U.S. patent application number 11/244299 was filed with the patent office on 2006-05-18 for pi3-kinases.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. Invention is credited to Eckhart Bauer, Trixi Brandl, Steffen Breitfelder, Frank Buettner, Matthias Grauert, Christoph Hoenke, Matthias Hoffmann, Anne T. Joergensen, Frank Kalkbrenner, Udo Maier, Alexander Pautsch, Stefan Peters, Gerhard Schaenzle.
Application Number | 20060106013 11/244299 |
Document ID | / |
Family ID | 35583390 |
Filed Date | 2006-05-18 |
United States Patent
Application |
20060106013 |
Kind Code |
A1 |
Breitfelder; Steffen ; et
al. |
May 18, 2006 |
PI3-kinases
Abstract
New compounds of formula 1 are provided which by virtue of their
pharmaceutical activity as PI3-kinase modulators may be used in the
therapeutic field for the treatment of inflammatory or allergic
diseases. ##STR1## Examples of these include inflammatory and
allergic respiratory complaints, inflammatory diseases of the
gastrointestinal tract and motor apparatus, inflammatory and
allergic skin diseases, inflammatory eye diseases, diseases of the
nasal mucosa, inflammatory or allergic conditions involving
autoimmune reactions or inflammations of the kidney.
Inventors: |
Breitfelder; Steffen;
(Assmannshardt, DE) ; Maier; Udo; (Senden, DE)
; Brandl; Trixi; (Warthausen, DE) ; Hoenke;
Christoph; (Ingelheim, DE) ; Grauert; Matthias;
(Biberach, DE) ; Pautsch; Alexander; (Ulm, DE)
; Hoffmann; Matthias; (Mittelbiberach, DE) ;
Kalkbrenner; Frank; (Ummendorf, DE) ; Joergensen;
Anne T.; (Biberach, DE) ; Schaenzle; Gerhard;
(Biberach, DE) ; Peters; Stefan; (Biberach,
DE) ; Buettner; Frank; (Attenweiler, DE) ;
Bauer; Eckhart; (Biberach, DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim
DE
55216
|
Family ID: |
35583390 |
Appl. No.: |
11/244299 |
Filed: |
October 5, 2005 |
Current U.S.
Class: |
514/232.5 ;
514/254.02; 514/322; 514/366; 544/133; 544/368; 546/199;
548/151 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 17/10 20180101; A61P 35/00 20180101; A61P 27/02 20180101; A61P
1/16 20180101; A61P 1/04 20180101; A61P 17/04 20180101; A61P 27/16
20180101; A61P 17/00 20180101; A61P 31/12 20180101; A61P 11/06
20180101; C07D 513/04 20130101; C07D 277/84 20130101; A61P 11/08
20180101; A61P 37/08 20180101; A61P 11/00 20180101; A61P 13/12
20180101; A61P 31/04 20180101; A61P 17/06 20180101; A61P 19/02
20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/232.5 ;
544/133; 544/368; 546/199; 548/151; 514/254.02; 514/366;
514/322 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/496 20060101 A61K031/496; A61K 31/454
20060101 A61K031/454; A61K 31/43 20060101 A61K031/43; C07D 498/02
20060101 C07D498/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 7, 2004 |
DE |
10 2004 048 877 |
Feb 9, 2005 |
DE |
10 2005 005 813 |
Claims
1. A compound of formula 1; ##STR1289## with the proviso that the
circular line designated A denotes an aromatic system; wherein Y
denotes carbon, nitrogen atom, sulphur; Z denotes carbon, nitrogen
atom, sulphur; i denotes 1, 2 or 3; k denotes 0 or 1; R.sup.a
denotes H, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2, OR.sup.8,
SR.sup.11, SOR.sup.11, SO.sub.2R.sup.11,
NHCO--C.sub.1-6-alkyl-NH.sub.2, or a group selected from among
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkenyl, C.sub.1-6-haloalkyl, aryl,
C.sub.7-11-aralkyl, spiro, het, hetaryl and CH.sub.2--O-aryl, which
may optionally be substituted; R.sup.8 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl, optionally
substituted by one or more halogens or C.sub.1-4-alkyl; R.sup.9
denotes H, COOR.sup.12, CONR.sup.12 or C.sub.1-6-alkyl, optionally
substituted by one or more COOH, N(C.sub.1-6-alkyl).sub.2 or het,
optionally substituted by one or more C.sub.1-6-alkyl; or R.sup.9
denotes het, optionally substituted by one or more C.sub.1-4-alkyl;
R.sup.10 denotes H, C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or
C.sub.2-6-alkynyl; R.sup.11 denotes C.sub.1-6-alkyl, optionally
substituted by one or more N(C.sub.1-4-alkyl).sub.2; R.sup.b
denotes R.sup.4, OR.sup.4, --CH.sub.2OR.sup.4, COR.sup.4,
COOR.sup.4, CONR.sup.4R.sup.5, NR.sup.4R.sup.5, NR.sup.5COR.sup.4,
NR.sup.5COOR.sup.4, NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; R.sup.4, R.sup.5 denote H,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH,
C.sub.2-6-alkenyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
C.sub.2-6-alkynyl, optionally substituted by
Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected from
among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur;
R.sup.c denotes NHR.sup.6 or a group selected from among
##STR1290## wherein B denotes a bond, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl; R.sup.6 denotes H or a
group selected from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl,
het, aryl, hetaryl optionally substituted by one or more groups
R.sup.6.1; R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); R.sup.7 denotes H, C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl,
NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2, hetaryl, het,
optionally substituted by C.sub.1-4-alkyl or CONH.sub.2; R.sup.7.1
denotes H, C.sub.1-6-alkyl, (CH.sub.2).sub.2-4R.sup.7.1.1 or
COObutyl; R.sup.7.2 denotes H, C.sub.1-6-alkyl, optionally
substituted by one or more OH; R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); R.sup.7.1.1.1 denotes H or C.sub.1-6-alkyl;
R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl; or a pharmacologically
acceptable salt thereof, with the proviso that R.sup.a cannot be H
or Me if Y is nitrogen; Z is nitrogen; j is 2; k is 0; R.sup.b is H
and R.sup.c is NHCONH-Et.
2. The compound of formula 1 according to claim 1; wherein R.sup.a
denotes a group selected from among aryl, C.sub.7-11-aralkyl and
hetaryl, which may optionally be substituted by one or more groups
selected from among R.sup.1, R.sup.2 and R.sup.3; R.sup.1 and
R.sup.2 independently of one another denote C.sub.1-6-alkyl,
C.sub.2-6-alkenyl C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkenyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkylene-COOH, C.sub.1-6-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SR.sup.1.1,
SOR.sup.1.1, SO.sub.2R.sup.1.1, het or hetaryl, R.sup.1.1 denotes
OH, C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
NR.sup.1.1.1R.sup.1.1.2 R.sup.1.1.1 denotes H, C.sub.1-6-alkyl,
optionally substituted by a group selected from among NH.sub.2,
NHMe, NMe.sub.2; R.sup.1.1.2 denotes H, C.sub.1-6-alkyl; or
R.sup.1.1.1 and R.sup.1.1.2 together form a five- or six-membered
heterocyclic ring, which may optionally be substituted by a group
selected from among methyl, ethyl, propyl; R.sup.3 denotes a group
selected from among ##STR1291## wherein X denotes a bond or
C.sub.1-4-alkylene; X' denotes C.sub.1-4-alkylene,
C.sub.2-4-alkenylene or C.sub.1-4-alkynylene R.sup.3a denotes a
group, which may be identical or different, selected from among
R.sup.3.1, R.sup.3.2 and R.sup.3.3; R.sup.3.1 denotes spiro or het,
while het may optionally be substituted by one or more R.sup.3.1.1;
R.sup.3.1.1 denotes C.sub.1-6-alkyl, C.sub.2-6-alkenyl, OH,
C.sub.1-4-alkylene-OH,
C.sub.1-4-alkylene-NR.sup.3.1.1.1R.sup.3.1.1.2, COR.sup.3.1.1.1,
COOR.sup.3.1.1.1, CONR.sup.3.1.1.1R.sup.3.1.1.2,
NR.sup.3.1.1.1R.sup.3.1.1.2, het, hetaryl, NHCOR.sup.3.1.1.1
R.sup.3.1.1.1 denotes a group selected from among H,
C.sub.1-4-alkyl, aryl and C.sub.7-11-aralkyl; optionally
substituted by a group selected from among halogen, OH and CN;
R.sup.3.1.1.2 denotes H, C.sub.1-4-alkyl; R.sup.3.2 denotes a group
selected from among C.sub.3-6-cycloalkyl, het, hetaryl and spiro
which is optionally substituted by one or more R.sup.3.2.1
R.sup.3.2.1 denotes C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, OH,
NR.sup.3.2.1.1R.sup.3.2.1.2, NHCOR.sup.3.2.1.3 or het, optionally
substituted by one or more groups selected from among
C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; R.sup.3.2.1.1 denotes H,
C.sub.1-4-alkyl or C.sub.7-11-aralkyl; R.sup.3.2.1.2 denotes H,
C.sub.1-4-alkyl or C.sub.7-11-aralkyl; R.sup.3.2.1.3 denotes aryl,
C.sub.7-11-aralkyl; or C.sub.1-6-alkyl, which is optionally
substituted by one or two R.sup.3.2.2; R.sup.3.2.2 denotes
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
COOR.sup.3.2.2.1, CONR.sup.3.2.2.1R.sup.3.2.2.2,
NR.sup.3.2.2.1R.sup.3.2.2.2, NHCOR.sup.3.2.2.1,
C.sub.1-6-haloalkyl, CN, OR.sup.3.2.2.1, SO.sub.2R.sup.3.2.2.1,
C.sub.3-6-cycloalkyl, CO-het, C.sub.2-4-alkynyl-hetaryl, guanidine
or a group selected from among het, hetaryl and aryl, which is
optionally substituted by one or more groups selected from among
halogen, C.sub.1-6-alkyl, CONR.sup.3.2.2.1R.sup.3.2.2.2 OH,
imidazolidinone; R.sup.3.2.2.1 denotes H or C.sub.1-6-alkyl, aryl,
C.sub.7-11-aralkyl R.sup.3.2.2.2 denotes H or C.sub.1-6-alkyl; or
aryl, which is optionally substituted by one or two R.sup.3.2.3
R.sup.3.2.3 denotes a group selected from among
NH--C.sub.1-16-alkyl-N(C.sub.1-6-alkyl).sub.2 or het, while het may
optionally be substituted by a C.sub.1-6-alkyl group; R.sup.3.3
denotes H or a group selected from among C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.1-6-haloalkyl and aryl,
which may optionally be substituted by one or more groups
R.sup.3.3.1; R.sup.3.3.1 denotes C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2,
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, optionally substituted by one or more groups selected from
among C.sub.1-4-alkyl, SO.sub.2 R.sup.3.2.1.1,
SO.sub.2C.sub.1-4-alkyl, SO.sub.2C.sub.7-11-aralkyl,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; R.sup.3.3.1.1,
R.sup.3.3.1.2 and R.sup.3.3.1.3 denote a group selected from among
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl, C.sub.2-4-alkynyl-aryl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-4-alkenyl-hetaryl,
C.sub.2-4-alkynyl-hetaryl, COC.sub.1-4-alkyl-hetaryl,
COC.sub.2-4-alkenyl-hetaryl, COC.sub.2-4-alkynyl-hetaryl; or two of
the groups R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 together
form a ring, consisting of carbon atoms and optionally a heteroatom
selected from among oxygen, nitrogen and sulphur; R.sup.a denotes
H, C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.3-8-cycloalkyl,
C.sub.3-8-cycloalkenyl, C.sub.1-6-haloalkyl, COR.sup.8,
NR.sup.9R.sup.10, NO.sub.2, OR.sup.8, SR.sup.11, SOR.sup.11,
SO.sub.2R.sup.11, NHCO--C.sub.1-6-alkyl-NH.sub.2, spiro or a group
selected from among C.sub.7-11-aralkyl, CH.sub.2--O-aryl and het
which may optionally be substituted by one or more halogens,
C.sub.1-6-alkyl, CO--C.sub.1-4-haloalkyl, C.sub.1-4-alkyl-NH.sub.2
or CH.sub.2NHCOOR.sup.12; R.sup.8 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl, optionally
substituted by one or more halogens or C.sub.1-4-alkyl; R.sup.9
denotes H, COOR.sup.12, CONR.sup.12 or C.sub.1-6-alkyl, optionally
substituted by one or more COOH, N(C.sub.1-6-alkyl).sub.2 or het,
optionally substituted by one or more C.sub.1-6-alkyl; or R.sup.9
denotes het, optionally substituted by one or more C.sub.1-4-alkyl;
R.sup.10 denotes H, C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or
C.sub.2-6-alkynyl; R.sup.11 denotes C.sub.1-6-alkyl, optionally
substituted by one or more N(C.sub.1-4-alkyl).sub.2; R.sup.12
denotes H, C.sub.1-6-alkyl; or a pharmacologically acceptable salt
thereof.
