, m, piperidine, piperidine-CH.sub.2).sub.3)
2.55-4.00(5H, m, piperidine, CONHCH.sub.2) 4.40-4.90(1H,
piperidine) 6.00-6.25(1H, m, NH) 6.48(1H, d, CH.dbd.CHCO, J=15.7Hz)
8.50-8.65(1H, m, Py) 8.65-8.80(1H, m, Py)
Example 24/
[0536]
N-(1-diphenylmethylazetidin-3-ylmethyl)-3-(pyridin-3-yl)-acrylamide
(Substance 2)
[0537] Production occurred analogously to Example 22.
[0538] Batch size: 4.3 g (28.7 mmol) 3-(3-pyridyl)-acrylic acid,
6.7 ml (78.4 mmol) oxalyl chloride and 6.6 g (26.1 mmol)
3-(1-diphenylmethylazet- idine-3-ylmethyl)-amine.
[0539] In the work up, the reaction mixture is washed with sodium
hydroxide solution. The aqueous phase is extracted twice, each with
50 ml dichloromethane. The combined organic phases are dried over
sodium sulfate and the solvent is removed under vacuum. The residue
is chromatigraphically pre-purified over silica gel with
CHCl.sub.3/CH.sub.3OH (98/2 to 95/5) and subsequently purified
twice by flash chromatography with CHCl.sub.3/CH.sub.3OH (99/1 to
95/5). An amorphous solid with a MP of 72-74.degree. C. remains
after the removal of the solvent; yield 0.75 g (7%).
25 C.sub.25H.sub.25N.sub.3O (383.5) IR-Spectrum (KBr): .nu.(NH)
3280 cm.sup.-1 .nu.(C.dbd.O) 1680, 1570 cm.sup.-1 .nu.(C.dbd.C)
1640 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 2.40-2.80(1H, m,
azetidine) 2.80-3.10(2H, m, azetidine) 3.10-3.40(2H, m, azetidine)
3.60(2H, dd, CONCH.sub.2 J=6.5Hz, J=12.8Hz) 4.36(1H, Ar.sub.2CH)
6.45-6.75(1H, m, NH) 6.50(1H, d, CH.dbd.CHCO, J=15.7Hz)
7.00-7.50(11H, m, Ar, Py) 7.62(1H, d, CH.dbd.CHCO, J=15.7Hz)
7.65-7.90(1H, m, Py) 8.50-8.70(1H, m, Py) 8.70-8.85(1H, m, Py)
Example 25
[0540]
N-(4-diphenylmethylmorpholin-2-ylmethyl)-3-(pyridin-3-yl)-acrylamid-
e (Substance 378)
[0541] Production occurred analogously to Example 22.
[0542] Batch size: 2.3 g (15.6 mmol) 3-(3-pyridyl)-acrylic acid,
5.4 g (42.5 mmol) oxalyl chloride and 3.6 g (14.7 mmol)
2-aminomethyl-4-dipheny- lmethylmorpholine.
[0543] In the work up, 40 ml 10% sodium hydroxide solution are
added to the reaction solution. The aqueous phase is extracted with
15 ml dichloromethane. The combined organic phases are washed
twice, each with 15 ml water, dried over sodium sulfate and the
solvent is removed under vacuum. The residue is chromatigraphically
purified three times over silica gel with CHCl/CH.sub.3OH (95/5,
90/10 and 90/10). An amorphous solid with a MP of 71-74.degree. C.
remains after the removal of the solvent; yield 0.8 g (13%).
26 C.sub.26H.sub.27N.sub.3O.sub.2 (413.5) IR-Spectrum (KBr):
.nu.(NH) 3370 cm.sup.-1 .nu.(C.dbd.O) 1655, 1540 cm.sup.-1
.nu.(C.dbd.C) 1620 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
1.70-2.30(2H, m, morpholine) 2.55-2.90(2H, m, morpholine)
3.00-3.35(1H, m, morpholine) 3.50-4.00(4H, m, CONHCH.sub.2,
morpholine) 4.20(1H, Ar.sub.2CH) 6.00-6.25(1H, m, NH) 6.47(1H, d,
CH.dbd.CHCO, J=15.7Hz) 4.36(1H, Ar.sub.2CH) 7.60(1H, d,
CH.dbd.CHCO, J=15.7Hz) 7.00-7.55(11H, m, Ar, Py) 7.60(1H, d,
CH.dbd.CHCO, J=15.7Hz) 7.65-7.90(1H, m, Py) 8.50-8.70(1H, m, Py)
8.70-8.80(1H, m, Py)
Example 26
[0544]
N-{4-[1-(9-oxo-9H-fluorene-4-carbonyl)-piperidine-4-yl]-butyl}-3-(p-
yridin-3-yl)-acrylamide (Substance 277)
[0545] 5.0 g (20.0 mmol) 95% 9-fluorene-1-acyl chloride were
dissolved in 70 ml abs. dichloromethane and 6.5 g (18.2 mmol)
N-[4-(piperidine-4-yl)bu- tyl]-3-(pyridine-3-yl)-acrylamide
dihydrochloride (substance 22) are added. The mixture is cooled to
ca 0.degree. C. under moisture exclusion and 4.0 g (40.0 mmol) TEA
dissolved in 10 ml abs. dichloromethane is added dropwise. The
batch is stirred without cooling at RT overnight. In the work up,
150 ml 10% sodium hydroxide solution are added to the reaction
solution and extracted by shaking. The organic phase is washed with
100 ml water, dried over sodium sulfate and the solution is removed
under vacuum. The residue is pre-purified over silica gel with
CHCl.sub.3/CH.sub.3OH (96/4 to 95/5) and subsequently purified by
flash chromatography with CHCl.sub.3/CH.sub.3OH (95/5). The product
remains as a yellow, vitreous solid with MP of 80-82.degree. C.
after removal of the solvent; yield: 2.3 g (25%)
27 C.sub.31H.sub.31N.sub.3O.sub.3 (493.6) IR-Spectrum (KBr):
.nu.(NH) 3320 cm.sup.-1 .nu.(C.dbd.O) 1730, 1640 cm.sup.-1
.nu.(C.dbd.C) 1620 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
0.70-2.05(11H, m, piperidine, piperidine-CH.sub.2).sub.3)
2.60-3.80(5H, m, piperidine, CONHCH.sub.2) 4.70-5.05(1H,
piperidine) 5.85-6.20(1H, m, NH) 6.47(1H, d, CH.dbd.CHO J=15.7Hz)
7.15-7.90(10H, m, Ar, PyCH.dbd.CHCO, J=15.7Hz) 8.50-8.65(1H, m, Py)
8.65-8.85(1H, m, Py)
Example 27
[0546]
N-[3-(1-benzylpiperidine-4-yloxy)-propyl]-3-(pyridin-yl)-acrylamide
(Substance 55)
[0547] 2.4 g (16.2 mmol) 3-(3-pyridyl)-acrylic acid and 2.3 g (16.2
mmol) TEA were suspended in 50 ml abs. tolueneand a solution of 1.5
ml (15.5 mmol) chloroformic ethyl ester in 20 ml abs. tolueneis
added dropwise under moisture exclusion and gentle cooling. This
yellow suspension is stirred two hours at RT and then a solution of
3.5 g (14.1 mmol) 3-(1-benzylpiperidine-4-yloxy)propylamine in 20
ml abs. tolueneis added dropwise. The mixture is stirred at RT and
subsequently extracted by shaking in the heat three timnes with 10
ml water, 2M sodium hydroxide solution and again with water,
respectively. The organic phase is concentrated under vacuum and
the orange colored, oily residue is chromatographically purified
twice over silica gel with CHCl.sub.3/CH.sub.3OH/NH.sub.4OH (90/9/1
and 95/50 to 90/10/0) and crystallized twice from 10 ml acetic acid
ethyl ester. Colorless crystals with a MP of 100-102.degree. C.
were recovered; yield: 1.9 g (35%).
28 C.sub.23H.sub.29N.sub.3O.sub.2 (379.5) IR-Spectrum (KBr):
.nu.(NH) 3290 cm.sup.-1 .nu.(C.dbd.O) 1650, 1530 cm.sup.-1
.nu.(C.dbd.C) 1610 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
1.50-2.45(8H, m, piperidine, C--CH.sub.2--C) 2.70-3.00(2H, m,
piperidine) 3.25-3.80(7H, m, piperidine, CONHCH.sub.2, Ar--
CH.sub.2, O--CH.sub.2) 6.54(1H, d, CH.dbd.CHCO, J=15.7Hz)
7.25-7.50(6H, m, Ar, Py) 7.69(1H, d, CH.dbd.CHCO, J=15.7Hz)
7.80-8.00(1H, m, Py) 8.60-8.75(1H, m, Py) 8.75-8.90(1H, m, Py)
Example 28
[0548]
N-[4-(1-benzoylpiperidine-3-yl)-butyl]-3-(pyridin-3-yl)acrylamide
(Substance 56)
[0549] Production occurred analogously to Example 27.
[0550] Batch size: 2.6 g (17.4 mmol) 3-(3-pyridyl)-acrylic acid,
1.6 ml (19.0 mmol) oxalyl chloride and 3.9 g (15.8 mmol)
4-(1-benzlypiperidine-3- -yl)-butylamine in 100 ml abs.
dichloromethane.
[0551] The reaction time is increased to 6 hours at RT. In the work
up, the batch is washed with 50 ml sodium hydroxide solution and
the aqueous phase is extracted with 50 ml dichloromethane. The
combined organic phases are concentrated under vacuum and the
residue is chromatigraphically purified twice over silica gel with
CHCl.sub.3/CH.sub.3OH (93/7 and 95/5), subsequently further
purified by flash chromatography with CHCl.sub.3/CH.sub.3OH, 95/5
and 97/3) and crystallized from 5 ml acetic acid ethyl ester.
Colorless crystals with a MP of 80-82.degree. C. were recovered;
yield 0.9 g (15%).
29 C.sub.24H.sub.31N.sub.3O (377.5) IR-Spectrum (KBr): .nu.(NH)
3300 cm.sup.-1 .nu.(C.dbd.O) 1650, 1530 cm.sup.-1 .nu.(C.dbd.C)
1610 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3): 1.00-2.10(13H, m,
piperidine, piperidine-CH.sub.2).sub.3) 2.65-2.95(2H, m,
piperidine) 3.37(2H, dt, CONHCH.sub.2, J= 6.5Hz, J= 12.7Hz)
3.50(2H, s, Ar--CH.sub.2) 5.65-5.95(1H, m NH) 6.46(1H, d,
CH.dbd.CHCO, J=15.6Hz) 7.10-7.40(6H, m, Ar, Py) 7.62(1H, d,
CH.dbd.CHCO, J=15.6Hz) 7.65-7.90(1H, m, Py) 8.50-8.65(1H, m, Py)
8.70-8.80(1H, m, Py)
Example 29
[0552]
N-[4(1-tert-butoxycarbonylpiperidine-4-yl)-butyl]-3-(pyridin-3-yl)--
acrylamide (Substance 367)
[0553] Production occurred analogously to Example 22. TEA is also
added dropwise with the addition of the amine.