3. The compound of formula 1 according to claim 1; wherein R.sup.a
denotes a group selected from among aryl, C.sub.7-11-aralkyl and
hetaryl, which may optionally be substituted by one or more groups
selected from among R.sup.1, R.sup.2 and R.sup.3; R.sup.1 and
R.sup.2 independently of one another denote C.sub.1-6-alkyl,
C.sub.2-6-alkenyl C.sub.2-6-alkynyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkenyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkylene-COOH, C.sub.1-6-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SR.sup.1.1,
SOR.sup.1.1, SO.sub.2R.sup.1.1, het or hetaryl, R.sup.1.1 denotes
OH, C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
NR.sup.1.1.1R.sup.1.1.2 R.sup.1.1.1 denotes H, C.sub.1-6-alkyl,
optionally substituted by a group selected from among NH.sub.2,
NHMe, NMe.sub.2; R.sup.1.1.2 denotes H, C.sub.1-6-alkyl; or
R.sup.1.1.1 and R.sup.1.1.2 together form a five- or six-membered
heterocyclic ring, which may optionally be substituted by a group
selected from among methyl, ethyl, propyl; R.sup.3 denotes a group
selected from among ##STR1292## wherein X denotes a bond or
C.sub.1-4-alkylene; R.sup.3a denotes a group, which may be
identical or different, selected from among R.sup.3.1, R.sup.3.2
and R.sup.3.3; R.sup.3.1 denotes spiro or het, while het may
optionally be substituted by one or more R.sup.3.1.1; R.sup.3.1.1
denotes C.sub.1-6-alkyl, C.sub.2-6-alkenyl, OH,
C.sub.1-4-alkylene-OH,
C.sub.1-4-alkylene-NR.sup.3.1.1.1R.sup.3.1.1.2, COR.sup.3.1.1.1,
COOR.sup.3.1.1.1, CONR.sup.3.1.1.1R.sup.3.1.1.2,
NR.sup.3.1.1.1R.sup.3.1.1.2, het, hetaryl, NHCOR.sup.3.1.1.1
R.sup.3.1.1.1 denotes a group selected from among H,
C.sub.1-4-alkyl, aryl and C.sub.7-11-aralkyl; optionally
substituted by a group selected from among halogen, OH and CN;
R.sup.3.1.1.2 denotes H, C.sub.1-4-alkyl; R.sup.3.2 denotes a group
selected from among C.sub.3-6-cycloalkyl, het, hetaryl and spiro
which is optionally substituted by one or more R.sup.3.2.1
R.sup.3.2.1 denotes C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, OH,
NR.sup.3.2.1.1R.sup.3.2.1.2, NHCOR.sup.3.2.1.3 or het, optionally
substituted by one or more groups selected from among
C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; R.sup.3.2.1.1 denotes H,
C.sub.1-4-alkyl or C.sub.7-11-aralkyl; R.sup.3.2.1.2 denotes H,
C.sub.1-4-alkyl or C.sub.7-11-aralkyl; R.sup.3.2.1.3 denotes aryl,
C.sub.7-11-aralkyl; or --C.sub.1-6-alkyl, which is optionally
substituted by one or two R.sup.3.2.2; R.sup.3.2.2 denotes
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
COOR.sup.3.2.2.1, CONR.sup.3.2.2.1R.sup.3.2.2.2,
NR.sup.3.2.2.1R.sup.3.2.2.2, NHCOR.sup.3.2.2.1,
C.sub.1-6-haloalkyl, CN, OR.sup.3.2.2.1, SO.sub.2R.sup.3.2.2.1,
C.sub.3-6-cycloalkyl, CO-het, C.sub.2-4-alkynyl-hetaryl, guanidine
or a group selected from among het, hetaryl and aryl, which is
optionally substituted by one or more groups selected from among
halogen, C.sub.1-6-alkyl, CONR.sup.3.2.2.1R.sup.3.2.2.2, OH,
imidazolidinone; R.sup.3.2.2.1 denotes H or C.sub.1-6-alkyl, aryl,
C.sub.7-11-aralkyl R.sup.3.2.2.2 denotes H or C.sub.1-6-alkyl; or
aryl, which is optionally substituted by one or two R.sup.3.2.3
R.sup.3.2.3 denotes a group selected from among
NH--C.sub.1-16-alkyl-N(C.sub.1-6-alkyl).sub.2 or het, while het may
optionally be substituted by a C.sub.1-6-alkyl group; R.sup.3.3
denotes H or a group selected from among C.sub.1-6-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.1-4-haloalkyl and aryl,
which may optionally be substituted by one or more groups
R.sup.3.3.1; R.sup.3.3.1 denotes C.sub.5-6-cycloalkyl,
C.sub.5-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2,
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, optionally substituted by one or more groups selected from
among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
SO.sub.2C.sub.1-4-alkyl, SO.sub.2C.sub.7-11-aralkyl,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; R.sup.3.3.1.1,
R.sup.3.3.1.2 and R.sup.3.3.1.3 denote a group selected from among
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl, C.sub.2-4-alkynyl-aryl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-4-alkenyl-hetaryl,
C.sub.2-4-alkynyl-hetaryl, COC.sub.1-4-alkyl-hetaryl,
COC.sub.2-4-alkenyl-hetaryl, COC.sub.2-4-alkynyl-hetaryl; or two of
the groups R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 together
form a five-, six- or seven-membered ring, consisting of carbon
atoms and optionally a heteroatom selected from among oxygen,
nitrogen and sulphur; R.sup.a denotes H, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl,
C.sub.1-6-haloalkyl, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2,
OR.sup.8, SR.sup.11, SOR.sup.11, SO.sub.2R.sup.11,
NHCO--C.sub.1-6-alkyl-NH.sub.2, spiro or a group selected from
among C.sub.7-11-aralkyl, CH.sub.2--O-aryl and het which may
optionally be substituted by one or more halogens, C.sub.1-6-alkyl,
CO--C.sub.1-4-haloalkyl, C.sub.1-4-alkyl-NH.sub.2 or
CH.sub.2NHCOOR.sup.12; R.sup.8 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl, optionally
substituted by one or more halogens or C.sub.1-4-alkyl; R.sup.9
denotes H, COOR.sup.12 or C.sub.1-4-alkyl, optionally substituted
by one or more COOH, N(C.sub.1-4-alkyl).sub.2 or het, optionally
substituted by one or more C.sub.1-4-alkyl; or R.sup.9 denotes het,
optionally substituted by one or more C.sub.1-4-alkyl; R.sup.10
denotes H, C.sub.1-6-alkyl, CO--C.sub.1-4-alkyl or
C.sub.2-6-alkynyl; R.sup.11 denotes C.sub.1-6-alkyl, optionally
substituted by one or more N(C.sub.1-4-alkyl).sub.2; R.sup.12
denotes C.sub.1-6-alkyl; R.sup.b denotes R.sup.4, OR.sup.4,
--CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5,
NR.sup.4R.sup.5, NR.sup.5COR.sup.4, NR.sup.5COOR.sup.4,
NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; R.sup.4 denotes H, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH, C.sub.2-6-alkenyl,
C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl, C.sub.2-4-alkynyl-aryl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-4-alkenyl-hetaryl,
C.sub.2-4-alkynyl-hetaryl, C.sub.2-6-alkynyl, optionally
substituted by Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a
group selected from among aryl, het, hetaryl and optionally
substituted by C.sub.1-4-alkyl; R.sup.5 denotes H or
C.sub.1-6-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur;
R.sup.c denotes NHR.sup.6 or a group selected from among
##STR1293## wherein B denotes a bond, C.sub.1-4-alkyl or
C.sub.2-4-alkynyl; R.sup.6 denotes H or a group selected from among
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, het, aryl, hetaryl
optionally substituted by one or more groups R.sup.6.1; R.sup.6.1
denotes halogen, CF.sub.3, OH, CN, OMe, SO.sub.2(C.sub.1-4-alkyl);
R.sup.7 denotes H, C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2,
OR.sup.7.2, SR.sup.7.2, hetaryl, het, optionally substituted by
C.sub.1-4-alkyl or CONH.sub.2; R.sup.7.1 denotes H,
C.sub.1-4-alkyl, (CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl;
R.sup.7.2 denotes H, C.sub.1-6-alkyl, optionally substituted by one
or more OH; R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2, het or
1-imidazolyl, 2-(N-ethylpyrrolidine); R.sup.7.1.1.1 denotes H or
C.sub.1-6-alkyl; R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl; or the
pharmacologically acceptable salt thereof.
4. The compound of formula 1 according to claim 1; wherein R.sup.a
denotes a group selected from among aryl and C.sub.7-11-aralkyl,
which may optionally be substituted by one or more groups selected
from among R.sup.1, R.sup.2 and R.sup.3; or hetaryl optionally
substituted by one or more C.sub.1-4-alkyl; R.sup.1 denotes
C.sub.1-4-alkyl, C.sub.1-4-haloalkyl, C.sub.1-4-alkylene-COOH,
C.sub.1-4-alkoxy, halogen, OH, CN, COR.sup.1.1,
O--C.sub.1-4-haloalkyl, NO.sub.2 or SO.sub.2R.sup.1.1; R.sup.1.1
denotes OH, methyl, NH.sub.2, NHMe, NMe.sub.2, ##STR1294## R.sup.2
denotes C.sub.1-4-alkyl, C.sub.1-4-alkoxy or halogen; R.sup.3
denotes a group selected from among ##STR1295## wherein n denotes 0
or 1; m denotes 0 or 1; o denotes 2; R.sup.3.1 denotes spiro or
het, while het may optionally be substituted by one or more
R.sup.3.1.1; R.sup.3.1.1 denotes C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, OH, C.sub.1-4-alkylene-OH, CH.sub.2NEt.sub.2,
COMe, COOH, CONH.sub.2, NH.sub.2, het, hetaryl, ##STR1296##
R.sup.3.2 denotes a group selected from among C.sub.3-6-cycloalkyl,
het, hetaryl and spiro which is optionally substituted by one or
two R.sup.3.2.1 R.sup.3.2.1 denotes C.sub.1-4-alkyl, cyclopentyl,
OH, --NR.sup.3.2.1.1R.sup.3.2.1.2 or ##STR1297## or het, is
optionally substituted by one or more groups selected from among
methyl, SO.sub.2R.sup.3.2.1.1, ##STR1298## R.sup.3.2.1.1 denotes H,
methyl or benzyl; R.sup.3.2.1.2 denotes H, methyl or benzyl; or
--C.sub.1-6-alkyl, which is optionally substituted by one or two
R.sup.3.2.2; R.sup.3.2.2 denotes C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, C.sub.1-4-haloalkyl, CN, OH,
SO.sub.2R.sup.3.2.2.1, C.sub.3-6-cycloalkyl or a group selected
from among ##STR1299## or a group selected from among het, hetaryl
and aryl, which is optionally substituted by one or more groups
selected from among Cl, methyl, CONR.sup.3.2.2.1R.sup.3.2.2.2, OH;
R.sup.3.2.2.1 denotes H or methyl; R.sup.3.2.2.2 denotes H or
methyl; or aryl, which is optionally substituted by one or two
R.sup.3.2.3 R.sup.3.2.3 denotes a group selected from among
##STR1300## R.sup.3.3 denotes H or a group selected from among
C.sub.1-6-alkyl and aryl, which may optionally be substituted by
one or more groups R.sup.3.3.1; R.sup.3.3.1 denotes
C.sub.5-6-cycloalkyl, C.sub.5-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2,
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, optionally substituted by one or more groups selected from
among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
SO.sub.2C.sub.1-4-alkyl, SO.sub.2C.sub.7-11-aralkyl, ##STR1301##
R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 denote a group
selected from among C.sub.1-4-alkyl, C.sub.7-11-aralkyl,
C.sub.1-4-alkyl-hetaryl, COC.sub.1-4-alkyl-hetaryl; R.sup.a denotes
H, C.sub.1-6-alklyl, C.sub.2-6-alkenyl, C.sub.3-6-cycloalkyl,
CF.sub.3, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2,
S(O).sub.nR.sup.11, or a group selected from among ##STR1302## or a
group selected from among ##STR1303## which may optionally be
substituted by one or more Cl; or a group selected from among
##STR1304## which may optionally be substituted by one or more
CH.sub.3, COCF.sub.3, CH.sub.2NH.sub.2 or CH.sub.2NHCOOR.sup.12;
R.sup.8 denotes C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2,
furanyl or phenyl, optionally substituted by one or more chlorine;
R.sup.9 denotes H, COOR.sup.12 or piperidino, optionally
substituted by one or more CH.sub.3, or a group selected from among
C.sub.1-4-alkyl, which may optionally be substituted by one or more
COOH, NMe.sub.2 or 4-methylpiperazine; R.sup.10 denotes H,
C.sub.1-4-alkyl, C.sub.2-4-alkynyl or COCH.sub.3; R.sup.11 denotes
C.sub.1-4-alkyl, optionally substituted by one or more NMe.sub.2,
R.sup.12 denotes C.sub.1-4-alkyl; R.sup.b denotes R.sup.4,
CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5,
NH.sub.2, NHCOOR.sup.4, NHCONR.sup.4R.sup.5 or OH; R.sup.4 denotes
H, C.sub.1-4-alkyl, C.sub.1-4-alkylene-OH, C.sub.2-4-alkynyl,
C.sub.1-6-haloalkyl, aryl, het, hetaryl, ##STR1305## R.sup.5
denotes H or C.sub.1-4-alkyl; R.sup.c denotes NHR.sup.6 or a group
selected from among ##STR1306## wherein B denotes a bond,
C.sub.1-4-alkyl or C.sub.2-4-alkynyl; R.sup.6 denotes H,
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, C.sub.7-11-aralkyl, aryl,
optionally substituted by SO.sub.2CH.sub.3; R.sup.7 denotes H,
NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2, hetaryl, het,
optionally substituted by C.sub.1-4-alkyl or CONH.sub.2, or a group
selected from among ##STR1307## R.sup.7.1 denotes H,
C.sub.1-4-alkyl, (CH.sub.2).sub.2R.sup.7.1.1 or COObutyl; R.sup.7.2
denotes H, C.sub.1-4-alkyl; R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); R.sup.7.1.1.1 denotes H or C.sub.1-6-alkyl;
R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl; or the
pharmacologically acceptable salt thereof.