[0554] Batch size: 16.4 g (110 mmol) 3-(3-pyridyl)-acrylic acid,
18.9 g (150 mmol) oxalyl chloride and 25.6 g (100 mmol)
4-(1-tert-butoxycarbonyl- piperidine-4-yl)-butylamine and 10.1 g
(100 mmol) TEA in 300 ml abs. dichloromethane.
[0555] In the work up, 100 ml 10% sodium hydroxide solution are
added to the reaction solution. The aqueous phase is extracted with
30 ml dichloromethane. The combined organic phases are washed
twice, each with 25 ml water and the solution is removed under
vacuum. The residue is dissolved in CHCl.sub.3/CH.sub.3OH (90/10)
and filtered through a thin silica gel layer. The crude product
remains as a red oil after the revomal of the solvent (44.0 g). For
purification this is chromatographed with
CHCl.sub.3/CH.sub.3OH,-(95/5) on a silica gel; yield 26.5 g (68%)
as a yellow viscous oil.
30 C.sub.22H.sub.33N.sub.3O.sub.3 (387.50) IR-Spectrum (KBr):
.nu.(NH) 3250 cm.sup.-1 .nu.(C.dbd.O) 1670, 1540 cm.sup.-1
.nu.(C.dbd.C) 1600 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
0.80-1.90(20H, m, piperidine, piperidine-CH.sub.2).sub.3,
tert.butyl) 2.30-2.90(2H, m, piperidine) 3.10-3.60(2H, m,
piperidine) 3.80-4.30(2H, m, CONHCH.sub.2) 6.15-6.55(1H, m NH)
6.43(1H, d, CH.dbd.CHCO, J=15.6Hz) 3.50(2H, s, Ar--CH.sub.2)
8.35-8.55(2H, m, Py) 8.55-8.70(1H, m, Py)
Example 30
[0556] N-[4-(piperidine-4-yl)butyl]-3-(pyridin-3-yl)-acrylamide
Dihydrochloride (Substance 22 as Dihydrochloride)
[0557] 44.0 g (<13.5 mmol) crude
N-[4-(1-tert-butoxycarbonylpiperidine--
4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide (substance 367) are
dissolved in 400 ml ethanol and added to 26.0 ml concentrated
hydrochloric acid. The mixture is heated to boiling for three hours
and the solvent is removed under vacuum after cooling. The yellow
residue is crystallized from 500 ml isopropanol. Beige colored
crystals with a MP of 178-188.degree. C. were recovered; yield:
32.6 g (90%).
31 C.sub.17H.sub.25N.sub.3O.sub.2 (360.3) IR-Spectrum (KBr):
.nu.(NH) 3260 cm.sup.-1 .nu.(C.dbd.O) 1670, 1545 cm.sup.-1
.nu.(C.dbd.C) 1630 cm.sup.-1 .sup.1H-NMR-Spectrum (CDCl.sub.3):
0.95-1.95(11H, m, piperidine, piperidine CH.sub.2).sub.3)
2.60-3.00(2H, m, piperidine) 3.00-3.40(4H, m, piperidine,
CONHCH.sub.2,) 6.73(1H, d, CH.dbd.CHCO, J=15.9Hz) 7.41(1H, d,
CH.dbd.CHCO, J=15.9Hz) 7.80-8.00(1H, m, Py) 8.50-8.65(2H, m, Py)
8.65-8.90(1H, m, Py)
[0558] Further examples of the synthesized compounds are listed in
the following Table 2, giving the structural features and melting
points, for the further illustration of the compounds used
according to the invention with the above characterized
pharacological activities.
32TABLE 2 Prepared compounds of formula (I) 447 MP [.degree. C.] Nr
R.sup.1 A D--E--G (solvent).sup.1 2 H CH.dbd.CH 448 72-74 (amorph;
CHCl.sub.3/MeOH) 5 H CH.dbd.CH 449 164-165 (EE) 21 H
CH.sub.2CH.sub.2 450 60-62 (CHCl.sub.3/MeOH) 22 H CH.dbd.CH 451
140-142 (amorph; CH.sub.2Cl.sub.2) 22 H CH.dbd.CH 452
178-188.sup.4(iPrOH) 23 H CH.sub.2CH.sub.2CH.sub.2CH.sub.2 453
57-59 (CHCl.sub.3) 24 H CH.dbd.CH--CH.dbd.CH 454
197-202.sup.4(iPrOH) 44 H CH.sub.2CH.sub.2 455 61-63 (iPr.sub.2O)
46 H CH.dbd.CH 456 88-90 (MeCN) 54 H CH.sub.2CH.sub.2 457 55-57
(BuCl) 55 H CH.dbd.CH 458 100-102 (EE) 56 H CH.dbd.CH 459 80-82
(EE) 74 H CH.sub.2CH.sub.2 460 125 (EE) 75 H CH.dbd.CH 461 147-149
(MeCN) 80 H CH.sub.2CH.sub.2 462 133-135 (EtOH) 81 H CH.dbd.CH 463
162-164 (EtOH) 83 H CH.sub.2CH.sub.2 464 109-110 (MeCN) 84 H
CH.dbd.CH 465 143-145 (MeCN) 89 H CH.dbd.CH 466 135-136 (EE) 95 H
CH.dbd.CH 467 141-143 (EE/PE) 96 H CH.sub.2CH.sub.2 468 109-110
(BuCl) 97 H CH.dbd.CH 469 110-113 (EE) 98 H CH.sub.2CH.sub.2 470
162-171.sup.4(iPrOH) 99 H CH.dbd.CH 471 139-140 (EE) 100 H
CH.sub.2CH.sub.2 472 139 (EE) 101 473 Harz.sup.4 102 2-OH
CH.sub.2CH.sub.2 474 135-136 (MeCN) 103 6-CH.sub.3O
CH.sub.2CH.sub.2 475 135-137 (BuCl) 104 H CH.dbd.CH 476 156 (EE)
104 H CH.dbd.CH 477 118-120.sup.5(Aceton) 104 H CH.dbd.CH 478
163.sup.4(iPrOH) 105 479 ca. 205 (Zers.) (CHCl.sub.3) 110 2-Cl
CH.dbd.CH 480 136-137 (BuCl) 111 6-C.sub.2H.sub.5S CH.dbd.CH 481
158-160 (EE) 112 6-C.sub.6H.sub.5O CH.dbd.CH 482 134-135 (BuCl) 115
H 483 484 132 (MeOH) 116 H 485 486 58-60 (BuCl) 117 H 487 488
139-140 (MeCN) 122 489 72-74 (BuCl/PE) 123 490 115-117
(iPrOH/iPr.sub.2O) 124 491 94-96 (EE) 129 H OCH.sub.2 492 103-105
(EE) 131 H CH.sub.2CH.sub.2CH.sub.2CH.sub.2 493 109 (EE) 132 H
CH.dbd.CH--CH.dbd.CH 494 164-166 (MeCN) 133 H
CH.sub.2NHCH.sub.2CH.sub.2 495 138-140.sup.4(iPrOH) 134 H 496 497
Harz.sup.4 142 H CH.sub.2CH.sub.2 498 112-114 (MeCN) 143 H
CH.dbd.CH 499 150-152 (iPrOH) 147 H CH.dbd.CH 500 178-180 (EE) 150
H CH.sub.2CH.sub.2 501 159-161 (MeCN) 153 H CH.sub.2CH.sub.2 502
78-78 (MeCN) 154 H CH.dbd.CH 503 129-131 (MeCN) 165 H CH.dbd.CH 504
190-192 (MeCN) 171 H CH.dbd.CH 505 108 (EE) 174 H CH.dbd.CH 506
79-81 (PE) 185 H CH.sub.2CH.sub.2 507 125 (iPrOH) 186 H CH.dbd.CH
508 129-131 (EE) 187 H CH.sub.2CH.sub.2CH.sub.2CH.sub.2 509
viskoses Ol.sup.4 195 H CH.sub.2CH.sub.2 510 82-57 (amorph;
CHCl.sub.3/MeOH) 198 H CH.dbd.CH 511 150-152 (MeCN) 209 H
CH.sub.2CH.sub.2 512 131-132 (MeCN) 218 H CH.sub.2CH.sub.2 513
113-115 (EE) 219 H CH.dbd.CH 514 125-127 (MeCN) 230 H
CH.sub.2CH.sub.2 515 110-112 (EE) 231 H CH.dbd.CH 516 139-141 (EE)
233 H CH.dbd.CH 517 89-91 (amorph; CHCl.sub.3/MeOH) 239 H CH.dbd.CH
518 Harz.sup.4 252 H CH.dbd.CH 519 161 (EtOH/Et.sub.2O) 253 H
CH.dbd.CH--CH.dbd.CH 520 77-79 (EE/BuCl) 254 H CH.dbd.CH 521
105-106 (MeCN/MTBE) 259 H CH.dbd.CH 522 100-102 (MeCN) 260 H
CH.dbd.CH--CH.dbd.CH 523 133-135 (EE/BuCl) 263 H CH.sub.2CH.sub.2
524 Harz.sup.4 266 H CH.sub.2CH.sub.2 525 104-105 (BuCl) 269 H
CH.sub.2CH.sub.2 526 Harz.sup.4 274 H CH.sub.2CH.sub.2 527
Harz.sup.4 277 H CH.dbd.CH 528 80-82 (amorph; CHCl.sub.3/MeOH) 280
H CH.sub.2CH.sub.2 529 98-99 (BuCl) 287 H CH.sub.2CH.sub.2 530
85-87 (EtOH) 305 H CH.sub.2CH.sub.2 531 143-144 (iPrOH) 306 H
CH.dbd.CH 532 196-200 (iPrOH) 315 H CH.dbd.CH 533 132-134 (EE) 316
H CH.dbd.CH--CH.dbd.CH 534 146-148 (iPrOH) 324 H CH.sub.2CH.sub.2
535 Harz.sup.4 325 H CH.sub.2CH.sub.2CH.sub.2CH.sub.2 536
Harz.sup.4 333 H CH.sub.2CH.sub.2 537 Harz.sup.4 337 H
CH.sub.2CH.sub.2 538 103-105 (EE) 338 H CH.dbd.CH 539 85-87
(amorph; CHCl.sub.3/MeOH) 339 H CH.sub.2CH.sub.2CH.sub.2CH.sub.2
540 97-98 (EE) 345 H CH.sub.2CH.sub.2 541 159-160 (MeCN) 356 H
CH.sub.2CH.sub.2 542 134-135 (iPr.sub.2O) 357 H CH.dbd.CH 543
154-155 (EE) 367 H CH.dbd.CH 544 Ol.sup.4 368 H
CH.dbd.CH--CH.dbd.CH 545 135-136 (EE) 378 H CH.dbd.CH 546 71-74
(amorph; CHCl.sub.3/MeOH) Table annotation .sup.1MeOH = methanol EE
= ethyl acetate iPrOH = isopropanol iPr.sub.2O = diisopropyl ether
MeCN = acetonitrile BuCl = 1-chlorobutane EtOH = ethanol PE =
petroleum ether Et.sub.2O = diethyl ether MTBE = methyl tert-butyl
ether .sup.2as a dihydrochloride .sup.3as a trihydrochloride
.sup.4purified by column chromatography .sup.5as a
methanesulfonate
[0559] In the following, the production of the starting materials
necessary for illustration of the reproducibility for providing the
compounds used according to the invention is described by means of
several examples.