5. The compound of formula 1 according to claim 1; wherein R.sup.a
denotes phenyl or benzyl, in each case optionally substituted by
one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; or ##STR1308## R.sup.1 denotes methyl, ethyl, propyl,
butyl, CF.sub.3, CH.sub.2COOH, methoxy, F, Cl, Br, OH, CN,
COR.sup.1.1, OCF.sub.3, NO.sub.2 or SO.sub.2R.sup.1.1; R.sup.1.1
denotes OH, methyl, NH.sub.2, NHMe, NMe.sub.2, ##STR1309## R.sup.2
denotes methyl, methoxy, F, Cl or Br; R.sup.3 denotes a group
selected from among ##STR1310## wherein n denotes 0 or 1; m denotes
0 or 1; o denotes 2; R.sup.3.1 denotes a group selected from among
##STR1311## or a group selected from among ##STR1312## which may
optionally be substituted by one or more R.sup.3.1.1; R.sup.3.1.1
denotes methyl, ethyl, OH, CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2NEt.sub.2, COMe, COOH, CONH.sub.2, NH.sub.2, ##STR1313##
R.sup.3.2 denotes a group selected from among ##STR1314## which is
optionally substituted by one or more groups selected from among
methyl, ethyl, cyclopentyl, OH, NH.sub.2; or cyclohexyl, which is
optionally substituted by one or two R.sup.3.2.1 R.sup.3.2.1
--NR.sup.3.2.1.1N.sup.3.2.1.3 or a group selected from among
##STR1315## or a group selected from among ##STR1316## which is
optionally substituted by one or more groups selected from among
methyl, SO.sub.2R.sup.3.2.1.1, ##STR1317## R.sup.3.2.1.1 denotes H,
methyl or benzyl; R.sup.3.2.1.2 denotes H, methyl or benzyl; or
--C.sub.1-6-alkyl, straight-chain or branched, which is optionally
substituted by one or two R.sup.3.2.2; R.sup.3.2.2 denotes
C.dbd.CH.sub.2, C.ident.CH, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2, NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, CF.sub.3, CN, OH, SO.sub.2R.sup.3.2.2.1 or a
group selected from among ##STR1318## or a group selected from
among ##STR1319## which is optionally substituted by one or more
groups selected from among Cl, methyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2, OH; R.sup.3.2.2.1 denotes H or
methyl; R.sup.3.2.2.2 denotes H or methyl; or phenyl, which is
optionally substituted by one or two R.sup.3.2.3 R.sup.3.2.3
denotes a group selected from among ##STR1320## R.sup.3.3 denotes
H, C.sub.1-6-alkyl, optionally substituted by one or more
R.sup.3.3.1; R.sup.3.3.1 denotes C.sub.5-6-cycloalkyl,
C.sub.5-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2,
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2,
SOR.sup.3.3.1.1SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or het
which is optionally substituted by one or more groups selected from
among methyl, SO.sub.2H, SO.sub.2CH.sub.3, SO.sub.2CH.sub.2phenyl,
##STR1321## R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 denote a
group selected from among C.sub.1-4-alkyl, C.sub.7-11-aralkyl,
C.sub.1-4-alkyl-hetaryl, COC.sub.1-4-alkyl-hetaryl; R.sup.a denotes
H, methyl, ethyl, propyl, butyl, 3-methyl-butyl, propenyl,
cyclopropyl, cyclohexyl, CF.sub.3, COR.sup.8, NR.sup.9R.sup.10,
NO.sub.2, OR.sup.8, SR.sup.11, SOR.sup.11, SO.sub.2R.sup.11 or a
group selected from among ##STR1322## or a group selected from
among ##STR1323## which may optionally be substituted by one or
more Cl, or a group selected from among ##STR1324## which may
optionally be substituted by one or more CH.sub.3, COCF.sub.3,
CH.sub.2NH.sub.2 or CH.sub.2NHCOOR.sup.12; R.sup.8 denotes methyl,
propyl, cyclopropyl, NH.sub.2, furanyl or phenyl, optionally
substituted by one or more chlorine; R.sup.9 denotes H, COOR.sup.12
or piperidino, optionally substituted by one or more CH.sub.3, or a
group selected from among methyl, ethyl and propyl, which may
optionally be substituted by one or more COOH, NMe.sub.2 or
4-methylpiperazine; R.sup.10 denotes H, methyl, COCH.sub.3,
C.ident.CH or CH.sub.2C.ident.CH; R.sup.11 denotes ethyl or propyl,
optionally substituted by one or more NMe.sub.2, R.sup.12 denotes
butyl R.sup.b denotes R.sup.4, CH.sub.2OR.sup.4, COR.sup.4,
COOR.sup.4, CONR.sup.4R.sup.5, NH.sub.2, NHCOOR.sup.4,
NHCONR.sup.4R.sup.5 or OH; R.sup.4 denotes H, methyl, ethyl,
2-hydroxyethyl, propyl, C.ident.CH, CF.sub.3, phenyl, ##STR1325##
R.sup.5 denotes H, methyl or ethyl; R.sup.c denotes NHR.sup.6 or a
group selected from among ##STR1326## wherein B denotes a bond,
methylene, ethylene, propylene or butynylene; R.sup.6 denotes H,
C.sub.1-4-alkyl, aryl, optionally substituted by SO.sub.2CH.sub.3;
R.sup.7 denotes H, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2 or a
group selected from among ##STR1327## R.sup.7.1 denotes H, methyl,
ethyl, (CH.sub.2).sub.2R.sup.7.1.1 or COObutyl; R.sup.7.2 denotes
H, methyl or ethyl; R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); R.sup.7.1.1.1 denotes H or C.sub.1-6-alkyl;
R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl; or the
pharmacologically acceptable salt thereof.
6. The compound of formula 1 according to claims 1; wherein R.sup.a
denotes phenyl or benzyl, in each case optionally substituted by
one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; or ##STR1328## R.sup.1 denotes methyl, ethyl, propyl,
butyl, CF.sub.3, CH.sub.2COOH, methoxy, F, Cl, Br, OH, CN,
COR.sup.1.1, OCF.sub.3, NO.sub.2 or SO.sub.2R.sup.1.1; R.sup.1.1
denotes OH, methyl, NH.sub.2, NHMe, NMe.sub.2, ##STR1329## R.sup.2
denotes methyl, methoxy, F, Cl or Br; R.sup.3 denotes a group
selected from among ##STR1330## wherein n denotes 0 or 1; m denotes
0 or 1; o denotes 2; R.sup.3.1 denotes a group selected from among
##STR1331## or a group selected from among ##STR1332## which may
optionally be substituted by one or more R.sup.3.1.1; R.sup.3.1.1
denotes methyl, ethyl, OH, CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2NEt.sub.2, COMe, COOH, CONH.sub.2, NH.sub.2, ##STR1333##
R.sup.3.2 denotes a group selected from among ##STR1334## which is
optionally substituted by one or more groups selected from among
methyl, ethyl, cyclopentyl, OH, NH.sub.2; or cyclohexyl, which is
optionally substituted by one or two R.sup.3.2.1 ##STR1335##
R.sup.3.2.1 denotes --NR.sup.3.2.1.1R.sup.3.2.1.2 or a group
selected from among or a group selected from among ##STR1336##
which is optionally substituted by one or more groups selected from
among methyl, SO.sub.2R.sup.3.2.1.1, ##STR1337## R.sup.3.2.1.1
denotes H, methyl or benzyl; R.sup.3.2.1.2 denotes H, methyl or
benzyl; or --C.sub.1-6-alkyl, straight-chain or branched, which is
optionally substituted by one or two R.sup.3.2.2; R.sup.3.2.2
denotes C.dbd.CH.sub.2, C.dbd.CH, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2, NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, CF.sub.3, CN, OH, SO.sub.2R.sup.3.2.2.1 or a
group selected from among ##STR1338## or a group selected from
among ##STR1339## which is optionally substituted by one or more
groups selected from among Cl, methyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2, OH; R.sup.3.2.2.1 denotes H or
methyl; R.sup.3.2.2.2 denotes H or methyl; or phenyl, which is
optionally substituted by one or two R.sup.3.2.3 R.sup.3.2.3
denotes a group selected from among ##STR1340## R.sup.3.3 denotes
H, methyl or ethyl; R.sup.b denotes R.sup.4, CH.sub.2OR.sup.4,
COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5, NH.sub.2, NHCOOR.sup.4,
NHCONR.sup.4R.sup.5 or OH; R.sup.4 denotes H, methyl, ethyl,
2-hydroxyethyl, propyl, C.ident.CH, CF.sub.3, phenyl, ##STR1341##
R.sup.5 denotes H, methyl or ethyl; R.sup.c denotes NHR.sup.6 or a
group selected from among ##STR1342## wherein B denotes a bond,
methylene, ethylene, propylene or butynylene; R.sup.6 denotes H,
phenyl, optionally substituted by SO.sub.2CH.sub.3; R.sup.7 denotes
H, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2 or a group selected
from among ##STR1343## R.sup.7.1 denotes H, methyl, ethyl,
(CH.sub.2).sub.2R.sup.7.1.1 or COObutyl; R.sup.7.2 denotes H,
methyl or ethyl; R.sup.7.1.1 denotes NMe.sub.2 or 1-imidazolyl or
the pharmacologically acceptable salt thereof.
7. The compound of formula 1 according to claim 1; wherein R.sup.c
denotes a group ##STR1344## wherein B denotes methylene, propylene;
R.sup.7 denotes H, NR.sup.7.1R.sup.7.2 or 1-imidazolyl; R.sup.7.1
denotes H or methyl; R.sup.7.2 denotes H or methyl; or the
pharmacologically acceptable salt thereof.
8. The compound of formula 1 according to claims 1; wherein R.sup.a
denotes phenyl, optionally substituted by one or more groups
selected from among R.sup.1, R.sup.2 and R.sup.3; or the
pharmacologically acceptable salt thereof.
9. The compound of formula 1 according to claim 1; wherein R.sup.a
denotes phenyl, optionally substituted by one or more groups
selected from among R.sup.1 and R.sup.3; R.sup.1 denotes methyl,
ethyl, propyl, CF.sub.3, methoxy, F, Cl or Br; R.sup.3 denotes a
group ##STR1345## or the pharmacologically acceptable salt
thereof.
10. The compound of formula 1 according to claim 1; wherein R.sup.a
denotes phenyl, optionally substituted by one or more groups
selected from among R.sup.1 and R.sup.3; R.sup.1 denotes methyl,
ethyl, propyl, CF.sub.3, methoxy, F, Cl or Br; R.sup.3 denotes a
group ##STR1346## or the pharmacologically acceptable salt
thereof.
11. A compound of formula 1.1 ##STR1347## wherein R.sup.a denotes
H, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2, OR.sup.8, SR.sup.11,
SOR.sup.11, SO.sub.2R.sup.11, NHCO--C.sub.1-6-alkyl-NH.sub.2, or a
group selected from among C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, C.sub.1-6-haloalkyl,
aryl, C.sub.7-11-aralkyl, spiro, het, hetaryl and CH.sub.2--O-aryl,
which may optionally be substituted; R.sup.8 denotes
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl,
optionally substituted by one or more halogens or C.sub.1-4-alkyl;
R.sup.9 denotes H, COOR.sup.12, CONR.sup.12 or C.sub.1-6-alkyl,
optionally substituted by one or more COOH,
N(CR.sub.16-alkyl).sub.2 or het, optionally substituted by one or
more C.sub.1-6-alkyl; or R.sup.9 denotes het, optionally
substituted by one or more C.sub.1-4-alkyl; R.sup.10 denotes H,
C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or C.sub.2-6-alkynyl; R.sup.11
denotes C.sub.1-6-alkyl, optionally substituted by one or more
N(C.sub.1-4-alkyl).sub.2; R.sup.b denotes R.sup.4, OR.sup.4,
--CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5,
NR.sup.4R.sup.5, NR.sup.5COR.sup.4, NR.sup.5COOR.sup.4,
NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; R.sup.4, R.sup.5 denote H,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH,
C.sub.2-6-alkenyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
C.sub.2-6-alkynyl, optionally substituted by
Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected from
among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur;
R.sup.c denotes NHR.sup.6 or a group selected from among
##STR1348## wherein B denotes a bond, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl; R.sup.6 denotes H or a
group selected from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl,
het, aryl, hetaryl optionally substituted by one or more groups
R.sup.6.1; R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); R.sup.7 denotes H, C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl,
NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2, hetaryl, het,
optionally substituted by C.sub.1-4-alkyl or CONH.sub.2; R.sup.7.1
denotes H, C.sub.1-6-alkyl, (CH.sub.2).sub.2-4R.sup.7.1.1 or
COObutyl; R.sup.7.2 denotes H, C.sub.1-6-alkyl, optionally
substituted by one or more OH; R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); R.sup.7.1.1.1 denotes H or C.sub.1-6-alkyl;
R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl; or a pharmacologically
acceptable salt thereof.
12. The compound of formula 1.1 according to claim 11; wherein
R.sup.a denotes phenyl, optionally substituted by one or more
groups selected from among R.sup.1, R.sup.2 and R.sup.3; or
##STR1349## R.sup.1 denotes methyl, ethyl, propyl, CF.sub.3,
CH.sub.2COOH, methoxy, F, Cl, Br, CN, COR.sup.1.1 or
SO.sub.2R.sup.1.1; R.sup.1.1 denotes OH, methyl, NH.sub.2, NHMe,
NMe.sub.2 or ##STR1350## R.sup.2 denotes methyl, F, Cl or Br;
R.sup.3 denotes a group selected from among ##STR1351## wherein n
denotes 0 or 1; m denotes 0 or 1; o denotes 2; R.sup.3.1 denotes a
group selected from among ##STR1352## or a group selected from
among ##STR1353## which may optionally be substituted by one or
more R.sup.3.1.1; R.sup.3.1.1 denotes methyl, OH, CH.sub.2OH,
CH.sub.2CH.sub.2OH, CH.sub.2NEt.sub.2, COMe, COOH, CONH.sub.2,
##STR1354## R.sup.3.2 denotes a group selected from among
##STR1355## which is optionally substituted by one or more groups
selected from among methyl, ethyl, cyclopentyl, OH, NH.sub.2; or
cyclohexyl, which is optionally substituted by one or two
R.sup.3.2.1 R.sup.3.2.1 denotes --NR.sup.3.2.1.1R.sup.3.2.1.2 or a
group selected from among ##STR1356## or a group selected from
among ##STR1357## which is optionally substituted by one or more
methyl groups R.sup.3.2.1.1 denotes H or methyl; R.sup.3.2.1.2
denotes H or methyl; or --C.sub.1-6-alkyl, straight-chain or
branched, which is optionally substituted by one or two
R.sup.3.2.2; R.sup.3.2.2 denotes C.dbd.CH.sub.2, C.ident.CH,
COOR.sup.3.2.2.1, CONR.sup.3.2.2.1R.sup.3.2.2.2,
NR.sup.3.2.2.1R.sup.3.2.2.2, CN, OH or a group selected from among
##STR1358## or a group selected from among ##STR1359## which is
optionally substituted by one or more groups selected from among
methyl, CONR.sup.3.2.2.1R.sup.3.2.2.2 OH; R.sup.3.2.2.1 denotes H
or methyl; R.sup.3.2.2.2 denotes H or methyl; or phenyl, which is
optionally substituted by one or two R.sup.3.2.3 R.sup.3.2.3
denotes a group selected from among ##STR1360## R.sup.3.3 denotes
H, methyl or ethyl; R.sup.b denotes R.sup.4, CH.sub.2OCH.sub.3,
COR.sup.4, COOH, COOCH.sub.3 CONR.sup.4R.sup.5, NH.sub.2,
NHCOOR.sup.4 or OH; R.sup.4 denotes H, methyl, propyl, C.ident.CH,
phenyl, ##STR1361## R.sup.5 denotes H or methyl; R.sup.c denotes a
group ##STR1362## wherein B denotes methylene, propylene; R.sup.7
denotes H, NR.sup.7.1R.sup.7.2 or 1-imidazolyl; R.sup.7.1 denotes H
or methyl; R.sup.7.2 denotes H or methyl; or the pharmacologically
acceptable salt thereof.
13. A compound of formula 1.2 ##STR1363## wherein R.sup.a denotes
H, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2, OR.sup.8, SR.sup.11,
SOR.sup.11, SO.sub.2R.sup.11, NHCO--C.sub.1-6-alkyl-NH.sub.2, or a
group selected from among C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, C.sub.1-6-haloalkyl,
aryl, C.sub.7-11-aralkyl, spiro, het, hetaryl and CH.sub.2--O-aryl,
which may optionally be substituted; is R.sup.8 denotes
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl,
optionally substituted by one or more halogens or C.sub.1-4-alkyl;
R.sup.9 denotes H, COOR.sup.12, CONR.sup.12 or C.sub.1-6-alkyl,
optionally substituted by one or more COOH,
N(C.sub.1-6-alkyl).sub.2 or het, optionally substituted by one or
more C.sub.1-6-alkyl; or R.sup.9 denotes het, optionally
substituted by one or more C.sub.1-4-alkyl; R.sup.10 denotes H,
C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or C.sub.2-6-alkynyl; R.sup.11
denotes C.sub.1-6-alkyl, optionally substituted by one or more
N(C.sub.1-4-alkyl).sub.2; R.sup.b denotes R.sup.4, OR.sup.4,
--CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5,
NR.sup.4R.sup.5, NR.sup.5COR.sup.4, NR.sup.5COOR.sup.4,
NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; R.sup.4, R.sup.5 denote H,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH,
C.sub.2-6-alkenyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
C.sub.2-6-alkynyl, optionally substituted by
Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected from
among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur;
R.sup.c denotes NHR.sup.6 or a group selected from among
##STR1364## wherein B denotes a bond, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl; R.sup.6 denotes H or a
group selected from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl,
het, aryl, hetaryl optionally substituted by one or more groups
R.sup.6.1; R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); R.sup.7 denotes H, C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl,
NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2, hetaryl, het,
optionally substituted by C.sub.1-4-alkyl or CONH.sub.2; R.sup.7.1
denotes H, C.sub.1-6-alkyl, (CH.sub.2).sub.2-4R.sup.7.1.1 or
COObutyl; R.sup.7.2 denotes H, C.sub.1-6-alkyl, optionally
substituted by one or more OH; R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); R.sup.7.1.1.1 denotes H or C.sub.1-6-alkyl;
R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl; or a pharmacologically
acceptable salt thereof
14. The compound of formula 1.2 according to claim 13; wherein
R.sup.a denotes phenyl, optionally substituted by one or more
groups selected from among R.sup.1 and R.sup.2; R.sup.1 denotes
methyl, ethyl, propyl, CF.sub.3, F, Cl, COR.sup.1.1 or
SO.sub.2R.sup.1.1; R.sup.1.1 denotes methyl; R.sup.2 denotes
methyl, F or Cl; R.sup.b denotes R.sup.4; R.sup.4 denotes H;
R.sup.c denotes NHR.sup.6 or a group ##STR1365## wherein B denotes
a bond, methylene, ethylene or propylene; R.sup.6 denotes H;
R.sup.7 denotes H or NR.sup.7.1R.sup.7.2, ##STR1366## R.sup.7.1
denotes H, methyl, ethyl, (CH.sub.2).sub.2R.sup.7.1.1 or COObutyl;
R.sup.7.2 denotes H, methyl or ethyl; R.sup.7.1.1 denotes NMe.sub.2
or 1-imidazolyl or the pharmacologically acceptable salt
thereof.
15. A compound of formula 1.3 ##STR1367## wherein R.sup.a denotes
H, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2, OR.sup.8, SR.sup.11,
SOR.sup.11, SO.sub.2R.sup.11, NHCO--C.sub.1-6-alkyl-NH.sub.2, or a
group selected from among C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, C.sub.1-6-haloalkyl,
aryl, C.sub.7-11-aralkyl, spiro, het, hetaryl and CH.sub.2--O-aryl,
which may optionally be substituted; R.sup.8 denotes
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl,
optionally substituted by one or more halogens or C.sub.1-4-alkyl;
R.sup.9 denotes H, COOR.sup.12, CONR.sup.12 or C.sub.1-6-alkyl,
optionally substituted by one or more COOH,
N(C.sub.1-6-alkyl).sub.2 or het, optionally substituted by one or
more C.sub.1-6-alkyl; or R.sup.9 denotes het, optionally
substituted by one or more C.sub.1-4-alkyl; R.sup.10 denotes H,
C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or C.sub.2-6-alkynyl; R.sup.11
denotes C.sub.1-6-alkyl, optionally substituted by one or more
N(C.sub.1-4-alkyl).sub.2; R.sup.b denotes R.sup.4, OR.sup.4,
--CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5,
NR.sup.4R.sup.5, NR.sup.5COR.sup.4, NR.sup.5COOR.sup.4,
NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; R.sup.4, R.sup.5 denote H,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH,
C.sub.2-6-alkenyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
C.sub.2-6-alkynyl, optionally substituted by
Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected from
among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur;
R.sup.c denotes NHR.sup.6 or a group selected from among
##STR1368## wherein B denotes a bond, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl; R.sup.6 denotes H or a
group selected from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl,
het, aryl, hetaryl optionally substituted by one or more groups
R.sup.6.1; R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); R.sup.7 denotes H, C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl,
NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2, hetaryl, het,
optionally substituted by C.sub.1-4-alkyl or CONH.sub.2; R.sup.7.1
denotes H, C.sub.1-6-alkyl, (CH.sub.2).sub.2-4R.sup.7.1.1 or
COObutyl; R.sup.7.2 denotes H, C.sub.1-6-alkyl, optionally
substituted by one or more OH; R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); R.sup.7.1.1.1 denotes H or C.sub.1-6-alkyl;
R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl; or a pharmacologically
acceptable salt thereof.
16. The compound of formula 1.3 according to one of claim 15;
wherein R.sup.a denotes phenyl, optionally substituted by one or
more groups selected from among R.sup.1 and R.sup.2; or ##STR1369##
R.sup.1 denotes methyl, methoxy, Cl, OH or COR.sup.1.1; R.sup.1.1
denotes NH.sub.2, NHMe or NMe.sub.2; R.sup.2 denotes methoxy or Cl;
R.sup.b denotes R.sup.4 or OH; R.sup.4 denotes H; R.sup.c denotes
NHR.sup.6 or a group ##STR1370## wherein B denotes a bond,
methylene, ethylene or propylene; R.sup.6 denotes H; R.sup.7
denotes H, NR.sup.7.1R.sup.7.2 or a group selected from among
##STR1371## R.sup.7.1 denotes H, methyl or
(CH.sub.2).sub.2R.sup.7.1.1; R.sup.7.2 denotes H, methyl or ethyl;
R.sup.7.1.1 denotes NMe.sub.2; or the pharmacologically acceptable
salt thereof.
17. A compound of formula 1.4 ##STR1372## wherein R.sup.a denotes
H, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2, OR.sup.8, SR.sup.11,
SOR.sup.11, SO.sub.2R.sup.11, NHCO--C.sub.1-6-alkyl-NH.sub.2, or a
group selected from among C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, C.sub.1-6-haloalkyl,
aryl, C.sub.7-11-aralkyl, spiro, het, hetaryl and CH.sub.2--O-aryl,
which may optionally be substituted; R.sup.8 denotes
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl,
optionally substituted by one or more halogens or C.sub.1-4-alkyl;
R.sup.9 denotes H, COOR.sup.12, CONR.sup.12 or C.sub.1-6-alkyl,
optionally substituted by one or more COOH,
N(C.sub.1-6-alkyl).sub.2 or het, optionally substituted by one or
more C.sub.1-6-alkyl; or R.sup.9 denotes het, optionally
substituted by one or more C.sub.1-4-alkyl; R.sup.10 denotes H,
C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or C.sub.2-6-alkynyl; R.sup.11
denotes C.sub.1-6-alkyl, optionally substituted by one or more
N(C.sub.1-4-alkyl).sub.2; R.sup.b denotes R.sup.4, OR.sup.4,
--CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5,
NR.sup.4R.sup.5, NR.sup.5COR.sup.4, NR.sup.5COOR.sup.4,
NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; R.sup.4, R.sup.5 denote H,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH,
C.sub.2-6-alkenyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
C.sub.2-6-alkynyl, optionally substituted by
Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected from
among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur;
R.sup.c denotes NHR.sup.6 or a group selected from among
##STR1373## wherein B denotes a bond, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl; R.sup.6 denotes H or a
group selected from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl,
het, aryl, hetaryl optionally substituted by one or more groups
R.sup.6.1; R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); R.sup.7 denotes H, C.sub.1-4-alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl,
NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2, hetaryl, het,
optionally substituted by C.sub.1-4-alkyl or CONH.sub.2; R.sup.7.1
denotes H, C.sub.1-6-alkyl, (CH.sub.2).sub.2-4R.sup.7.1.1 or
COObutyl; R.sup.7.2 denotes H, C.sub.1-6-alkyl, optionally
substituted by one or more OH; R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); R.sup.7.1.1.1 denotes H or C.sub.1-6-alkyl;
R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl; or a pharmacologically
acceptable salt thereof.
18. The compound of formula 1.4 according to claim 17; wherein
R.sup.a denotes phenyl, optionally substituted by one or more
groups selected from among R.sup.1 and R.sup.3; or R.sup.1 denotes
methyl, F, Cl or Br; R.sup.3 denotes a group selected from among
##STR1374## wherein m denotes 0; R.sup.3.2 denotes a group
##STR1375## which is optionally substituted by a group selected
from among methyl and cyclopentyl; cyclohexyl, which is optionally
substituted by a R.sup.3.2.1 R.sup.3.2.1 denotes a group
##STR1376## R.sup.3.3 denotes H; R.sup.b denotes R.sup.4; R.sup.4
denotes a group selected from among ##STR1377## R.sup.c denotes a
group ##STR1378## wherein B denotes methylene; R.sup.7 denotes H;
or the pharmacologically acceptable salt thereof.
19. The compound of formula 1 according to claim 1; wherein R.sup.a
denotes H, C.sub.1-6-alklyl, C.sub.2-6-alkenyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, CF.sub.3, COR.sup.8,
NR.sup.9R.sup.10, NO.sub.2, S(O).sub.nR.sup.11, spiro,
NHCO--C.sub.1-6-alkyl-NH.sub.2 or a group selected from among
C.sub.7-11-aralkyl and CH.sub.2O-aryl, which may optionally be
substituted by one or more Cl; or a group selected from among het,
which may optionally be substituted by one or more C.sub.1-4-alkyl,
COCF.sub.3, CH.sub.2NH.sub.2 or CH.sub.2NHCOOR.sup.12; R.sup.8
denotes C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl,
aryl, optionally substituted by one or more chlorine; R.sup.9
denotes H, COOR.sup.12 or het, optionally substituted by one or
more C.sub.1-4-alkyl, or a group selected from among
C.sub.1-4-alkyl, which may optionally be substituted by one or more
COOH, N(C.sub.1-4-alkyl).sub.2 or 4-methylpiperazine; R.sup.10
denotes H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl or COCH.sub.3;
R.sup.11 denotes C.sub.1-4-alkyl, optionally substituted by one or
more N(C.sub.1-4-alkyl).sub.2, R.sup.12 denotes C.sub.1-4-alkyl; n
denotes 0 or 2; R.sup.b denotes H, OH or COOEt; R.sup.c denotes
NH.sub.2 or NHCOR.sup.13; R.sup.13 denotes C.sub.1-4-alkyl, or
NR.sup.13.1R.sup.13.2, R.sup.13.1 denotes H or C.sub.1-4-alkyl;
R.sup.13.2 denotes H or C.sub.1-4-alkyl; or the pharmacologically
acceptable salt thereof.