Example 1A
[0560]
4-{1-[bis(4-fluorophenyl)-methyl]-piperidin-4-yl)-butane-1-ol
[0561] 20 g (103 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride
are suspended in 70 ml 3,4-dihydro-2H-pyrane and added to 1.0 g
pyridinium tosylate. The mixture is stirred for two days at RT.
After addition of 5 g potassium carbonate, this is concentrated
under vacuum to dryness. The resulting
4-[4-tetrahydropyran-2-yloxy)-butyl]-piperidine is dissolved
without further purification in 100 ml acetonitrile and added to
25.18 (105 mmol) bis-(4-fluorophenyl)-chloromethane, 30 g (217
mmol) potassium carbonate and 5.0 g (30 mmol) potassium iodide and
stirred for four days at RT. The mixture is filtered and the
solvent is removed under vacuum. The resulting
1-[bis-(4-fluorophenyl)-methyl]-4-[4-(tetrahydropyran-2-ylo-
xy)-butyl]-piperidine is dissolved without further purification in
150 ml methanol, added to enough 6 M methanolic hydrochloric acid
until the pH of the mixture is acidic and left to stand for two
days at RT. Subsequently, the solvent is drawn off under vacuum and
the residue is dispersed between sodium hydroxide solution and
acetic acid ethyl ester. The aqueous solution is extracted three
times with acetic acid. The combined organic phases are dried over
sodium sulfate and the residue is chromatographically purified over
silica gel with CH.sub.2Cl.sub.2/CH.sub- .3OH(99/1 to 94/4). Yield:
23.8 g (63%).
Example 2A
[0562]
2-(4-{1-[bis(4-fluorophenyl)-methyl]-piperidin-4-yl}-butyl)-isoindo-
l-1,3-dione
[0563] 23.1 g (62.5 mmol)
4-{1-[bis(4-fluoraphenyl)-methyl]-piperidin-4-yl- }-butan-1-ol,
16.4 g (62.5 mmol) triphenylphosphine and 9.2 g (62.5 mmol)
phthalimide are suspended in THF and 10.9 g (62.5 mmol)
azodicarboxylic acid diethyl ester is added dropwise under a
protective atmosphere and light cooling (ca. 15-25.degree. C.). The
mixture is stirred for three hours at RT and subsequently the
solvent is removed under vacuum. The residue is chromatographically
purified over silica gel with CH.sub.2Cl.sub.2/CH.sub.3OH
(99.5/0.5) Yield: 27.6 g (90%).
Example 3A
[0564]
4-[1-bis(4-fluorophenyl)-methylpiperidin-4-yl]-butylamine
[0565] 27.6 g (56.3 mmol)
2-(4-{(1-[bis(4-fluorophenyl)-methyl]-piperidin--
4-yl}-butyl)-isoindol-1,3-dione are suspended in 120 ml ethanol and
added to 5.6 g (112 mmol) hydrazine hydrate and heated to boiling
for four hours. Afer cooling, the mixture is filtered and the
solvent is removed under vacuum. The residue is dispersed between
10% sodium hydroxide solution and acetic acid ethyl ester. The
aqueous phase is extracted three times with acetic acid ethyl
ester. The combined organic phases are dried over sodium sulfate.
The solvent is removed under vacuum and the residue is
chromatographically purified over silica gel with
CHCl.sub.3/CH.sub.3OH/NHOH (95/5/0 to 90/10/1). Yield: 14.6 g
(73%).
Example 4A
[0566]
4-[1-(10,11-dihydro-1H-dibenzo-[a,d]cyclohepten-5-yl)-piperidin-4-y-
l]-butane-1-ol
[0567] 26.3 g (<109 mmol)
4-[4-tetrahydropyran-2-yloxy)-butyl]-piperidi- ne (crude product)
and 23.3 g (229 mmol) TEA are dissolved in 150 ml acetonitrile and
added in portions to 25.0 g (109 mmol)
5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene under cooling.
The mixture is stirred at RT overnight Subsequently, the solvent is
removed under vacuum and the residue is dispersed betweenacetic
acid ethyl ester and water. The organic phase is dried over sodium
sulfate and the solvent is removed under vacuum. The resulting
1-(10,11-dihydro-5H-dibenzo[a,d]cy- cloheptene-5-yl)-4-[4
(tetrahydropyran-2-yloxy)-butyl]-piperidine is dissolved without
further purification in 200 ml methanol, added to enough 6 M
methanolic hydrochloric acid until the pH of the mixture is acidic
and stirred for five hours at RT. Subsequently, the solvent is
removed under vacuum and the residue is dispersed between 10%
sodium hydroxide solution and dichloromethane. The organic phase is
dried over sodium sulfate and the solvent is removed under vacuum.
The residue is processed further without additional purification.
Yield: 38.2 g.
Example 5A
[0568]
2-{4-[1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperidin-4--
yl]-butyl}-isoindol-1,3-dione
[0569] Production occurs analogously to Example 2a
[0570] Batch size: 15.0 g (<43 mmol)
4-[1-(10,11-dihydro-5H-dibenzo[a,d-
]cyclohepten-5-yl)-piperidin-4-yl]-butan-1-ol (crude product), 11.3
g (43.1 mmol) triphenylphosphine, 6.4 g (43.5 mmol) phthalimide and
7.5 g (43.0 mmol) azodicarboxylic acid diethyl ester in 200 nml
THF. For purification, this is chromatographed over silica gel
first with dichloromethane and then with petroleum ether/acetic
acid ethyl ester (10/1 to 5/1). Yield: 12.0 g (57%)
Example 6A
[0571]
4-[1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperidin-4-yl-
]-butylamine
[0572] Production occurs analogously to Example 3a.
[0573] Batch size: 11.5 g (24.0 mmol)
2-(4-[1-(10,11-dihydro-5H-dibenzo[a,-
d]cyclohepten-5-yl)-piperidin-4-yl]-butyl}-isoindol-1,3-dione and
2.4 g (48.0 mmol) hydrazine hydrate in 100 ml ethanol.
[0574] For work up, the reaction solution is filtered and the
filter cake is dispersed between 300 ml acetic acid ethyl ester and
100 ml 10% sodium hydroxide solution. The organic phase is dried
over sodium sulfate and the solvent is removed under vacuum. The
residue is chromatographically purified over silica gel with
CHCl.sub.3/CH.sub.3OH/TEA (95/510 to 94/5/1). Yield: 5.6 g
(67%)
Example 7A
[0575] (1-diphenylmethylpiperidineyliden)acetonitrile
[0576] 2.9 g (97 mmol) 80% sodium hydride are suspended in abs. THF
and a solution of 21.5 g (121 mmol)
diethyl-(cyanomethyl)-phosphonate in 150 ml abs. THF is added
dropwise under light cooling. The mixture is subsequently stirred
30 minutes at RT and then a solution of 26.5 g (100 mmol)
N-(diphenylmethyl)-4-piperidone in 80 ml abs. THF is added
dropwise. The suspension is left to stand overnight and
subsequently added to 200 ml acetic acid ethyl ester and 100 ml
water. The organic phase is separated and washed with 100 ml water,
dried over sodium sulfate and the solvent is removed under vacuum.
The residue is chromatographically purified over silica gel with
dichloromethane. Yield: 22.7 g (78%).
Example 8A
[0577] (1-diphenylmethylpiperidine-4-yl)-acetonitrile
[0578] 9.8 g (33.5 mmol)
(1-diphenylmethylpiperidine-4-ylidine)-acetonitri- le are dissolved
in a mixture of 60 ml dioxane and 70 ml ethanol and added dropwise
to 1.5 g palladium (5%) on activated carbon. The mixture is stirred
at RT under hydrogen atomosphere until consumption of the
theoretical amount of hydrogen to be taken up (ca. 14 hours). The
mixture is filtered from the catalyst and the solvent is removed
under vacuum The residue is chromatographically purified over
silica gel with CHCl.sub.3/CH.sub.3OH (96/4). Yield of yellow oil:
8.4 g (85%).
Example 9A
[0579] 2-(1-diphenylmethylpiperidin 4-yl)ethylamine
[0580] 2.2 g (58.2 mmol) sodium borohydroxide are suspended in 50
ml abs. THF and cooled to ca. 0.degree. C. under moisture
exclusion. 6.7 g (23.1 mmol)
(1-diphenylmethylpiperidin-4-yl)acetonitrile are added and the
mixture is subsequently cooled to -5.degree. C. to -10.degree. C.
and added dropwise to 1.5 ml (26.7 mmol) 95% sulfuric acid
(vigorous foaming). The suspension is left to stand for two days at
RT without further cooling. Under renewed cooling to ca. 0.degree.
C., 40 ml 2 M sodium hydroxide solution is added dropwise. The
aqueous phase is extracted with 30 ml THF and thereafter the
combined organic phases are washed twice, each with 30 ml saturated
NaCl solution, dried over sodium sulfate and the solution is
removed under vacuum. The residue is chromatographically purified
over silica gel with CHCl.sub.3/CH.sub.3OH/N- H.sub.4OH (90/10/1).
Yield: 3.9 g (57%).
Example 10A
[0581]
4-{1-[bis(2-chlorophenyl)-methyl]-piperidin-4-yl}-butyronitrile
[0582] 20 g (106 mmol) 4-(3-cyanoprop-1-yl)-piperidin
hydrochloride, 40.2 g (127 mmol) bis(2-chlorophenyl)-bromomethane
and 35.2 g (254 mmol) potassium carbonate are heated to boiling in
90 ml acetone for six hours. After cooling, the mixture is freed
from solution under vacuum. The residue is dispersed between 90 ml
toluene and 90 ml water. The aqueous phase is extracted with 10 ml
tolueneand the combined organic phases are washed with 10 ml water.
The organic phase is concentrated and the residue is
chromatographically purified over silica gel with CHCL3. Yield:
11.2 g (27%)
Example 11A
[0583]
4-{1-[bis(2-chlorophenyl)methyl]-piperidin-4-yl}-butylamine
[0584] 80 g (20.6 mmol)
4-{1-[bis(2-chlorophenyl)-methyl)-piperidin-4-yl}-- butyronitrile
are dissolved in 240 ml dioxane/ethanol (1/5) and added to 1.5 g
Raney-nickel, The mixture is stirred at RT under hydrogen
atmosphere until uptake of the theoretical amount of hydrogen. The
reaction solution is filtered from the catalyst and the solvent is
removed under vacuum. The residue is dispersed between 100 ml 10%
sodium hydroxide solution and 300 ml acetic acid ethyl ester. The
organic phase is dried with sodium sulfate and the solvent is
removed under vacuum. The resin is processed further without
additional purification.
Example 12A
[0585] 3(1-diphenylmethylpiperidin-4-yl)-propan-1-ol
[0586] 20 g (111 mmol) 3-piperidin-4-yl-propan-1-ol hydrochloride
are suspended in 70 ml 3,4-dihydro-2H-pyrane and added to 0.5 g
pyridinium tosylate. The mixture is stirred for two days at RT.
After addition of 1 g potassium carbonate, this is concentrated
under vacuum to dryness. The resulting
4-[3-tetrahydropyran-2-yloxy)-propyl]-piperidine is dissolved in 90
ml acetonitrile without further purification and added to 35 g (135
mmol) diphenyl bromomethane (95%) and 29 g (210 mmol) potassium
carbonate and stirred for four days at RT. The mixture is filtered
and the solvent is removed under vacuum. The resulting
1-diphenylmethyl-4-[3-tetrahydropy- ran-2-yloxy)-propyl]-piperidine
is dissolved without further purification in 130 ml methanol and
added to 25 ml conc. hydrochloric acid, and the mixture is stirred
at RT overnight. Subsequently, the solvent is removed under vacuum
and the residue is taken up with 300 ml water and extracted with
300 ml acetic acid ethyl ester. The organic phase is discarded and
the aqueous phase is made alkaline with 17 g sodium hydroxide and
extracted with 300 g acetic acid ethyl ester. After washing the
organic phase with 40 ml water, this is dried over sodium sulfate
and the solvent is removed under vacuum. The oil is dried under
high-vacuum and processed further without purification Yield: 22.4
g (65%).
Example 13A
[0587]
2-[3-(1-diphenylmethylpiperidine-4-yl)-propyl]-isoindol-1,3-dione
[0588] 20.3 g (65.6 mmol)
3-(1-diphenylmethylpiperidin-4-yl)-propan-1-ol, 17.2 g (65.6 mmol)
triphenylphosphine and 9.7 g (65.6 mmol) phthalimide are suspended
in 220 nml THF and a solution of 10.4 ml (65.6 mmol) azodicarbonic
acid diethyl ester in SO ml THF is added dropwise within one hour
under protective atmosphere and light cooling (ca. 15-25.degree.
C.). After a further three hours, the solvent is removed under
vacuum and the residue is crystallized from 60 ml 1-chlorobutane.
Yield: 12.9 g (45%).
Example 14A
[0589] 3-(1-diphenylmethylpiperidin-4-yl)-propanylamine
[0590] 12.8 g (29.2 mmol)
2-[3-(1-diphenylmethylpiperidine-4-yl)-propyl]-i- soindol-],3-dione
are suspended in 110 ml ethanol and added to 2.2 ml (58.4 mmol)
hydrazine hydrate and heated to boiling for three hours. After
cooling, the mixture is concentrated under vacuum. The residue is
dispersed between 300 ml dichloromethane and 50 ml 10% sodium
hydroxide solution. The aqueous phase is extracted twice, each with
200 ml dichloromethane. The combined organic phases are washed
twice, each with 20 ml water, and dried over sodium sulfate. The
solvent is removed under vacuum and the residue is processed
fruther without additional purification. Yield 7.3 g (81%)
Example 15A
[0591] 4-(1-diphenylmethylpiperidin-4-yl)-butan-1-ol
[0592] 120 g (620 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride
are suspended in 400 ml 3,4-dihydro-2H-pyran and added to 1.5 g
pyridinium tosylate and 5 ml 8 M methanolic hydrochloric acid. This
is stirred for three hours and left to stand at RT overnight. After
addition of 5 g potassium carbonate, this is concentrated under
vacuum to dryness. The resulting
4-[4-tetrahydropyran-2-yloxy)-butyl]-piperidine is dissolved in 500
ml acetonitrile without further purification and added to 193 g
(742 mmol) diphenylmethylbromide (95%) and 160 g (1157 mmol)
potassium carbonate and stirred for three days at RT. The mixture
is filtered and the filtrate is stirred for one day at RT with a
further 20 g (76.8 mmol) diphenylmethylbromide (95%) and 16 g
(115.8 mmol) potassium carbonate. The mixture is filtered and the
solvent is removed under vacuum. The resulting
1-diphenylmethyl-4-[-(tetrahydropyran-2-yloxy)-butly]-piperidin- e
is dissolved in 700 ml methanol without further purification, added
to 120 ml conc. hydrochloric acid, and the mixture is left to stand
for two days at RT. Subsequently, the solvent is removed under
vacuum and the residue is taken up with 1500 ml water and extracted
with 1500 ml acetic acid ethyl ester. The organic phase is
discarded and the aqueous phase is adjusted to alkaline with sodium
hydroxide and extracted with 700 ml acetic acid ethyl ester. After
washing the organic phase with 200 ml water, this is dried over
sodium sulfate and the solvent is removed under vacuum. The brown
oil is dried under high-vacuum and processed further without
purification. Yield: 145 g (72%).
Example 16A
[0593]
2-[4-(1-diphenylmethylpiperidin-4-yl)butyl]-isoindol-1,3-dione
[0594] 135.0 g (417 mmol)
4-(1-diphenylmethylpiperidin-4-yl)butan-1-ol, 109.5 g (417 mmol)
triphenylphosphine and 61.3 g (417 mmol) phthalimide are suspended
in THF and 72.6 g (417 mmol) azodicarboxylic acid diethyl ester are
added dropwise within 21/2 hours under protective atmosphere and
light cooling (ca. 15-25.degree. C.). After a further hour, the
solvent is removed under vacuum and the residue is crystallized
three times from acetic acid ester (1000 ml, 1200 ml and 1100 ml).
Colorless crystals with a MP of 150-152 were recovered. Yield: 103
g (54.5%).
Example 17A
[0595] 4-(1-diphenylmethylpiperidin-4-yl)-butylamine
[0596] 88.9 g (196 mmol)
2-[4-(1-diphenylmethylpiperidin-4-yl)butyl]-isoin- dol-1,3-dione
are suspended in 1000 ml ethanol and added to 22.0 g (440 mmol)
hydrazine hydrate and heated to boiling for four hours. After
cooling, the mixture is filtered and the solvent is removed under
vacuum. The solid residue is distributed together with the filter
residue under heat between 300 ml 10% sodium hydroxide solution and
300 ml acetic acid ethyl ester. The aqueous phase is extracted once
again with 150 ml warm acetic acid ethyl ester. The combined
organic phases are extracted twice, each with 300 ml 10%
hydrochloric acid. The combined aqueous phases are adjusted to
alkaline with 10% sodium hydroxide solution and extracted twice,
each with 400 ml acetic acid ethyl ester. The combined organic
phases are washed with 100 ml water and dried over sodium sulfate.
The solvent is removed under vacuum, the residue is dried under
high-vacuum and further processed without additional purification.
Yield of gradually solidifying resin: 63 g (99%)
Example 18A
[0597] 5-(1-diphenylmethylpiperidin-4-yl)-pentanitrile
[0598] 24.9 g (69.2 mmol)
4-(1-diphenylmethylpiperidin-4-yl)butan-1-ol hydrochloride are
suspended in 160 ml abs. dichloromethane and cooled to ca.
0.degree. C. under moisture exclusion. At this temperature, 16.0 g
(159 mmol) TEA is first added, and thereafter, a solution of 10.3 g
(90.0 mmol) methanesulfonic acid chloride in a little abs.
dichloromethane is added dropwise. The mixture is subsequently
stirred for three hours at RT and then placed in ice water. The
organic phase is washed once with 50 ml water, dried over sodium
sulfate and the solvent is removed under vacuum. The resulting
methanesulfonic acid-4-(1-diphenylmethylpiperidin-4-yl)-but- yl
ester is dissolved in 120 ml DMF without further purification and
added to 7.7 g (158 mmol) sodium cyanide and two drops 15-crown-5
and stirred six hours at 65.degree. C. After cooling, the mixture
is poured in ice water. The precipitated solid is drawn off and
dried under high-vacuum at 40.degree. C. The solid is processed
further without additional purification. Yield: 19.9 g (86%).
Example 19A
[0599] 5(1-diphenylmethylpiperidin-4-yl)pentylamine
[0600] 19.0 g (57.1 mmol)
5(1-diphenylmethylpiperidin-4-yl)pentanitrile are dissolved in 240
ml dioxane/ethanol (1/1) and added to 3.2 g Raney-Nickel. The
mixture is stirred at RT under hydrogen atmosphere until uptake of
the theoretical amount of hydrogen. The mixture is filtered from
the catalyst and the solvent is removed under vacuum. The residue
is dispersed between 100 ml water and 250 ml acetic acid ethyl
ester. The organic phase is dried with sodium sulfate and the
solvent is removed under vacuum. The resin is processed further
without additional purification Yield: 17.0 g (88%).
Example 20A
[0601] 4-(1-tert-butoxycarbonylpiperidin-4-yl)-butan-1-ol
[0602] 100 g (458 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride
are dissolved in 120 ml water, added to 216 ml (1550 mmol) TEA and
cooled to ca. 5-10.degree. C. 122 g (559 mmol) di-tert-butyl
dicarbonate dissolved in 400 ml THF are added dropwise within four
hours under further cooling. The mixture is left to stand at RT
overnight without further cooling. Subsequently, the THY is largely
removed under vacuum and the residue is extracted twice with 300 ml
and 200 ml CHCl.sub.3 and the combined organic phases are washed
twice, each with 20 ml water. The solvent is removed under vacuum,
the residue dried under high-vacuum and processed further without
additional purification. Yield: 136 g.
Example 21A
[0603]
2-[4-(1-tert-butoxycarbonylpiperidin-4-yl)-butyl]-isoindol-1,3-dion-
e
[0604] 136.0 g (<528 mmol)
4-(1-tert-butoxycarbonylpiperidin-4-ylfibuta- n-1-ol (crude
product), 135.3 g (516 mmol) triphenylphosphine and 75.9 g (516
mmol) phthalimide are suspended in THF and 89.9 g (516 mmol)
azodicarboxylic acid diethyl ester are added dropwise within 3
hours under protective atmosphere and light cooling (ca. 15.degree.
C.). The mixture is left to stand at RT overnight without further
cooling. Subsequently, the solvent is removed under vacuum and the
oily residue is dissolved in 500 ml acetic acid ethyl ester and
held overnight at 0.degree. C. The sedimented precipitate is
filtered and discarded. The solution is concentrated under vacuum
and the oily residue is chromatographically purified over silica
gel with CHCl.sub.3 and crystallized from 200 ml isopropanol after
drawing off the solvent. Colorless crystals with a MP of
100-102.degree. C. were recovered; yield: 108.5 g (57%).