20. The compound of formula 1 according to claim 19; wherein
R.sup.a denotes H, methyl, ethyl, propyl, butyl, 3-methyl-butyl,
propenyl, cyclopropyl, cyclohexyl, CF.sub.3, COR.sup.8,
NR.sup.9R.sup.10, NO.sub.2, S(O).sub.nR.sup.11, or a group selected
from among ##STR1379## or a group selected from among ##STR1380##
which may optionally be substituted by one or more Cl; or a group
selected from among ##STR1381## which may optionally be substituted
by one or more CH.sub.3, COCF.sub.3, CH.sub.2NH.sub.2 or
CH.sub.2NHCOOR.sup.12; R.sup.8 denotes methyl, propyl, cyclopropyl,
NH.sub.2, furanyl or phenyl, optionally substituted by one or more
chlorine; R.sup.9 denotes H, COOR.sup.12 or piperidino, optionally
substituted by one or more CH.sub.3, or a group selected from among
methyl, ethyl and propyl, which may optionally be substituted by
one or more COOH, NMe.sub.2 or 4-methylpiperazine; R.sup.10 denotes
H, methyl, COCH.sub.3, C.ident.CH or CH.sub.2C.ident.CH; R.sup.11
denotes ethyl or propyl, optionally substituted by one or more
NMe.sub.2, R.sup.12 denotes butyl R.sup.b denotes H, OH or COOEt;
R.sup.c denotes NH.sub.2 or NHCOR.sup.13; R.sup.13 denotes methyl
or NR.sup.13; R.sup.13.1 denotes H or methyl; R.sup.13.2 denotes H
or methyl. or the pharmacologically acceptable salt thereof.
21. A pharmaceutical composition of matter comprising a compound
according to claim 1 and one or more pharmaceutically acceptable
excipients or carriers.
22. A method of treating a warm blooded animal for a disease whose
pathology involves an activity of PI3-kinases, which comprises
administering to the animal a therapeutically effective amount of a
compound according to claim 1.
23. The method according to claim 22, characterised in that the
disease is selected from inflammatory and allergic diseases of the
airways.
24. The method according to claim 23, characterised in that the
disease is selected from among chronic bronchitis, acute
bronchitis, bronchitis caused by bacterial or viral infection or
fungi or helminths, allergic bronchitis, toxic bronchitis, chronic
obstructive bronchitis (COPD), asthma (intrinsic or allergic),
paediatric asthma, bronchiectasis, allergic alveolitis, allergic or
non-allergic rhinitis, chronic sinusitis, cystic fibrosis or
mucoviscidosis, alpha-1-antitrypsin deficiency, cough, pulmonary
emphysema, interstitial lung diseases, alveolitis, hyperreactive
airways, nasal polyps, pulmonary oedema, pneumonitis of different
origins, e.g. radiation-induced or caused by aspiration, or
infectious pneumonitis, collagenoses such as lupus eryth, systemic
sclerodermy, sarcoidosis and Boeck's disease.
25. The method according to claim 22, characterised in that the
disease relates to inflammatory and allergic diseases of the
skin.
26. The method according to claim 22, characterised in that the
disease is selected from among psoriasis, contact dermatitis,
atopic dermatitis, alopecia greata (circular hair loss), erythema
exsudativum multiforme (Stevens-Johnson Syndrome), dermatitis
herpetiformis, sclerodermy, vitiligo, nettle rash (urticaria),
lupus erythematodes, follicular and surface pyodermy, endogenous
and exogenous acne, acne rosacea and other inflammatory and
allergic or proliferative skin diseases.
27. The method according to claim 22, characterised in that the
disease relates to inflammation of the eye.
28. The method according to claim 27, characterised in that it
relates to a disease selected from among inflammation of the
conjunctiva (conjunctivitis) of various kinds, such as e.g. caused
by infection with fungi or bacteria, allergic conjunctivitis,
irritable conjunctivitis, drug-induced conjunctivitis, keratitis
and uveitis.
29. The method according to claim 22, characterised in that the
disease relates to diseases of the nasal mucosa.
30. The method according to claim 29, characterised in that the
disease is selected from among allergic rhinitis, allergic
sinusitis and nasal polyps.
31. The method according to claim 22, characterised in that the
disease relates to inflammatory or allergic conditions involving
autoimmune reactions.
32. The method according to claim 31, characterised in that the
disease is selected from among Crohn's disease, ulcerative colitis,
systemic lupus erythematodes, chronic hepatitis, multiple
sclerosis, rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, and rheumatoid spondylitis.
33. The method according to claim 22, characterised in that the
disease relates to kidney inflammations.
34. The method according to claim 33, characterised in that the
disease is selected from among glomerulonephritis, interstitial
nephritis and idiopathic nephrotic syndrome.
Description
TECHNICAL FIELD
[0001] Phosphatidylinositol-3-kinases (PI3-kinases) are a subfamily
of the lipid kinases which catalyse the transfer of a phosphate
group to the 3'-position of the inositol ring of phosphoinositides
(Vanhaesebroeck and Waterfield, Exp Cell Res. 1999 Nov. 25;
253(1):239-54).
[0002] They have an important role in numerous cell processes such
as e.g. cell growth and differentiation processes, the control of
cytoskeletal changes and the regulation of intracellular transport
processes (Vanhaesebroeck et al., Annu Rev Biochem. 2001;
70:535-602). In view of their in vitro specificity for particular
phosphoinositide substrates the PI3-kinases may be divided into
various classes. The members of the receptor-regulated class I are
heterodimeric enzymes which are made up of a catalytic subunit
(p110) weighing 110-120 kDa and a non-catalytic subunit (p50, p55,
p85, p101) weighing 50-101 kDa. The most highly conserved region in
all the PI3-kinases is the C-terminally situated kinase domain. It
has structural features which can also be found in the majority of
known protein kinases. These also include e.g. highly conserved
amino acids which are responsible for the coordination of the ATP
molecule (Walker et al., Nature. 1999 Nov. 18;
402(6759):313-20).
[0003] Three of the four members of the class I PI3-kinases
associate constitutively with an adaptor subunit weighing 50-85
kDa, of which p85 is the prototype. The interaction takes place via
the so-called p85 binding domain which can be found on the
catalytic subunits of the PI3-kinase .alpha., .beta. and .delta..
The three forms are grouped in class IA on account of this
structural feature. The catalytic subunit .gamma. of the
PI3-kinase, p110.gamma., associates instead with a regulatory
protein weighing 101 kDa, which is known as p101. It constitutes
Class IB of the PI3-kinases--of which it is currently the sole
member. This structural division into class IA and IB also shows
parallels in the functional properties of the corresponding
PI3-kinase isoforms (Vanhaesebroeck and Waterfield, Exp Cell Res.
1999 Nov. 25; 253(1):239-54)
[0004] Thus, the PI3-kinase .alpha., .beta. and .delta. are
activated predominantly by receptor-tyrosine-kinases (RTKs) or
soluble tyrosine kinases. The p85-subunit serves as an adaptor, as
it is able to recognise and bind the phosphorylated tyrosine groups
of specific amino acid sequences (YxxM) with its SH2 domains. The
PI3K.gamma. on the other hand is activated mainly by
G.beta..gamma.-subunits which are released from heterotrimeric
G-proteins after activation of heptahelical receptors. This
differing coupling to cell surface receptors combined with a more
or less restrictive expression necessarily results in very
different tasks and functions for the 4 class I PI3-kinases in the
intact organism (Wymann et al., Trends Pharmacol Sci. 2003 July;
24(7):366-76).
[0005] A number of independent findings would appear to indicate
that class IA PI3-kinases are involved in uncontrolled cell growth
and differentiation processes. Thus, the first detected PI3-kinase
activity was associated with the transforming activity of viral
oncogenes, such as e.g. the middle T antigen of polyomaviruses, Src
tyrosine kinases or activated growth factors (Workman, Biochem Soc
Trans. 2004 April; 32(Pt 2):393-6). In many tumours, such as e.g.
breast cancer, ovarian or pancreatic carcinoma, there is found to
be an overactivity of Akt/PKB, which is activated directly by the
lipid products of class I PI3-kinases and thus transmits the
signals on into the cell. Moreover, it was found just recently that
the PIK3CA-gene which codes for p110.alpha. has a high mutation
frequency in various types of tumour, such as colon, breast or lung
carcinomas, some examples of which were able to be characterised as
activating mutations (Samuels et al., Science. 2004 Apr. 23;
304(5670):554).
[0006] The most recent member of the class IA PI3-kinases,
PI3K.delta., is expressed more restrictively than PI3K.alpha. and
.beta.. In so-called "knock-in" mice in which the catalytic subunit
of PI3K.delta., p110.delta., had been replaced by an inactive
mutant, it was demonstrated that this PI3K-isoenzyme plays a
specific part in the signal transmission of B- and T-lymphocytes
after antigen receptor stimulation (Okkenhaug et al., Science. 2002
August; 297(5583):1031-4). These are mechanisms which play a part
especially in autoimmune diseases such as e.g. Crohn's disease or
rheumatoid arthritis.
[0007] The PI3K.gamma. is activated almost exclusively by
G.sub.i-coupling heptahelical receptors. Thus, in neutrophils in
mice which express no PI3K.gamma., no PI3,4,5-P.sub.3 formation was
observed if they were stimulated with IL-8, fMLP, LTB.sub.4 or C5a
(Hirsch et al., Science. 2000 Feb. 11; 287(5455):1049-53). This
shows that at least in this type of cell PI3K.gamma. is the only
PI3-kinase isoform which binds to these heptahelical receptors.
Moreover, isolated neutrophils and macrophages from the
PI3K.gamma.-deficient mice exhibited a sharply reduced chemotactic
activity or production of oxygen radicals compared with a whole
series of chemokines and chemoattractors. Also reduced was the
IgE-mediated activation of mast cells which had been isolated from
p110.gamma.-deficient mice. There has been some discussion that the
mechanism responsible might be a positive feedback mechanism in
which the PI3K.gamma. is activated by G.sub.i-coupling adenosine
A.sub.3 receptors (Laffargue et al., Immunity. 2002 March;
16(3):441-51). In spite of this decreased ability to react to
inflammation mediators, the p110.gamma.-deficient mice have normal
viability and reproductive powers and have the same life expectancy
as wild-type comparison animals reared identically. From this it
can be concluded that the class IB PI3K.gamma. plays a central role
in the activation of various inflammatory cells, and therefore
isoform-specific inhibitors represent an attractive possibility for
anti-inflammatory therapy with comparatively minor side effects
(Ward and Finan, Curr Opin Pharmacol. 2003 August; 3(4):426-34).
Apart from its function in leukocytes PI3K.gamma. also appears to
be involved in the cardiovascular system, despite its low
expression in cardiomyocytes. Thus, p110.gamma.-deficient mice
exhibited an increase in cardiac muscle contractility which may
presumably be explained by an overproduction of cAMP (Crackower et
al., Cell. 2002 Sep. 20; 110(6):737-49). It has only recently been
possible to demonstrate that PI3K.gamma. is also involved in the
development of cardiac hypertrophy. Thus, p110.gamma.-deficient
mice exhibited significantly reduced hypertrophy and fibrosis
compared with wild-type animals in an isoproterenol-induced cardiac
insufficiency model (Oudit et al., Circulation. 2003 Oct. 28;
108(17):2147-52).
[0008] The problem of the present invention was to provide new
compounds which by virtue of their pharmaceutical efficacy as
PI3-kinase modulators may be used in the therapeutic field for the
treatment of inflammatory or allergic diseases. Examples which may
be mentioned here include inflammatory and allergic respiratory
complaints, inflammatory diseases of the gastrointestinal tract,
rheumatoid arthritis, inflammatory and allergic skin diseases,
inflammatory eye diseases, diseases of the nasal mucosa,
inflammatory or allergic conditions involving autoimmune reactions,
or inflammation of the kidneys.
PRIOR ART
[0009] PI3-kinase inhibitors for the treatment of inflammatory
diseases are known in the literature. Thus, WO 03/072557 discloses
5-phenylthiazole derivatives, WO 04/029055 discloses annelated
azolepyrimidines and WO 04/007491 discloses azolidinone-vinyl
linked benzene derivatives. Moreover, the two specifications WO
04/052373 and WO 04/056820 disclose benzoxazine into
benzoxazin-3-one derivatives.