Example 22A
[0605] 4-(1-tert-butoxycarbonylpiperidin-4-yl)-butylamine
[0606] 113.0 g (292 mmol)
2-[4-(1-tert-butoxycarbonylpiperidin-4-yl)-butyl-
]-isoindol-1,3-dione are dissolved in 600 ml ethanol and added to
29.3 g (585 mmol) hydrazine hydrate are added thereto and heated to
boiling for three hours. After cooling the solution, the mixture is
filtered and the filtrate is concentrated under vacuum. The residue
is distributed under heat between 500 ml toluene and 500 ml 10%
sodium hydroxide solution. The organic phase is washed once with 50
ml 10% sodium hydroxide solution and twice, each with 50 ml water.
The solvent is removed under vacuum, the residue is dried under
high-vacuum at 70.degree. C. and further processed without
additional purification. Yield of colorless oil: 64.0 g (85%),
Example 23A
[0607] (1-diphenylmethylazetidin-3-ylmethyl)-amine
[0608] A solution of 10 g (40 mmol)
1-diphenylmethylazetidin-3-carbonitril- e in 20 ml abs. THF are
added dropwise at RT to a suspension of 3.1 g (80 mmol) lithium
aluminum hydride in 80 ml abs. THF and stirred overnight. 2 ml
ethanol are carefully added to the batch and the batch is filtered.
The filtrate is concentrated under vacuum and dispersed between
CHCl.sub.3 and water. The aqueous phase is extracted twice, each
with 50 ml CHCl.sub.3, and the combined organic phases are dried
over sodium sulfate and the solvent is removed under vacuum. The
residue is chromatographically purified over silica gel with
CHCl.sub.3/CH.sub.3OH/N- FLOH (90/10/0 to 90/10/1). Yield: 5.6 g
(57%) of slowly solidifying resin.
Example 24A
[0609] 3-(1-benzylpiperidin-4-yloxy)-propylamine
[0610] 1.0 g (40.9 mmol) 3-(1-benylpiperidin-4-yloxy)-propionitrile
are dissolved in 100 ml ethanol and added to a spatula tip of
Raney-Nickel. The mixture is stirred at RT under hydrogen
atmosphere until the uptake of the theoretical amount of hydrogen
(ca. 2 days). The mixture is filtered from the catalyst and the
solvent is removed under vacuum. The residue is distilled in a
ball-pipe apparatus. Yield of colorless oil: 7.5 g (73%)
Example 25A
[0611] 4-(1-benzylpiperidin-3-ylidene)-butyronitrile
[0612] 77.3 g (188.3 mmol) 3-cyanopropyl triphenylphosphonium
bromide are suspended in 300 ml tolueneand added to 22.0 g (191.9
mmol) potassium-tert-butylate. The mixture is cooled to ca.
0.degree. C. under moisture exclusion and a solution of 34.6 g
(182.8 mmol) 1-benzyl-3-piperidone in 50 ml tolueneare added
dropwise under cooling. The batch is left to stand overnight at ca.
0.degree. C., subsequently diluted with 200 ml tolueneand washed
twice, each with 100 ml water. The organic phase is extracted with
150 ml half-concentrated hydrochloric acid. Subsequently, the
aqueous phase is made basic with 200 ml 10% sodium hydroxide
solution and extracted twice, each with 250 ml toluol. The solvent
is removed under vacuum and the residue is chromatographically
purified over silica gel with CHCl.sub.3/CH.sub.3OH (97/3). After
drawing off the solvent, a light brown oil remains which is further
processed without additional purification. Yield: 47.4 g (90%).
Example 26A
[0613] 4-(1-benzylpiperidin-3-yl)butylamine
[0614] 8.0 g (33.3 mmol)
4-(1-benzylpiperidin-3-ylidene)-butyronitrile are dissolved in 80
ml ethanol and added to a spatula tip of Raney-Nickel. The mixture
is stirred under hydrogen atmosphere until consumption of the
theoretical amount of hydrogen to be taken up (ca. 5 days). The
mixture is filtered from the catalyst and the solvent is removed
under vacuum. The residue is chromatographically purified twice
over silica gel with CHCl.sub.3/CH.sub.3OH/NH.sub.4OH (90/10/1).
After drawing off the solvent, a colorless oil remains which is
further processed without additional purification. Yield: 3.9 g
(47%).
[0615] The active ingredients used according to the invention can
be processed to the desired medicaments in the form of their acid
addition salts, hydrates or solvates individually or in combination
with each other or with others, optionally under addition of other
active ingredients, for the indications tumor treatment or
immunosuppression. In the case of the combination of active
ingredients according to the invention with other medicinal forms,
these can also optionally be separately present next to each other
in the medicine packaging, for example as tablets next to viles,
depending on the requirements.
[0616] Therefore, further subject-matter of the invention is a
medicament with an amount of compounds according to the above
defined general formula (I) in combination with the further
cytostatic agent, cancerostatic agent, immunosuppressing agent
and/or immunomodulatory agent. Therewith, a method for the
production of medicaments with an amount of one or more compounds
according to formula (I), optionally together with another
cytostatic agent or immunosuppressive agent and optionally next to
further active ingredients and additives customary and suitable for
these indications together with respective pharmaceutically
acceptable carriers and adjuvents for providing the finished
medical form also falls within the scope of protection according to
the invention.
[0617] The invention is more closely illustrated in the following
by means of the production of respective medicaments suitable for
the use according to the invention and the combinations according
to the invention as well-as by means of a series of examples for
various medical forms suitable for the respective indications.
Therapeutic Administration Forms
[0618] The production of medicaments with an amount of one or more
compounds according to the invention and/or their use in the
application according to the invention occurs in the customary
manner by means of common pharmaceutical technology methods. For
this, the active ingredients as such or in the form of their salts
are processed together with suitable, pharmaceutically acceptable
adjuvents and carriers to medicinal forms suitable for the various
indications and types of application. Thereby, the medicaments can
be produced in such a manner that the respective desired release
rate is obtained, for example a quick flooding and/or a sustained
or depot effect.
[0619] Preparations for parenteral use, to which injections and
infusions belong, are among the most important systemically
employed medicaments for tumor treatment as well as for other
indications.
[0620] Preferably, injections are administered for the treatment of
tumors. These are prepared either in the form of vials or also as
so-called ready-to-use injection preparations, for example as
ready-to-use syringes or single use syringes in addition to
perforation bottles for multiple withdrawals. Administration of the
injection preparations can occur in the form of subcutaneous
(s.c.), intramuscular (i.m.), intravenous (i.v.) or intracutaneous
(i.c.) application. The respective suitable injection forms can
especially be produced as solutions, crystal suspensions,
nanoparticular or colloid-disperse systems, such as for example,
hydrosols.
[0621] The injectable formulations can also be produced as
concentrates which can be adjusted with aqueous isotonic dilution
agents to the desired active ingredient dosage. Furthermore, they
can also be produced as powders, such as for example lyophilisates,
which are then preferably dissolved or dispersed immediately before
application with suitable diluents. The infusions can also be
formulated in the form of isotonic solutions, fat emulsions,
liposome formulations, microemulsions and liquids based on mixed
micells, for example, based on phospholipids. As with injection
preparations, infusion formulations can also be prepared in the
form of concentrates to dilute. The injectable formulations can
also be applied in the form of continuous infusions as in
stationary as well as in out-patient therapy, for example in the
form of mini-pumps.
[0622] Albumin, plasma expanders, surface active compounds, organic
solvents, pH influencing compounds, complex forming compounds or
polymeric compounds can be added to the parenteral medicinal forms,
especially as substances for influencing the adsorption of the
active ingredients to protein or polymers or also with the aim of
decreasing the adsorption of the active ingredient to materials
such as injection instruments or packaging materials, for example
plastic or glass.
[0623] The active ingredients can be bound to nanoparticles in the
preparations for parenteral use, for example on finely dispersed
particles based on poly(meth)acrylates, polyacetates,
polyglycolates, polyamino acids or polyether urethanes. The
parenteral formulations can also be constructively modified as
depot preparations, for example on the multiple unit principle,
where the active ingredients are incorporated in a most finely
distributed and/or dispersed, suspended form or as crystal
suspensions, or on the single unit principle, where the active
ingredient is enclosed in a medicinal form, for example, a tablet
or a seed which is subsequently implanted. Often, these
implantations or depot medicaments in single unit and multiple unit
medicinal forms consist of so-called biodegradable polymers, such
as for example, polyether urethanes of lactic and glycolic acid,
polyether urethanes, polyamino acids, poly(meth)acrylates or
polysaccharides.
[0624] Sterilized water, pH value influencing substances, such as
for example organic and inorganic acids or bases as well as their
salts, buffer substances for setting the pH value, agents for
isotonicity, such as for example sodium chloride, monosodium
carbonate, glucose and fructose, tensides and/or surface active
substances and emulsifiers, such as for example, partial fatty acid
esters of polyoxyethylene sorbitan (Tween.RTM.) or for example
fatty acid esters of polyoxethylene (Cremophor.RTM.), fatty oils
such as for example peanut oil, soybean oil and castor oil,
synthetic fatty acid esters, such as for example ethyl oleate,
isopropyl myristate and neutral oil (Miglyolq.RTM.) as well as
polymer adjuvents such as for example gelatin, dextran,
polyvinylpyrrolidone, organic solvent additives which increase
solubility, such as for example propylene glycol, ethanol,
N,N-dimethylacetamide, propylene glycol or complex forming
compounds such as for example citrates and urea, preservatives,
such as for example hydroxypropyl benzoate and hydroxymethyl
benzoate, benzyl alcohol, anti-oxidants, such as for example sodium
sulfite and stabilizers, such as for example EDTA, are suitable as
adjuvents and carriers in the production of preparations for
parenteral use.
[0625] In suspensions, addition of thickening agents to prevent the
settling of the active ingredients from tensides and peptizers, to
secure the ability of the sediment to be shaken, or complex
formers, such as EDTA, ensues. This can also be achieved with the
various polymeric agent complexes, for example with polyethylene
glycols, polystyrol, carboxymethylcellulose, Pluronics.RTM. or
polyethylene glycol sorbitan fatty acid esters. The active
ingredient can also be incorporated in liquid formulations in the
form of inclusion compounds, for example with cyclodextrins. As
further adjuvents, dispersion agents are also suitable. For
production of lyophilisates, builders are also used, such as for
example mannite, dextran, saccharose, human albumin, lactose, PVP
or gelatin varieties.
[0626] As long as the active ingredients are not incorporated in
the liquid medicinal formulations in the form of a base, they are
used in the form of their acid addition salts, hydrates or solvates
in the preparations for parenteral use.