DETAILED DESCRIPTION OF THE INVENTION
[0010] Surprisingly it has been found that the above-mentioned
problems are solved by compounds of formula 1. Accordingly, the
present invention relates to compounds of formula 1, ##STR2## with
the proviso that the circular line designated A denotes an aromatic
system; wherein [0011] Y denotes carbon, nitrogen atom, sulphur;
preferably carbon, nitrogen; [0012] z denotes carbon, nitrogen
atom, sulphur; preferably carbon, nitrogen; [0013] j denotes 1, 2
or 3; [0014] k denotes 0 or 1; [0015] R.sup.a denotes H, COR.sup.8,
NR.sup.9R.sup.10, NO.sub.2, OR.sup.8, SR.sup.11, SOR.sup.11,
SO.sub.2R.sup.11, NHCO--C.sub.1-6-alkyl-NH.sub.2, or a group
selected from among C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, C.sub.1-6-Haloalkyl,
aryl, C.sub.7-11-aralkyl, Spiro, het, heteroaryl and
CH.sub.2--O-aryl, which may optionally be substituted; [0016]
R.sup.8 denotes C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2,
hetaryl or aryl, optionally substituted by one or more halogens or
C.sub.1-4-alkyl; [0017] R.sup.9 denotes H, COOR.sup.12, CONR.sup.12
or C.sub.1-alkyl, optionally substituted by one or more COOH,
N(C.sub.1-6-alkyl).sub.2 or het, optionally substituted by one or
more C.sub.1-6-alkyl; or R.sup.9 denotes het, optionally
substituted by one or more C.sub.1-4-alkyl; [0018] R.sup.10 denotes
H, C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or C.sub.2-4-alkynyl;
[0019] R.sup.11 denotes C.sub.1-6-alkyl, optionally substituted by
one or more N(C.sub.1-4-alkyl).sub.2; [0020] R.sup.b denotes
R.sup.4, OR.sup.4, --CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NR.sup.4R.sup.5, NR.sup.5COR.sup.4,
NR.sup.5COOR.sup.4, NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; [0021] R.sup.4, R.sup.5 denote H,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH,
C.sub.2-6-alkenyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
C.sub.2-6-alkynyl, optionally substituted by
Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected from
among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur;
R.sup.c denotes NHR.sup.6 or a group selected from among ##STR3##
wherein [0022] B denotes a bond, C.sub.1-6-alkyl, C.sub.2-6-alkenyl
or C.sub.2-6-alkynyl; [0023] R.sup.6 denotes H or a group selected
from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
Cm-cycloalkyl, C.sub.3-6-cycloalkenyl, het, aryl, hetaryl
optionally substituted by one or more groups R.sup.6.1; [0024]
R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); [0025] R.sup.7 denotes H,
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2,
hetaryl, het, optionally substituted by C.sub.1-4-alkyl or
CONH.sub.2; [0026] R.sup.7.1 denotes H, C.sub.1-6alkyl,
(CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl; [0027] R.sup.7.2 denotes
H, C.sub.1-6alkyl, optionally substituted by one or more OH; [0028]
R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2, het or
1-imidazolyl, 2-(N-ethylpyrrolidine); [0029] R.sup.7.1.1.1 denotes
H or C.sub.1-6alkyl; [0030] R.sup.7.1.1.2 denotes H or
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof, with the proviso that R.sup.a cannot be H or Me if
Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0031] Preferred compounds of formula 1 mentioned above are those
wherein [0032] R.sup.a denotes a group selected from among aryl,
C.sub.7-11-aralkyl and heteroaryl, which may optionally be
substituted by one or more groups selected from among R.sup.1,
R.sup.2 and R.sup.3; [0033] R.sup.1 and R.sup.2 independently of
one another denote C.sub.1-6-alkyl, C.sub.2-6-alkenyl
C.sub.2-4-alkynyl, C.sub.3-4-cycloalkyl, C.sub.3-4-cycloalkenyl,
C.sub.1-6-haloalkyl, C.sub.1-6alkylene-COOH, C.sub.1-6alkoxy,
halogen, OH, CN, COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or
SR.sup.1.1, SOR.sup.1.1, SO.sub.2R.sup.1.1, het or hetaryl, [0034]
R.sup.1.1 denotes OH, C.sub.1-6alkyl, C.sub.2-4-alkenyl
C.sub.2-4-alkynyl, NR.sup.1.1.1R.sup.1.1.2 [0035] R.sup.1.1.1
denotes H, C.sub.1-6-alkyl, optionally substituted by a group
selected from among NH.sub.2, NHMe, NMe.sub.2; [0036] R.sup.1.1.2
denotes H, C.sub.1-6-alkyl; [0037] or R.sup.1.1.1 and R.sup.1.1.2
together form a five- or six-membered heterocyclic ring, which may
optionally be substituted by a group selected from among methyl,
ethyl, propyl; [0038] R.sup.3 denotes a group selected from among
##STR4## [0039] wherein [0040] X denotes a bond or
C.sub.1-4-alkylene; [0041] X' denotes C.sub.1-4-alkylene,
C.sub.2-4-alkenylene or C.sub.1-4-alkynylene [0042] R.sup.3a
denotes a group, which may be identical or different, selected from
among R.sup.3.1, R.sup.3.2 and R.sup.3.3; [0043] R.sup.3.1 denotes
spiro or het, while het may optionally be substituted by one or
more [0044] R.sup.3.1.1 denotes C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
OH, C.sub.1-4-alkylene-OH,
C.sub.1-4-alkylene-NR.sup.3.1.1.1R.sup.3.1.1.2 COR.sup.3.1.1.1,
COOR.sup.3.1.1.1, CONR.sup.3.1.1.1R.sup.3.1.1.2,
NR.sup.3.1.1.1R.sup.3.1.1.2, het, hetaryl, NHCOR.sup.3.1.1.1 [0045]
R.sup.3.1.1.1 denotes a group selected from among H,
C.sub.1-4-alkyl, aryl and C.sub.7-11-aralkyl; optionally
substituted by a group selected from among halogen, OH and CN;
[0046] R.sup.3.1.1.2 denotes H, C.sub.1-4-alkyl; [0047] R.sup.3.2
denotes a group selected from among C.sub.3-6-cycloalkyl, het,
hetaryl and spiro which is optionally substituted by one or more
R.sup.3.2.1 [0048] R.sup.3.2.1 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, OH, NR.sup.3.2.1.1R.sup.3.2.1.2,
NHCOR.sup.3.2.1.3 or het, optionally substituted by one or more
groups selected from among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; [0049] R.sup.3.2.1.1
denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl; [0050]
R.sup.3.2.1.2 denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl;
[0051] R.sup.3.2.1.3 denotes aryl, C.sub.7-11-aralkyl; or [0052]
C.sub.1-6-alkyl, which is optionally substituted by one or two
R.sup.3.2.2, [0053] R.sup.3.2.2 denotes C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2, NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, C.sub.1-haloalkyl, CN, OR.sup.3.2.2.1,
SO.sub.2R.sup.3.2.2.1, C.sub.3-cycloalkyl, CO-het,
C.sub.2-4-alkynyl-hetaryl, guanidine or a group selected from among
het, hetaryl and aryl, which is optionally substituted by one or
more groups selected from among halogen, C.sub.1-6-alkyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2 OH, imidazolidinone; [0054]
R.sup.3.2.2.1 denotes H or C.sub.1-6-alkyl, aryl,
C.sub.7-11-aralkyl [0055] R.sup.3.2.2.2 denotes H or
C.sub.1-6-alkyl; or [0056] aryl, which is optionally substituted by
one or two R.sup.3.2.3 [0057] R.sup.3.2.3 denotes a group selected
from among NH--C.sub.1-6-alkyl-N(C.sub.1-6-alkyl).sub.2 or het,
while het may optionally be substituted by a C.sub.1-6-alkyl group;
[0058] R.sup.3.3 denotes H or a group selected from among
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.1-6-haloalkyl and aryl, which may optionally be substituted
by one or more groups R.sup.3.3.1; [0059] R.sup.3.3.1 denotes
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2,
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, optionally substituted by one or more groups selected from
among C.sub.1-4-alkyl, SO.sub.2H, SO.sub.2--C.sub.1-4-alkyl,
SO.sub.2C.sub.7-11-aralkyl, CH.sub.2--C.sub.3-6-cycloalkyl and
aryl; [0060] R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 denote
a group selected from among C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.7-1 .sub.1-aralkyl,
C.sub.2-4-alkenyl-aryl, C.sub.2-4-alkynyl-aryl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-4-alkenyl-hetaryl,
C.sub.2-4-alkynyl-hetaryl, COC.sub.1-4-alkyl-hetaryl,
COC.sub.2-4-alkenyl-hetaryl, COC.sub.2-4-alkynyl-hetaryl; or [0061]
two of the groups R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3
together form a ring, consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur; [0062]
R.sup.a denotes H, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, C.sub.1-6-haloalkyl,
COR.sup.8, NR.sup.9R.sup.10, NO.sub.2, OR.sup.8, SR.sup.11,
SOR.sup.11, SO.sub.2R.sup.11, NHCO--C.sub.1-6-alkyl-NH.sub.2, spiro
or a group selected from among C.sub.7-11-aralkyl, CH.sub.2--O-aryl
and het which may optionally be substituted by one or more
halogens, C.sub.1-6-alkyl, CO--C.sub.1-4-haloalkyl,
C.sub.1-4-alkyl-NH.sub.2 or CH.sub.2NHCOOR.sup.12; [0063] R.sup.8
denotes C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or
aryl, optionally substituted by one or more halogens or
C.sub.1-4-alkyl; [0064] R.sup.9 denotes H, COOR.sup.12, CONR.sup.12
or C.sub.1-6-alkyl, optionally substituted by one or more COOH,
N(C.sub.1-6-alkyl).sub.2 or het, optionally substituted by one or
more C.sub.1-6-alkyl; or R.sup.9 denotes het, optionally
substituted by one or more C.sub.1-4-alkyl; [0065] R.sup.10 denotes
H, C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or C.sub.2-6-alkynyl;
[0066] R.sup.11 denotes C.sub.1-6-alkyl, optionally substituted by
one or more N(C.sub.1-4-alkyl).sub.2; [0067] R.sup.12 denotes H,
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof, with the proviso that R.sup.a cannot be H or Me if
Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0068] Preferred compounds of formula 1 mentioned above are those
wherein [0069] R.sup.a denotes a group selected from among aryl,
C.sub.7-11-aralkyl and hetaryl, which may optionally be substituted
by one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; [0070] R.sup.1 and R.sup.2 independently of one another
denote C.sub.1-6-alkyl, C.sub.2-4-alkenyl C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, C.sub.1-6-haloalkyl,
C.sub.1-6alkylene-COOH, C.sub.1-6-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SR.sup.1.1,
SOR.sup.1.1, SO.sub.2R.sup.1.1, het or hetaryl, [0071] R.sup.1.1
denotes OH, C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
NR.sup.1.1.1R.sup.1.1.2 [0072] R.sup.1.1.1 denotes H,
C.sub.1-6-alkyl, optionally substituted by a group selected from
among NH.sub.2, NHMe, NMe.sub.2; [0073] R.sup.1.1.2 denotes H,
C.sub.1-6-alkyl; [0074] or R.sup.1.1.1 and R.sup.1.1.2 together
form a five- or six-membered heterocyclic ring, which may
optionally be substituted by a group selected from among methyl,
ethyl, propyl; [0075] R.sup.3 denotes a group selected from among
##STR5## [0076] wherein [0077] X denotes a bond or
C.sub.1-4-alkylene; [0078] R.sup.3a denotes a group, which may be
identical or different, selected from among R.sup.3.1, R.sup.3.2
and R.sup.3.3; [0079] R.sup.3.1 denotes spiro or het, while het may
optionally be substituted by one or more R.sup.3.1.1; [0080]
R.sup.3.1.1 denotes C.sub.1-6alkyl, C.sub.2-6-alkenyl, OH,
C.sub.1-4-alkylene-OH,
C.sub.1-4-alkylene-NR.sup.3.1.1.1R.sup.3.1.1.2, COR.sup.3.1.1.1,
COOR.sup.3.1.1.1, CONR.sup.3.1.1.1R.sup.3.1.1.2,
NR.sup.3.1.1.1R.sup.3.1.1.2, het, hetaryl, NHCOR.sup.3.1.1.1 [0081]
R.sup.3.1.1.1 denotes a group selected from among H,
C.sub.1-4-alkyl, aryl and C.sub.7-11-aralkyl; optionally
substituted by a group selected from among halogen, OH and CN;
[0082] R.sup.3.1.1.2 denotes H, C.sub.1-4-alkyl; [0083] R.sup.3.2
denotes a group selected from among C.sub.3-4-cycloalkyl, het,
hetaryl and spiro which is optionally substituted by one or more
R.sup.3.2.1 [0084] R.sup.3.2.1.1 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, OH, NR.sup.3.2.1.1R.sup.3.2.1.2,
NHCOR.sup.3.2.1.3 or het, optionally substituted by one or more
groups selected from among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
CH.sub.2--C.sub.3-6 cycloalkyl and aryl; [0085] R.sup.3.2.1.1
denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl; [0086]
R.sup.3.2.1.2 denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl;
[0087] R.sup.3.2.1.3 denotes aryl, C.sub.7-11-aralkyl; or [0088]
C.sub.1-6alkyl, which is optionally substituted by one or two
R.sup.3.2.2; [0089] R.sup.3.2.2 denotes C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2, NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, C.sub.1-6-haloalkyl, CN, OR.sup.3.2.2.1,
SO.sub.2R.sup.3.2.2.1, C.sub.3-1-cycloalkyl, CO-het,
C.sub.2-4-alkynyl-hetaryl, guanidine or a group selected from among
het, hetaryl and aryl, which is optionally substituted by one or
more groups selected from among halogen, C.sub.1-6-alkyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2, OH, imidazolidinone; [0090]
R.sup.3.2.2.1 denotes H or C.sub.1-6-alkyl, aryl,
C.sub.7-11-aralkyl [0091] R.sup.3.2.2.2 denotes H or
C.sub.1-6-alkyl; or [0092] aryl, which is optionally substituted by
one or two R.sup.3.2.3 [0093] R.sup.3.2.3 denotes a group selected
from among NH--C.sub.1-6-alkyl-N(C.sub.1-6-alkyl).sub.2 or het,
while het may optionally be substituted by a C.sub.1-6-alkyl group;
[0094] R.sup.3.3 denotes H or a group selected from among
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.1-6-haloalkyl and aryl, which may optionally be substituted
by one or more groups R.sup.3.3.1.1; [0095] R.sup.3.3.1 denotes
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, OR.sup.3.3.1.1,
N.sup.3.3.1.1R.sup.3.3.1.2, C.sup.3.3.1.1R.sup.3.3.1.2,
COOR.sup.3.3.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3 OH, CN, halogen or het,