[0627] A further systemic application form of importance is peroral
administration as tablets, hard or soft gelatin capsules, coated
tablets, powders, pellets, microcapsules, oblong compressives,
granules, chewable tablets, lozenges, gums or sachets. These solid
peroral administration forms can also be prepared as sustained
action and/or depot systems. Among these are medicaments with an
amount of one or more micronized active ingredients, diffusions and
erosion forms based on matrices, for example by using fats,
wax-like and/or polymeric compounds, or so-called reservoir
systems. As a retarding agent and/or agent for controlled release,
film or matrix forming substances, such as for example
ethylcellulose, hydroxypropylmethylcellulose, poly(meth)acrylate
derivatives (for example Eudragit.RTM.),
hydroxypropylmethylcellulose phthalate are suitable in organic
solutions as well as in the form of aqueous dispersions. In this
connection, so-called bio-adhesive preparations are also to be
named in which the increased retention time in the body is achieved
by intensive contact with the mucus membranes of the body. An
example of a bio-adhesive polymer is the group of
Carbomers.RTM..
[0628] For sublingual application, compressives, such as for
example non-disintegrating tablets in oblong form of a suitable
size with a slow release of active ingredient, are especially
suitable. For purposes of a targeted release of active ingredients
in the various sections of the gastrointestinal tract, mixtures of
pellets which release at the various places are employable, for
example mixtures of gastric fluid soluble and small intestine
soluble and/or gastric fluid resistant and large intestine soluble
pellets. The same goal of releasing at various sections of the
gastrointestinal tract can also be conceived by suitably produced
laminated tablets with a core, whereby the coating of the agent is
quickly released in gastric fluid and the core of the agent is
slowly released in the small intestine milieu. The goal of
controlled release at various sections of the gastrointestinal
tract can also be attained by multilayer tablets. The pellet
mixtures with differentially released agent can be filled into hard
gelatin capsules.
[0629] Anti-stick and lubricant and separating agents, dispersion
agents such as flame dispersed silicone dioxide, disintegrants,
such as various starch types, PVC, cellulose esters as granulating
or retarding agents, such as for example wax-like and/or polymeric
compounds on the basis of Eudragit.RTM., cellulose or
Cremophor.RTM. are used as a further adjuvents for the production
of compressives, such as for example tablets or hard and soft
gelatin capsules as well as coated tablets and granulates.
[0630] Anti-oxidants, sweetening agents, such as for example
saccharose, xylite or mannite, masking flavors, aromatics,
preservatives, colorants, buffer substances, direct tableting
agents, such as for example microcrystalline cellulose, starch and
starch hydrolysates (for example Celutab.RTM.), lactose,
polyethylene glycols, polyvinylpyrrolidone and dicalcium phosphate,
lubricants, fillers, such as lactose or starch, binding agents in
the form of lactose, starch varieties, such as for example wheat or
corn and/or rice starch, cellulose derivatives, for example
methylcellulose, hydroxypropylcellulose or silica, talcum powder,
stearates, such as for example magnesium stearate, aluminum
stearate, calcium stearate, talc, siliconized talc, stearic acid,
acetyl alcohol and hydrated fats are used.
[0631] In this connection, oral therapeutic systems constructed
especially on osmotic principles, such as for example GIT
(gastrointestinal therapeutic system) or OROS (oral osmotic
system), are also to be mentioned.
[0632] Effervescent tablets or tabs, both of which represent
immediately drinkable instant medicinal forms which are quickly
dissolved or suspended in water are among the perorally
administratable compressives. Among the perorally administratable
forms are also solutions, for example drops, juices and
suspensions, which can be produced according to the above given
method, and can still contain preservatives for increasing
stability and optionally aromatics for reasons of easier intake,
and colorants for better differentiation as well as antioxidants
and/or vitamins and sweeteners such as sugar or artificial
sweetening agents. This is also true for inspisated juices which
are formulated with water before ingestion. Ion exchange resins in
combination with one or more active ingredients are also to be
mentioned for the production of liquid ingestable forms.
[0633] A special release form consists in the preparation of
so-called floating medicinal forms, for example based on tablets or
pellets which develop gas after contact with body fluids and
therefore float on the surface of the gastric fluid. Furthermore,
so-called electronically controlled release systems can also be
formulated by which active ingredient release can be selectively
adjusted to individual needs.
[0634] A further group of systemic administration and also
optionally topically effective medicinal forms are represented by
rectally applicable medicaments. Among these are suppositories and
enema formulations. The enema formulations can be prepared based on
tablets with aqueous solvents for producing this administration
form. Rectal capsules can also be made available based on gelatin
or other carriers.
[0635] Hardened fat, such as for example Witepsol.RTM., Massa
Estarinum.RTM., Novata.RTM., coconut fat, glycerol-gelatin masses,
glycerol-soap-gels and polyethylene glycols are suitable as
suppository bases.
[0636] For long-term application with a systematic active
ingredient release up to several weeks, pressed implants are
suitable which are preferably formulated on the basis of so-called
biodegradable polymers.
[0637] As a further important group of systemically active
medicaments, transdermal systems are also to be emphasized which
distinguish themselves, as with the above-mentioned rectal forms,
by circumventing the liver circulation system and/or liver
metabolism. These plasters can be especially prepared as
transdermal systems which are capable of releasing the active
ingredient in a controlled manner over longer or shorter time
periods based on different layers and/or mixtures of suitable
adjuvents and carriers. Aside from suitable adjuvents and carriers
such as solvents and polymeric components, for example based on
Eudragit.RTM., membrane infiltration increasing substances and/or
permeation promoters, such as for example oleic acid, Azone.RTM.,
adipinic acid derivatives, ethanol, urea, propylglycol are suitable
in the production of transdermal systems of this type for the
purpose of improved and/or accelerated penetration.
[0638] As topically, locally or regionally administration
medicaments, the following are suitable as special formulations:
vaginally or genitally applicable emulsions, creams, foam tablets,
depot implants, ovular or transurethral adminstration installation
solutions. For opthalmological application, highly sterile eye
ointments, solutions and/or drops or creams and emulsions are
suitable.
[0639] In the same manner, corresponding otological drops,
ointments or creams can be designated for application to the ear.
For both of the above-mentioned applications, the adminstration of
semi-solid formulations, such as for example gels based on
Carbopols.RTM. or other polymer compounds such as for example
polyvinylpyrolidone and cellulose derivatives is also possible.
[0640] For customary application to the skin or also to the mucus
membrane, normal emulsions, gels, ointments, creams or mixed phase
and/or amphiphilic emulsion systems (oil/water-water/oil mixed
phase) as well as liposomes and transfersomes can be named. Sodium
algenate as a gel builder for production of a suitable foundation
or celluolose derivatives, such as for example guar or xanthene
gum, inorganic gel builders, such as for example aluminum
hydroxides or bentonites (so-called thixotropic gel builder),
polyacrylic acid derivatives, such as for example Carbopol.RTM.,
polyvinylpyrolidone, microcrystalline cellulose or
carboxymethylcellulose are suitable as adjuvents and/or carriers.
Furthermore, amphiphilic low and high molecular weight compounds as
well as phospholipids are suitable. The gels can be present either
as hydrogels based on water or as hydrophobic organogels, for
example based on mixtures of low and high molecular paraffin
hydrocarbons and vaseline.
[0641] Anionic, cationic or neutral tensides can be employed as
emulsifiers, for example alkalized soaps, methyl soaps, amine
soaps, sulfanated compounds, cationic soaps, high fatty alcohols,
partial fatty acid esters of sorbitan and polyoxyethylene sorbitan,
for example lanette types, wool wax, lanolin, or other synthetic
products for the production of oil/water and/or water/oil
emulsions.
[0642] Hydrophilic organogels can be formulated, for example, on
the basis of high molecular polyethylene glycols. These gel-like
forms are washable. Vaseline, natural or synthetic waxes, fatty
acids, fatty alcohols, fatty acid esters, for example as mono-,
di-, or triglycerides, paraffin oil or vegetable oils, hardened
castor oil or coconut oil, pig fat, synthetic fats, for example
based on acrylic, caprinic, lauric and stearic acid, such as for
example Softisan.RTM. or triglyceride mixtures such as Miglyol.RTM.
are employed as lipids in the form of fat and/or oil and/or
wax-like components for the production of ointments, creams or
emulsions.
[0643] Osmotically effective acids and bases, such as for example
hydrochloric acid, citric acid, sodium hydroxide solution,
potassium hydroxide solution, monosodium carbonate, further buffer
systems, such as for example citrate, phosphate, Tris-buffer or
triethanol amine are used for adjusting the pH value.
[0644] Preservatives, for example such as methyl- or propyl
benzoate (parabenes) or sorbic acid can be added for increasing
stability.
[0645] Pastes, powders or solutions are to be mentioned as further
topically applicable forms. Pastes often contain lipophilic and
hydrophilic auxiliary agents with very high amounts of fatty matter
as a consistency-giving base.
[0646] Powders or topically applicable powders can contain for
example starch varieties such as wheat or rice starch, flame
dispersed silicon dioxide or silica, which also serve as diluents,
for increasing flowability as well as lubricity as well as for
preventing agglomerates.
[0647] Nose drops or nose sprays serve as nasal application forms.
In this connection, nebulizers or nose creams or ointments can come
to use.
[0648] Furthermore, nose spray or dry powder formulations as well
as controlled dosage aerosols are also suitable for systemic
administeration of the active ingredients.
[0649] These pressure and/or controlled dosage aerosols and dry
powder formulations can be inhaled and/or insufflated.
Administration forms of this type also certainly have importance
for direct, regional application in the lung or bronchi and larynx.
Thereby, the dry powder compositions can be formulated for example
as active ingredient-soft pellets, as an active ingredient-pellet
mixture with suitable carriers, such as for example lactose and/or
glucose. For inhalation or insufflation, common applicators are
suitable which are suitable for the treatment of the nose, mouth
and/or pharynx. The active ingredients can also be applied by means
of an ultrasonic nebulizing device. As a propellant gas for aerosol
spray formulations and/or controlled dosage aerosols,
tetrafluoroethane or HFC 134a and/or heptafluoropropane or HFC 227
are suitable, wherein non-fluorinated hydrocarbons or other
propellants which are gaseous at normal pressure and room
temperature, such as for example propane, butane or dimethyl ether
can be preferred. Instead of controlled dosage aerosols,
propellant-free, manual pump systems can also be used.
[0650] The propellant gas aerosols can also suitably contain
surface active adjuvents, such as for example isopropyl myristate,
polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate,
lecithins or soya lecithin.
[0651] For regional application in situ, solutions for
installation, for example for transurethral administration in
bladder tumors or genital tumors, or for profusion in liver tumors
or other organ carcinomas are suitable.
[0652] The respective suitable medicinal forms can be produced in
accordance with the prescription and procedures based on
pharmaceutical-physical fundamentals as they are described for
example in the following handbooks and are included in the present
inventive subject-matter with respect to the production of the
respective suitable medicaments:
[0653] Physical Pharmacy (A. N. Martin, J. Swarbrick, A.