optionally substituted by one or more groups selected from among
C.sub.1-4-alkyl, SO.sub.2H, SO.sub.2--C.sub.1-4-alkyl,
SO.sub.2C.sub.7-11-aralkyl, CH.sub.2--C.sub.3-6-cycloalkyl and
aryl; [0096] R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 denote
a group selected from among C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
COC.sub.1-4-alkyl-hetaryl, COC.sub.2-4-alkenyl-hetaryl,
COC.sub.2-4-alkynyl-hetaryl, or [0097] two of the groups
R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 together form a
ring, consisting of carbon atoms and optionally a heteroatom
selected from among oxygen, nitrogen and sulphur; [0098] R.sup.a
denotes H, C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl, C.sub.1-6-haloalkyl,
COR.sup.8, NR.sup.9R.sup.10, NO.sub.2, OR.sup.8, SR.sup.11,
SOR.sup.11, SO.sub.2R.sup.11, NHCO--C.sub.1-6-alkyl-NH.sub.2, spiro
or a group selected from among C.sub.7-11-aralkyl, CH.sub.2--O-aryl
and het which may optionally be substituted by one or more
halogens, C.sub.1-6-alkyl, CO--C.sub.1-4-haloalkyl,
ClA-alkyl-NH.sub.2 or CH.sub.2NHCOOR.sup.12; [0099] R.sup.8 denotes
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl,
optionally substituted by one or more halogens or C.sub.1-4-alkyl;
[0100] R.sup.9 denotes H, COOR.sup.12, CONR.sup.12 or
C.sub.1-6-alkyl, optionally substituted by one or more COOH,
N(C.sub.1-6-alkyl).sub.2 or het, optionally substituted by one or
more C.sub.1-6-alkyl; or R.sup.9 denotes het, optionally
substituted by one or more C.sub.1-4-alkyl; [0101] R.sup.10 denotes
H, C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or C.sub.2-6-alkynyl;
[0102] R.sup.11 denotes C.sub.1-6-alkyl, optionally substituted by
one or more N(C.sub.1-4-alkyl).sub.2; [0103] R.sup.12 denotes H,
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof, with the proviso that R.sup.a cannot be H or Me if
Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0104] Preferred compounds of formula 1 mentioned above are those
wherein [0105] R.sup.a denotes a group selected from among aryl,
C.sub.7-11-aralkyl and hetaryl, which may optionally be substituted
by one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; [0106] R.sup.1 and R.sup.2 independently of one another
denote C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkylene-COOH, C.sub.1-6-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SR.sup.1.1,
SOR.sup.1.1, SO.sub.2R.sup.1.1, het or hetaryl, [0107] R.sup.1.1
denotes OH, C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
NR.sup.1.1.1R.sup.1.1.2 [0108] R.sup.1.1.1 denotes H,
C.sub.1-6-alkyl, optionally substituted by a group selected from
among NH.sub.2, NHMe, NMe.sub.2; [0109] R.sup.1.1.2 denotes H,
C.sub.1-6-alkyl; [0110] or R.sup.1.1.1 and R.sup.1.1.2 together
form a five- or six-membered heterocyclic ring, which may
optionally be substituted by a group selected from among methyl,
ethyl, propyl; [0111] R.sup.3 denotes a group selected from among
##STR6## [0112] wherein [0113] X denotes a bond or
C.sub.1-4-alkylene; [0114] R.sup.3a denotes a group, which may be
identical or different, selected from among R.sup.3.1, R.sup.3.2
and R.sup.3.3; [0115] R.sup.3.1 denotes spiro or het, while het may
optionally be substituted by one or more R.sup.3.1.1; [0116]
R.sup.3.1.1 denotes C.sub.1-6alkyl, C.sub.2-6-alkenyl, OH,
C.sub.1-4-alkylene-OH,
C.sub.1-4-alkylene-NR.sup.3.1.1.1R.sup.3.1.1.2, COR.sup.3.1.1.1,
COOR.sup.3.1.1.1, CONR.sup.3.1.1.1R.sup.3.1.1.2,
NR.sup.3.1.1.1R.sup.3.1.1.2, het, hetaryl, NHCOR.sup.3.1.1.1 [0117]
R.sup.3.1.1.1 denotes a group selected from among H,
C.sub.1-4-alkyl, aryl and C.sub.7-11-aralkyl; optionally
substituted by a group selected from among halogen, OH and CN;
[0118] R.sup.3.1.1.2 denotes H, C.sub.1-4-alkyl; [0119] R.sup.3.2
denotes a group selected from among C.sub.3-6-cycloalkyl, het,
hetaryl and spiro which is optionally substituted by one or more
R.sup.3.2.1 [0120] R.sup.3.2.1 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, OH, --NR.sup.3.2.1.1R.sup.3.2.1.2,
NHCOR.sup.3.2.1.3 or het, optionally substituted by one or more
groups selected from among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
CH.sub.2--C.sub.3-6 cycloalkyl and aryl; [0121] R.sup.3.2.1.1
denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl; [0122]
R.sup.3.2.1.2 denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl;
[0123] R.sup.3.2.1.3 denotes aryl, C.sub.7-11-aralkyl; or [0124]
--C.sub.1-6-alkyl, which is optionally substituted by one or two
R.sup.3.2.2; [0125] R.sup.3.2.2 denotes C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2 NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, C.sub.1-6-haloalkyl, CN, OR.sup.3.2.2.1,
SO.sub.2R.sup.3.2.2.1, C.sub.3-6-cycloalkyl, CO-het,
C.sub.2-4-alkynyl-hetaryl, guanidine or a group selected from among
het, hetaryl and aryl, which is optionally substituted by one or
more groups selected from among halogen, C.sub.1-6-alkyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2 OH, imidazolidinone; [0126]
R.sup.3.2.2.1 denotes H or C.sub.1-6-alkyl, aryl,
C.sub.7-11-aralkyl [0127] R.sup.3.2.2.2 denotes H or
C.sub.1-6-alkyl; or [0128] aryl, which is optionally substituted by
one or two R.sup.3.2.3 [0129] R.sup.3.2.3 denotes a group selected
from among NH--C.sub.1-6-alkyl-N(C.sub.1-6-alkyl).sub.2 or het,
while het may optionally be substituted by a C.sub.1-6-alkyl group;
[0130] R.sup.3.3 denotes H or a group selected from among
C.sub.1-6-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-4-haloalkyl and aryl, which may optionally be substituted
by one or more groups R.sup.3.3.1; [0131] R.sup.3.3.1 denotes
C.sub.5-6-cycloalkyl, C.sub.5-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, optionally substituted by one or more groups selected from
among C.sub.1-4-alkyl, SO.sub.2H, SO.sub.2--C.sub.1-4-alkyl,
SO.sub.2C.sub.7-11-aralkyl, CH.sub.2--C.sub.3-4-cycloalkyl and
aryl; [0132] R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 denote
a group selected from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
COC.sub.1-4-alkyl-hetaryl, COC.sub.2-4-alkenyl-hetaryl,
COC.sub.2-4-alkynyl-hetaryl; or [0133] two of the groups
R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 together form a
five-, six- or seven-membered ring, consisting of carbon atoms and
optionally a heteroatom selected from among oxygen, nitrogen and
sulphur; [0134] R.sup.a denotes H, C.sub.1-6alkyl,
C.sub.2-4-alkenyl, C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl,
C.sub.1-6-haloalkyl, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2,
OR.sup.8, SR.sup.11, SOR.sup.11, SO.sub.2R.sup.11,
NHCO--C.sub.1-4-alkyl-NH.sub.2, spiro or a group selected from
among C.sub.7-11-aralkyl, CH.sub.2--O-aryl and het which may
optionally be substituted by one or more halogens, C.sub.1-6-alkyl,
CO--C.sub.1-4-haloalkyl, C.sub.1-4-alkyl-NH.sub.2 or
CH.sub.2NHCOOR.sup.12; [0135] R.sup.8 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl, optionally
substituted by one or more halogens or C.sub.1-4-alkyl; [0136]
R.sup.9 denotes H, COOR.sup.12 or C.sub.1-4-alkyl, optionally
substituted by one or more COOH, N(C.sub.1-4-alkyl).sub.2 or het,
optionally substituted by one or more C.sub.1-4-alkyl; or R.sup.9
denotes het, optionally substituted by one or more C.sub.1-4-alkyl;
[0137] R.sup.10 denotes H, C.sub.1-6-alkyl, CO--C.sub.1-4-alkyl or
C.sub.2-6-alkynyl; R.sup.11 denotes C.sub.1-6-alkyl, optionally
substituted by one or more N(C.sub.1-4-alkyl).sub.2; [0138]
R.sup.12 denotes C.sub.1-6-alkyl; [0139] R.sup.b denotes R.sup.4,
OR.sup.4, --CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NR.sup.4R.sup.5, NR.sup.5COR.sup.4,
NR.sup.5COOR.sup.4, NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; [0140] R.sup.4 denotes H, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH, C.sub.2-6-alkenyl,
C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl, C.sub.2-4-alkynyl-aryl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-4-alkenyl-hetaryl,
C.sub.2-4-alkynyl-hetaryl, C.sub.2-6-alkynyl, optionally
substituted by Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a
group selected from among aryl, het, hetaryl and optionally
substituted by C.sub.1-4-alkyl; [0141] R.sup.5 denotes H or
C.sub.1-6-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur; [0142]
R.sup.c denotes NHR.sup.6 or a group selected from among ##STR7##
[0143] wherein [0144] B denotes a bond, C.sub.1-4-alkyl or
C.sub.2-4-alkynyl; [0145] R.sup.6 denotes H or a group selected
from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, het, aryl, hetaryl
optionally substituted by one or more groups R.sup.6.1; [0146]
R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); [0147] R.sup.7 denotes H,
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2,
hetaryl, het, optionally substituted by C.sub.1-4-alkyl or
CONH.sub.2; [0148] R.sup.7.1 denotes H, C.sub.1-4-alkyl,
(CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl; [0149] R.sup.7.2 denotes
H, C.sub.1-6-alkyl, optionally substituted by one or more OH;
[0150] R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2, het or
1-imidazolyl, 2-(N-ethylpyrrolidine); [0151] R.sup.7.1.1.1 denotes
H or C.sub.1-6-alkyl; [0152] R.sup.7.1.1.2 denotes H or
C.sub.1-4alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof, with the proviso that R.sup.a cannot be H or Me if
Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0153] Preferred compounds of formula 1 mentioned above are those
wherein [0154] R.sup.a denotes a group selected from among aryl,
C.sub.7-11-aralkyl and hetaryl, which may optionally be substituted
by one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; [0155] R.sup.1 and R.sup.2 independently of one another
denote C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkylene-COOH, C.sub.1-6-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SR.sup.1.1,
SOR.sup.1.1, SO.sub.2R.sup.1.1, het or hetaryl, [0156] R.sup.1.1
denotes OH, C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
NR.sup.1.1.1R.sup.1.1.2 [0157] R.sup.1.1.1 denotes H,
C.sub.1-6-alkyl, optionally substituted by a group selected from
among NH.sub.2, NHMe, NMe.sub.2; [0158] R.sup.1.1.2 denotes H,
C.sub.1-6-alkyl; [0159] or R.sup.1.1.1 and R.sup.1.1.2 together
form a five- or six-membered heterocyclic ring, which may
optionally be substituted by a group selected from among methyl,
ethyl, propyl; [0160] R.sup.3 denotes a group selected from among
##STR8## [0161] wherein [0162] X denotes a bond or
C.sub.1-4-alkylene; [0163] R.sup.3a denotes a group, which may be
identical or different, selected from among R.sup.3.1, R.sup.3.2
and R.sup.3.3; [0164] R.sup.3.1 denotes spiro or het, while het may
optionally be substituted by one or more R.sup.3.1.1; [0165]
R.sup.3.1.1 denotes C.sub.1-6-alkyl, C.sub.2-6-alkenyl, OH,
C.sub.1-4-alkylene-OH,
C.sub.1-4-alkylene-NR.sup.3.1.1.1R.sup.3.1.1.2. COR.sup.3.1.1.1,
COOR.sup.3.1.1.1, CONR.sup.3.1.1.1R.sup.3.1.1.2 NR.sup.3.1.1.2,
het, hetaryl, NHCOR.sup.3.1.1.1 [0166] R.sup.3.1.1.1 denotes a
group selected from among H, C.sub.1-4-alkyl, aryl and
C.sub.7-11-aralkyl; optionally substituted by a group selected from
among halogen, OH and CN; [0167] R.sup.3.1.1.2 denotes H,
C.sub.1-4-alkyl; [0168] R.sup.3.2 denotes a group selected from
among C.sub.3-6-cycloalkyl, het, hetaryl and spiro which is
optionally substituted by one or more R.sup.3.2.1 [0169]
R.sup.3.2.1 denotes C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, OH,
--NR.sup.3.2.1.1R.sup.3.2.1.2, NHCOR.sup.3.2.1.3 or het, optionally
substituted by one or more groups selected from among
C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; [0170] R.sup.3.2.1.1
denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl; [0171]
R.sup.3.2.1.2 denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl;
[0172] R.sup.3.2.1.3 denotes aryl, C.sub.7-11-aralkyl; or [0173]
--C.sub.1-6-alkyl, which is optionally substituted by one or two
R.sup.3.2.2; [0174] R.sup.3.2.2 denotes C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1N.sup.3.2.2.2, N.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, C.sub.1-6-haloalkyl, CN, OR.sup.3.2.2.1,
SO.sub.2R.sup.3.2.2.1, C.sub.3-6-cycloalkyl, CO-het,
C.sub.2-4-alkynyl-hetaryl, guanidine or a group selected from among
het, hetaryl and aryl, which is optionally substituted by one or
more groups selected from among halogen, C.sub.1-6-alkyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2, OH, imidazolidinone; [0175]
R.sup.3.2.2.1 denotes H or C.sub.1-6-alkyl, aryl,
C.sub.7-11-aralkyl [0176] R.sup.3.2.2.2 denotes H or
C.sub.1-6-alkyl; or [0177] aryl, which is optionally substituted by
one or two R.sup.3.2.3 [0178] R.sup.3.2.3 denotes a group selected
from among NH--C.sub.1-6-alkyl-N(C.sub.1-6-alkyl).sub.2 or het,
while het may optionally be substituted by a C.sub.1-6-alkyl group;
[0179] R.sup.3.3 denotes H or a group selected from among
C.sub.1-6-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl and aryl,
which may optionally be substituted by one or more groups
R.sup.3.3.1; [0180] R.sup.3.3.1 denotes C.sub.5-6-cycloalkyl,
C.sub.5-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1.