Cammarata), 2nd Ed., Philadelphia Pa., (1970), German version:
Physikalische Pharmazie, (1987), 3rd edition; Stuttgart;
[0654] R. Voigt, M. Bomschein, Lehrbuch der pharmazeutischen
Technologie, Verlag Chemie, Weinheim, (1984), 5th edition;
[0655] P. H. List, Arzneimformenlehre, Wissenschaftliche
Verlagsgesellschaft mbH, Stuttgart (1985), 4th edition;
[0656] H. Sucker, P. Fuchs, P. Speiser, Pharmazeutische
Technologie, Georg Thieme Verlag, Stuttgart--New York, (1991), 2nd
edition;
[0657] A. T. Florence, D. Attwood, Physicochemical Principles of
Pharmacy, The Maximillan Press Ltd., Hong Kong, (1981);
[0658] L. A. Trissel, Handbook on Injectable Drugs, American
Society of Hospital Pharmacists, (1994), 8th edition;
[0659] Y. W. Chien, Transdermal Controlled Systemic Medications,
Marcel Dekker Inc., New York--Basel, (1987);
[0660] K. E. Avis, L. Lachmann, H. A Liebermann, Pharmaceutical
Dosage Forms: Parenteral Medications, volume 2, Marcel Dekker Inc.,
New York--Basel, (1986);
[0661] B. W. Muiller, Controlled Drug Delivery, Paperback APV,
volume 17, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart,
(1987);
[0662] H. Asch, D. Essig, P. C. Schmidt, Technologie von Salben,
Suspensionen und Emulsionen, Wissenschaftliche Verlagsgesellschaft
mbH, Stuttgart, (1984);
[0663] H. A. Liebermann, L. Lachman, J. B. Schwartz, Pharmaceutical
Dosage forms: Tablets, Volume 1, Marcel Dekker Inc., New York, 2nd
Edition (1989);
[0664] D. Chulin, M. Deleuil, Y. Pourcelot, Powder Technology and
Pharmaceutical Processes, in J. C. Williams, T. Allen, Handbook of
Powder Technology, Elsevier Amsterdam--London--New York--Tokyo,
(1994);
[0665] J. T. Carstensen, Pharmaceutical Principles of Solid Dosage
Forms, Technomic Publishing Co., Inc., Lancaster--Basel,
(1993).
PRODUCTION EXAMPLES
[0666] 1. Injection Therapeutics
[0667] a) Parenteral Solution
33 active ingredient used according to the invention 5.000 g acid
sodium phosphate 5.000 g sodium tartrate 12.000 g benzyl alcohol
7.500 g water for injection purposes to 1000.000 ml
[0668] The solution is produced according to the customary method,
sterilized and filled into 10 ml vials. One vial contains 50 mg of
the compound according to the invention.
[0669] b) Penteral Solution
34 active ingredient used according to the invention 1.000 g
hydrochloric acid, dilute 5.000 g sodium chloride 6.000 g water for
injection purposes to 1000.000 ml
[0670] The solution is produced according to a customary method by
stirring; the medicinal form is adjusted to a suitable pH value by
acid addition and subsequently filled into 100 ml vials and
sterilized. A vial contains 100 mg of the compound according to the
invention.
[0671] c) Parenteral Dispersion
35 active ingredient used according to the invention 10.000 g soya
lecithin 20.000 g saturated triglycerides 100.000 g sodium
hydroxide 7.650 g water for injection purposes to 1000.000 ml
[0672] The active ingredient(s) used according to the invention is
dispersed in the saturated triglycerides. Then the soya lecithin is
added under stirring, and subsequent to this, the aqueous solution
of sodium hydroxide is added with subsequent homogenization. The
dispersion is sterilized and filled into 10 ml vials. A vial
contains 50 mg of the compound according to the invention.
[0673] d) Biodegradable Parenteral Depot Medicinal Form
36 active ingredient used according to the invention 10.000
polylactic acid/polygylcolic acid polymer 70.000
polyvinylpyrrolidone 0.200 gelatin 2.000 soya lecithin 2.000
isotonic sodium chloride solution to 1000.000 ml
[0674] First, the active ingredient is incorporated into the
biodegradable polymer comprising polylactic acid and polyglycolic
acid by a suitable method (spray drying, solvent-evaporation or
phase separation) and subsequently subjected to a sterilization
process. The particles are introduced into a 2-chamber ready-made
syringe in which the adjuvent solution, which is also produced in a
sterile manner, is filled. The biodegradable microparticles are
mixed with the dispersion agent shortly before application and
dispersed. The content of a ready-made syringe is measured such
that this contains 200 mg of the active ingredient according to the
invention.
[0675] e) Parenteral Dispersion for Subcutaneous Installation
37 active ingredient used according to the invention 25,000 g soya
lecithin 25,000 g arachis oil 400,000 g benzyl alcohol 50,000 g
Miglyole .RTM. to 1000,000 g
[0676] The active ingredient is dispersed together with soya
lecithin and arachis oil. The benzyl alcohol is dissolved in
Miglyole.RTM. and added to the dispersion. The entire dispersion is
sterilized and subsequently filled into vials with 2 ml content. A
vial contains 50 mg active ingredient.
[0677] f) Parenteral Perfusions Solution
[0678] The solution named under example b) can also be used for
perfusion of liver for example.
[0679] According to need, instead of ampules with injection
solution, so-called perforation bottles (vials), which can also be
optionally preserved, and infusion solutions with an amount of one
or more active ingredients according to the invention can also be
made available in the customary manner under addition of buffer
substances for adjustment of physiological pH value and/or the
isotonicity and/or a best possible suitable pH value for the
medicinal form (euhydria) and optional further required nutrients,
vitamins, amino acids, stablizers and other necessary adjuvents,
possibly in combination with further medicinal agents suitable for
the mentioned indications.
[0680] 2. Solid, Peroral Administration Medicaments
[0681] a) Tablets
38 active ingredient used according to the invention 10,000 g
lactose 5,200 g starch, soluble 1,800 g
hydroxypropylmethylcellulose 900 g magnesium stearate 100 g
[0682] The above components are mixed with each other and compacted
in a conventional manner, wherein a tablet weight of 180 mg is set.
Each tablet contain's 100 mg active ingredient. If desired, the
tablets obtained in this manner are coated, provided with a film
coat and/or enterically coated.
[0683] b) Coated Tablet Core
39 active ingredient used according to the invention 10,000 g flame
dispersed silicon dioxide 500 g corn starch 2,250 g stearic acid
350 g ethanol 3.0 l gelatin 900 g purified water 10.0 l talcum 300
g magnesium stearate 180 g
[0684] From these components, a granulate is produced which is
pressed to the desired coated tablet cores. Each core contains 50
mg of active ingredient. The core can be further processed in a
customary manner to coated tablets. If desired, a gastric fluid
resistant or retarding film coat can be applied in a known
manner.
[0685] c) Drink Suspension in Vials
40 active ingredient used according to the invention 0.050 g
glycerin 0.500 g sorbite, 70% solution 0.500 g sodium saccharinate
0.010 g methyl-p-hydroxybenzoate 0.040 g aromatic agent q.s.
sterile wasser q.s. to 5 ml
[0686] The above-mentioned components are mixed in a customary
manner to a suspension and filled in a suitable drink vial having 5
ml content.
[0687] d) Poorly Soluble Sublingual Tablets
41 active ingredient used according to the invention 0.030 g
lactose 0.100 g stearic acid 0.004 g talcum purum 0.015 g sweetener
q.s. aromatic agent q.s. rice starch q.s. to 0.500 g
[0688] The active ingredient is compacted together with the
adjuvents under high pressure to sublingual tablets, favorably in
oblong form.
[0689] e) Soft Gel Capsule
42 active ingredient used according to the invention 0.050 g fatty
acid glyceride mixture (Miglyole .RTM.) q.s. to 0.500 g
[0690] The active ingredient is impasted together with the fluid
carrier mixture and mixed together with further adjuvents suitable
for the incapsulation and filled into elastic soft gelatin capsules
which are sealed.
43 f) Hard Gelatin Capsules active ingredient used according to the
invention 0.150 g microcrystalline cellulose 0.100 g
hydroxypropylmethylcellulose 0.030 g mannite 0.100 g ethylcellulose
0.050 g triethyl citrate 0.010 g
[0691] The active ingredient is mixed together with the adjuvents,
microcrystalline cellulose, hydroxypropylmethylcellulose and
mannite, wet with granulation liquid and formed into pellets. These
are subsequently coated with a solution of ethylcellulose and
triethyl citrate in organic solvents in a fluidized-bed apparatus.
A hard gelatin capsule contains 150 mg of active ingredient.
[0692] 3. Topically Administratable Medicinal Forms
44 a) Hydrophilic Ointment active ingredient used according to the
invention 0.500 g Eucerinum .RTM. anhydricum 60.000 g
microcrystalline wax 15.000 g vaseline oil q.s. to 100.000 g
[0693] The above-mentioned adjuvents are melted and further
processed together with the active ingredient to an ointment in a
customary manner.
45 b) Lipophilic Ointment active ingredient used according to the
invention 10.000 g propylene glycol 50.000 g paraffin, liquid
100.000 g paraffin wax 100.000 g vaseline to 1000.000 ml
[0694] The active ingredient(s) used according to the invention is
dissolved in propylene glycol at ca. 60.degree. C. At the same
time, the lipophilic components are melted at 60-70.degree. C. and
subsequently combined with the active ingredient solution. The
ointment is emulsified at first at 60-70.degree. C. and
subsequently cooled to 35-40.degree. C. under constant
emulsification and then filled in 10 g tubes. A tube contains 100
mg of the compound according to the invention.
[0695] 4. Inhalation Therapeutic
[0696] Further subject-matter is a pharmaceutical formulation which
is characterized in that it contians an active ingredient(s) used
according to the invention as a base or a physiologically
acceptable salt thereof together with carriers and/or diluents
customary for this and suitable for administration by means of
inhalation.
[0697] In this connection, particularly suitable physiologically
acceptable salts of the active ingredients are, as already
illustrated in the synthesis section, acid addition salts derived
from inorganic or organic acids such as for example especially
hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate,
citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate,
4-chlorobenzoate, p-toluolsulfonate, methanosulfonate, ascorbate,
salicylate, acetate, formate, succinate, lactate, glutarate,
gluconate or tricarballylate.
[0698] The administration of the active ingredient(s) used of the
invention by means of inhalation occurs according to the invention
in conventional ways customary for administrations of this form,
for example in the form of a commercial controlled dosage aerosol
or in combination with a spacer. In controlled dosage aerosols, a
metering valve is delivered with whose help, a dosed amount of the
composition is administered. For spraying, the present compositions
can be formulated for example as aqueous solutions or suspensions
and be administered by means of an atomizer. Aerosol spray
formulations in which the active ingredient is either suspended
with one or two stabilizers in a propellant as a carrier and/or
diluent, for example tetrafluoroethane or HFC 134a and/or
heptafluoropropane or HFC 227 can equally be used, whereby however,
non-fluorinated hydrocarbons or other propellants which are gaseous
at normal pressure and room temperature, such as propane, butane or
dimethyl ether, can be preferred. Thereby, propellant-free manual
pump systems or dry powder systems as desribed below can also be
used.
[0699] Suitably, the propellant aerosols can also contain surface
active adjuvents, such as for example isopropyl myristate,
polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate,
lecithins, oleic acid.
[0700] For administration by means of inhalation and/or
insufflation, the medicaments with an amount of compounds according
to the invention can also be formulated in the form of dry powder
compositions, for example as active ingredient-soft pellets or as
an active ingredient-powder mixture with a suitable carrier, such
as for example lactose and/or glucose. The powder compositions can
be formulated and administered as single doses or as multiple
doses.
[0701] The compounds according to the invention are preferably
administered by means of a controlled dosage aerosol or in the form
of a dry powder dosage formulation, wherein the latter preferably
contains glucose and/or lactose as a carrier substance.
[0702] As applicators for inhalation of the pharmaceutical
formulations containing one or more of the active ingredient(s)
used according to the invention, all applicators are generally
suitable which are suitable for controlled dosage aerosols and/or a
dry powder dosage formulation, such as for example usual
applicators for the nose, mouth and or pharynx, or also devices
standing under propellant gas for the delivery of a spray (as
controlled dosage aerosol or dry powder dosage formulation) as they
are also used for inhalations in the nose, mouth and/or
pharynx.
[0703] A further embodiment can also consist of an aqueous solution
of the active ingredient(s) used according to the invention, which
also optionally contains further active ingredients and/or
additives, which are applied by means of an ultrasound
atomizer.
46 Intended dose per aerosol per stroke % by weight a) Controlled
Dosage Aerosol active ingredient used according 0.500 mg 0.66 to
the invention stabilizer 0.075 mg 0.10 HFC 134a 75.500 mg 99.24 b)
Controlled Dosage Aerosol active ingredient used according 0.250 mg
0.32 to the invention Stabilizer 0.038 mg 0.05 HFC 227 79.180 mg
99.63
[0704] In the examples a) and b) the micronized active ingredient
is, after previous dispersion in a small amount of the stabilizer,
placed in a suspension vessel in which the bulk amount of
propellant gas solution is found. The corresponding suspension is
dispersed by means of a suitable stirring system (for example high
performance mixer or ultrasound mixer) until an ultra-fine
dispersion results. The suspension is then continuously held in
flux in a filling apparatus suitable for cold propellants or
pressure fillings. Alternatively, the suspension can also be
produced in a suitable cooled stabilizer solution in HFC
134a/227.
[0705] The examples c) to d) describe the composition and
production of dosage dry powder formulations.
47 mg/dose c) Dosage-Dry Powder Formulation active ingredient used
according to the invention 0.500 mg d) Dosage-Dry Powder
Formulation active ingredient used according to the invention 0.500
mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg e) Dosage-Dry Powder
Formulation active ingredient used according to the invention 0.250
mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg
[0706] Im example c) the active ingredient is formulated after
micronization under addition of steam as pellets with an MMAD
between 0,1 and 0,3 mm diameter and brought to use in a multi-dose
powder applicator.
[0707] In the examples d) and e) the active ingredient is
micronized, thereafter, bulk material is mixed with the lactose in
the given amounts, and subsequently, filled in a multi-dose powder
inhilator.
[0708] In all of the examples set forth above, the active
ingredient or the medicinal agent in the form of the respective
suitable pharmaceutical acceptable salt and/or acid addition salts
can be present, insofar as the base is not preferred in each
case.
[0709] In the following, the pharmaceutical test results obtained
in connection with the newly found indications based, in a
representative manner, on the specifically structured compounds
failling under formula (I) are reproduced and the experimental
results are discussed.
Pharmaceutical Experimental Section
[0710] 1. Growth Inhibition of Human Tumor Cells
[0711] The tumor growth inhibiting activity of the substances was
determined on human tumor cells in standardized in vitro test
systems. In the screening tests, the substances gave
IC.sub.50-values in a concentration range of 0.1 nM bis 10
.mu.M.
EXAMPLE
[0712] HepG2 cells plated at a density of 20,000 cells/ml in
12-well plastic dishes. Cultivation occured in Richters IMEM-ZO
nutrient medium with 5% fetal calf serum (FCS) in a tissue culture
incubator with a gas mixture of 5% CO.sub.2 and 95% air at a
temperature of 37.degree. C. One day after plating, the culture
medium was aspirated from the cells and replaced by fresh medium
which contained the respective concentrations of the test
substances. For the individual concentrations and the controls
without test substances, three-fold batches were done for each.
Three days after the beginning of treatment, the medium was again
renewed with the test compounds. After six days of substance
incubation, the test was ended and the protein amount in the
individual wells was determined with the sulforhodamin-B-method
(according to P. Skehan et al.: New Colorimetric Cytotoxicity Assay
for Anticancer-Drug Screening. J. Natl. Cancer Inst. 82: 1107-1112,
1990). The IC.sub.50-values (defined as that concentration in which
the cell growth was inhibited by 50%) was taken from the
dose-response curves and given as a comparative measurement for the
activity of the test compounds.
[0713] The following results were obtained:
48 Test substance No. IC.sub.50-value [.mu.M] 46 0.04 75 0.2 81
0.07 84 0.02 95 0.03 97 0.08 104 0.01 143 0.02 171 0.05 174 0.05
186 0.02 198 0.08 219 0.02
[0714] 2. Indications
[0715] The compounds of formula (I) and their salts permit a
therapeutic use in malignant illnesses of humans and animals
through their excellent inhibition of the growth of tumor cells.
The anti-neoplastic activity of the described substances can be
used for prophylactic, adjunct, palliative, and curative treatment
of solid tumors, leukemic illnesses and lymphomas as well as for
decreasing or preventing metastasis formation in humans and
animals. The therapeutic use is possible in the following illnesses
for example: gynecological tumors, such as of the vulva or the
uterus, ovarian carcinomas, testicle tumors, prostate carcinomas,
skin cancer, kidney cancer, bladder tumors, esophagus carcinomas,
stomach cancer, rectal carcinomas, pancreas carcinomas, thyroid
cancer, adrenal tumors, various types of leukemia and lymphomas,
Hodgkin's disease, tumor illnesses of the CNS, soft-tissue
sarcomas, bone sarcomas, benign and malignant mesotheliomas,
especially intestine cancer, liver cancer, breast cancer, bronchial
and lung carcinomas, melanomas, acute and chronic leukemias. Benign
papillomatosis tumors can also be inhibited in their growth with
the named substances.
[0716] The broad activity of the new compounds was tested in-vitro
according to the method described under point 1. Thereby, the
following IC.sub.50-values were obtained for compound number
104:
49 Cell-Line Source IC.sub.50-value [.mu.M] NCI-H69 small cell lung
carcinoma 0.02 WERI-Rb-1 retinoblastoma 0.008 THP-1 monocytic
leukemia 0.02
[0717] With respect to the compounds used according to the
invention, an independent activity profile is suggested by the
findings with the observed activity against the various tumor
types. Thus, tumors which are resistant to customary cytostatic
agents, for example, respond entirely to these substances. In
addition, based on the independent characteristics of the compounds
used according to the invention, combinations of these compounds
together with known chemo-therapeutically used pharmaceuticals, for
example cytostatic agents or immunosuppresive agents, etc., are
created especially taking a possible complimentation of their
properties into consideration.
[0718] The integration of the presently used compounds with their
specific structures in a therapy scheme is successful with one or
more substances from the following classes for example:
anti-metabolites (for example cytarabine, 5-fluorouracil,
6-mercaptopurine, methotrexate), alkylating agents (for example
busuffan, carmustine, cisplatin, carboplatin, cyclophosphamide,
dacarbazine, melphalane, thiotepa), DNA-intercalating substances
and topoisomerase inhibitors (for example actinomycin D,
daunorubicin, doxorubicin, mitomycin C, mitoxantrone, etoposide,
teniposide, topotecan, irinotecan), spindle poisons (for example
vincristine, navelbin, taxol, taxoter), hormonally active agents
(for example tamoxifen, flutamide, formestan, goserelin) or other
cytostatic agents with complex modes of action (for example
L-asparaginase, bleomycin, hydroxyurea). Resistant tumor cells can
be made sensitive again by interaction of the new compounds with a
mechanism of resistance for common cytostatic agents (for example
P-glycoprotein, MRP, glutathione-S-transferase,
metallothionein).
[0719] A combination with other therapeutic physical measures or
other measures for tumor patients, such as for example
radiotherapy, hyperthenmia or immuno therapy is also possible with
the compounds used according to the invention. Therefore, further
subject-matter under the invention is also combinations of this
type in form of new medicaments.
[0720] 3. Immuno Suppressing Activity
[0721] Many anti-tumor agents have not only a cytotoxic effect on
tumor cells, but also on the blood cell system. This leads to a
weakening of the immune defence, which can, in turn, be
specifically employed to suppress the rejection reaction after an
organ transplantation for example. Therefore, a use of the main
compounds, optionally in combination with other compounds effective
for these indications is suitable in diseases such as psoriasis or
autoimmune diseases. In order to test the possibility for a
therapeutic use in illnesses of this type, the substance activity
was tested on freshly isolated lymphocytes as follows:
[0722] The spleen of a Swiss mouse served as a lymphocyte source.
The lymphocyte population was isolated from the spleen cell
suspension over a ficoll gradient and taken up in IMEM-ZO culture
medium with 0,1% dextran 70,000 and 2% fetal calf serum. The cells
were plated at a density of ca. 500,000 cells/well/ml in a 12-well
plate, 1 ml doubly concentrated test substance solution was
pipetted per well and this was subsequently incubated in a tissue
culture incubator at 37.degree. C. and 5% CO.sub.2. After 2 days, a
1 ml-aliquot with 5 .mu.l of the fluorescent dye solutions
propidium iodide (8 mg/ml) and 3,3'-dihexyloxacarbocyanin iodide
(40 .mu.g/ml) each was added per well, and incubated for 3 minutes
at room temperature. Subsequently, 10,000 cells per each sample
were measured on a flow-through cytometer and the percentage amount
of vital cells in the population was determined. By means of the
dose-response curves, IC.sub.50-values were calculated which were
also employed in the following Tables for the characterization of
the individual substances:
50 Test Substance No. IC.sub.50 [.mu.M] 46 0.03 252 0.0002 254
0.00008 306 0.002 315 0.00004
[0723] Hence, the special, independent class of the compounds used
according to the invention is also suitable for a combination with
known immunosuppressive agents from the class of macrolides, for
example cyclosporin A, tacrolimus, raparnycin, or anti-metabolites,
for example azathioprin or methotrexate and glucocorticoids.
Combination of this and/or medicaments with an amount of compounds
used according to the invention together with known
immunosuppressive agents as well as a method for their production
represents further subject-matter of the invention.
[0724] The invention is in no was limited to the present respective
concretely named active ingredients concentrations, dosages,
combinations with one or more other cytostatic agents, tumor
inhibitors, cancerostatic agents, immunosuppressive agents or
further medicinal agents suitable for the respective specific
indications or the type of tumor to treated or immunological
illness, etc.
* * * * *