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, optionally substituted by one or more groups selected from
among C.sub.1-4-alkyl, SO.sub.2H, SO.sub.2--C.sub.1-4-alkyl,
SO.sub.2C.sub.7-11-aralkyl, CH.sub.2--C.sub.3-6-cycloalkyl and
aryl; [0181] R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 denote
a group selected from among C.sub.1-4-alkyl, C.sub.7-1-aralkyl,
C.sub.1-4-alkyl-hetaryl, COC.sub.1-4-alkyl-hetaryl; or [0182] two
of the groups R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3
together form a five-, six- or seven-membered ring, consisting of
carbon atoms and optionally a heteroatom selected from among
oxygen, nitrogen and sulphur; [0183] R.sup.a denotes H,
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.3-6-cycloalkyl,
C.sub.3-4-cycloalkenyl, C.sub.1-6-haloalkyl, COR.sup.8,
NR.sup.9R.sup.10, NO.sub.2, OR.sup.8, SR.sup.11, SOR.sup.11,
SO.sub.2R.sup.11, NHCO--C.sub.1-6-alkyl-NH.sub.2, spiro or a group
selected from among C.sub.7-11-aralkyl, CH.sub.2--O-aryl and het
which may optionally be substituted by one or more halogens,
C.sub.1-6-alkyl, CO--C.sub.1-4-haloalkyl, C.sub.1-4-alkyl-NH.sub.2
or CH.sub.2NHCOOR.sup.12; [0184] R.sup.8 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl, optionally
substituted by one or more halogens or C.sub.1-4-alkyl; [0185]
R.sup.9 denotes H, COOR.sup.12 or C.sub.1-4-alkyl, optionally
substituted by one or more COOH, N(C.sub.1-4-alkyl).sub.2 or het,
optionally substituted by one or more C.sub.1-4-alkyl; or R.sup.9
denotes het, optionally substituted by one or more C.sub.1-4-alkyl;
[0186] R.sup.10 denotes H, C.sub.1-6-alkyl, CO--C.sub.1-4-alkyl or
C.sub.2-6-alkynyl; [0187] R.sup.11 denotes C.sub.1-6-alkyl,
optionally substituted by one or more N(C.sub.1-4-alkyl).sub.2;
[0188] R.sup.12 denotes C.sub.1-6-alkyl; [0189] R.sup.b denotes
R.sup.4, OR.sup.4, --CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NH.sub.2, NR.sup.5COOR.sup.4,
NR.sup.5CONR.sup.4R.sup.5 or NR.sup.5SOR.sup.4; [0190] R.sup.4
denotes H, C.sub.1-6-alkyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkylene-OH, C.sub.2-6-alkenyl, C.sub.7-11-aralkyl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-6-alkynyl, optionally substituted
by Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected
from among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; [0191] R.sup.5 denotes H or C.sub.1-6-alkyl; or
R.sup.4 and R.sup.5 together form a five-, six- or seven-membered
ring consisting of carbon atoms and optionally a heteroatom
selected from among oxygen, nitrogen and sulphur; [0192] R.sup.c
denotes NHR.sup.6 or a group selected from among ##STR9## [0193]
wherein [0194] B denotes a bond, C.sub.1-4-alkyl or
C.sub.2-4-alkynyl; [0195] R.sup.6 denotes H or a group selected
from among C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, het, aryl,
hetaryl optionally substituted by one or more groups R.sup.6.1;
[0196] R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); [0197] R.sup.7 denotes H,
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2,
OR.sup.7.2, SR.sup.7.2, hetaryl, het, optionally substituted by
C.sub.1-4-alkyl or CONH.sub.2; [0198] R.sup.7.1 denotes H,
C.sub.1-4-alkyl, (CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl; [0199]
R.sup.7.2 denotes H, C.sub.1-6alkyl, optionally substituted by one
or more OH; [0200] R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2,
het or 1-imidazolyl, 2-(N-ethylpyrrolidine); [0201] R.sup.7.1.1.1
denotes H or C.sub.1-6alkyl; [0202] R.sup.7.1.1.2 denotes H or
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof, with the proviso that R.sup.a cannot be H or Me if
Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0203] Preferred compounds of formula 1 mentioned above are those
wherein [0204] R.sup.a denotes a group selected from among aryl and
C.sub.7-11-aralkyl, which may optionally be substituted by one or
more groups selected from among R.sup.1, R.sup.2 and R.sup.3; or
hetaryl optionally substituted by one or more C.sub.1-4-alkyl;
[0205] R.sup.1 denotes C.sub.1-4-alkyl, C.sub.1-4-haloalkyl,
C.sub.1-4-alkylene-COOH, C.sub.1-4-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SO.sub.2R.sup.1.1;
[0206] R.sup.1.1 denotes OH, methyl, NH.sub.2, NHMe, NMe.sub.2,
##STR10## [0207] R.sup.2 denotes C.sub.1-4-alkyl, C.sub.1-4-alkoxy
or halogen; [0208] R.sup.3 denotes a group selected from among
##STR11## [0209] wherein [0210] n denotes 0 or 1; [0211] m denotes
0 or 1; [0212] o denotes 2; [0213] R.sup.3.1 denotes spiro or het,
while het may optionally be substituted by one or more R.sup.3.1.1;
[0214] R.sup.3.1.1 denotes C.sub.1-4-alkyl, C.sub.2-4-alkenyl, OH,
C.sub.1-4-alkylene-OH, CH.sub.2NEt.sub.2, COMe, COOH, CONH.sub.2,
NH.sub.2, het, hetaryl, ##STR12## [0215] R.sup.3.2 denotes a group
selected from among C.sub.3-6-cycloalkyl, het, hetaryl and spiro
which is optionally substituted by one or two R.sup.3.2.1 [0216]
R.sup.3.2.1 denotes C.sub.1-4-alkyl, cyclopentyl, OH,
--NR.sup.3.2.1.1R.sup.3.2.1.2 or ##STR13## [0217] or het, is
optionally substituted by one or more groups selected from among
methyl, SO.sub.2R.sup.3.2.1.1, ##STR14## [0218] R.sup.3.2.1.1
denotes H, methyl or benzyl; [0219] R.sup.3.2.1.2 denotes H, methyl
or benzyl; or [0220] --C.sub.1-6alkyl, which is optionally
substituted by one or two R.sup.3.2.2; [0221] R.sup.3.2.2 denotes
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2, NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, C.sub.1-4-haloalkyl, CN, OH,
SO.sub.2R.sup.3.2.2.1, C.sub.3-2-cycloalkyl or a group selected
from among ##STR15## [0222] or a group selected from among het,
hetaryl and aryl, which is optionally substituted by one or more
groups selected from among Cl, methyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2 OH; [0223] R.sup.3.2.2.1 denotes H or
methyl; [0224] R.sup.3.2.2.2 denotes H or methyl; or [0225] aryl,
which is optionally substituted by one or two R.sup.3.2.3 [0226]
R.sup.3.2.3 denotes a group selected from among ##STR16## [0227]
R.sup.3.3 denotes H or a group selected from among C.sub.1-6-alkyl
and aryl, which may optionally be substituted by one or more groups
R.sup.3.3.1; [0228] R.sup.3.3.1 denotes C.sub.5-6-cycloalkyl,
C.sub.5-6-cycloalkenyl, OR.sup.3.3.1.1 NR.sup.3.3.1.1R.sup.3.3.1.2,
CONR.sup.3.3.1.1R.sup.3.3.1.2 COOR.sup.3.3.1.1,
NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, is optionally substituted by one or more groups selected from
among methyl, SO.sub.2H, SO.sub.2--C.sub.1-4-alkyl,
SO.sub.2C.sub.7-1-aralkyl, ##STR17## [0229] R.sup.3.3.1.1,
R.sup.3.3.1.2 and R.sup.3.3.1.3 denote a group selected from among
C.sub.1-4-alkyl, C.sub.7-11-aralkyl, C.sub.1-4-alkyl-hetaryl,
COC.sub.1-4-alkyl-hetaryl; [0230] R.sup.a denotes H,
C.sub.1-6-alklyl, C.sub.2-4-alkenyl, C.sub.3-6-cycloalkyl,
CF.sub.3, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2,
S(O).sub.nR.sup.11, or a group selected from among ##STR18## [0231]
or a group selected from among ##STR19## [0232] which may
optionally be substituted by one or more Cl; [0233] or a group
selected from among ##STR20## [0234] which may optionally be
substituted by one or more CH.sub.3, COCF.sub.3, CH.sub.2NH.sub.2
or CH.sub.2NHCOOR.sup.12; [0235] R.sup.8 denotes C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, furanyl or phenyl, optionally
substituted by one or more chlorine; [0236] R.sup.9 denotes H,
COOR.sup.12 or piperidino, optionally substituted by one or more
CH.sub.3, or a group selected from among C.sub.1-4-alkyl, which may
optionally be substituted by one or more COOH, NMe.sub.2 or
4-methylpiperazine; [0237] R.sup.10 denotes H, C.sub.1-4-alkyl,
C.sub.2-4-alkynyl or COCH.sub.3; [0238] R.sup.11 denotes
C.sub.1-4-alkyl, optionally substituted by one or more NMe.sub.2,
[0239] R.sup.12 denotes C.sub.1-4-alkyl; [0240] R.sup.b denotes
R.sup.4, CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NH.sub.2, NHCOOR.sup.4, NHCONR.sup.4R.sup.5 or
OH; [0241] R.sup.4 denotes H, C.sub.1-4-alkyl,
C.sub.1-4-alkylene-OH, C.sub.2-4-alkynyl, C.sub.1-6-haloalkyl,
aryl, het, hetaryl, ##STR21## [0242] R.sup.5 denotes H or
C.sub.1-4-alkyl; [0243] R.sup.c denotes NHR.sup.6 or a group
selected from among ##STR22## [0244] wherein [0245] B denotes a
bond, C.sub.1-4-alkyl or C.sub.2-4-alkynyl; [0246] R.sup.6 denotes
H, C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, C.sub.7-11-aralkyl, aryl,
optionally substituted by SO.sub.2CH.sub.3; [0247] R.sup.7 denotes
H, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2, hetaryl, het,
optionally substituted by C.sub.1-4-alkyl or CONH.sub.2, or a group
selected from among ##STR23## [0248] R.sup.7.1 denotes H,
C.sub.1-4-alkyl, (CH.sub.2).sub.2R.sup.7.1.1 or COObutyl; [0249]
R.sup.7.2 denotes H, C.sub.1-4-alkyl; [0250] R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); [0251] R.sup.7.1.1 denotes H or
C.sub.1-6-alkyl; [0252] R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl;
and the pharmacologically acceptable salts, diastereomers,
enantiomers, racemates, hydrates or solvates thereof, with the
proviso that R.sup.a cannot be H or Me if Y=nitrogen; Z=nitrogen;
j=2; k=0; R.sup.b=H and R.sup.c=NHCONH-Et.
[0253] Preferred compounds of formula 1 mentioned above are those
wherein [0254] R.sup.a denotes phenyl or benzyl, in each case
optionally substituted by one or more groups selected from among
R.sup.1, R.sup.2 and R.sup.3; or ##STR24## [0255] R.sup.1 denotes
methyl, ethyl, propyl, butyl, CF.sub.3, CH.sub.2COOH, methoxy, F,
Cl, Br, OH, CN, COR.sup.1.1, OCF.sub.3, NO.sub.2 or
SO.sub.2R.sup.1.1; [0256] R.sup.1.1 denotes OH, methyl, NH.sub.2,
NHMe, NMe.sub.2, ##STR25## [0257] R.sup.2 denotes methyl, methoxy,
F, Cl or Br; [0258] R.sup.3 denotes a group selected from among
##STR26## [0259] wherein [0260] n denotes 0 or 1; [0261] m denotes
0 or 1; [0262] o denotes 2; [0263] R.sup.3.1 denotes a group
selected from among ##STR27## [0264] or a group selected from among
##STR28## [0265] which may optionally be substituted by one or more
R.sup.3.1.1; [0266] R.sup.3.1.1 denotes methyl, ethyl, OH,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2NEt.sub.2, COMe, COOH,
CONH.sub.2, NH.sub.2, ##STR29## [0267] R.sup.3.2 denotes a group
selected from among ##STR30## [0268] which is optionally
substituted by one or more groups selected from among methyl,
ethyl, cyclopentyl, OH, NH.sub.2; or [0269] cyclohexyl, which is
optionally substituted by one or two R.sup.3.2.1 [0270]
R.sup.3.2.1--NR.sup.3.2.1.1R.sup.3.2.1.2 or a group selected from
among ##STR31## [0271] or a group selected from among ##STR32##
[0272] which is optionally substituted by one or more groups
selected from among methyl, SO.sub.2R.sup.3.2.1.1, ##STR33## [0273]
R.sup.3.2.1.1 denotes H, methyl or benzyl; [0274] R.sup.3.2.1.2
denotes H, methyl or benzyl; or [0275] --C.sub.1-6-alkyl,
straight-chain or branched, which is optionally substituted by one
or two R.sup.3.2.2; [0276] R.sup.3.2.2 denotes C.dbd.CH.sub.2,
C.ident.CH, COOR.sup.3.2.2.1, CONR.sup.3.2.2.1R.sup.3.2.2.2,
NR.sup.3.2.2.1R.sup.3.2.2.2, NHCOR.sup.3.2.2.1, CF.sub.3, CN, OH,
SO.sub.2R.sup.3.2.2.1; or group selected from among ##STR34##
[0277] or a group selected from among ##STR35## [0278] which is
optionally substituted by one or more groups selected from among
Cl, methyl, CONR.sup.3.2.2.1R.sup.3.2.2.2, OH; [0279] R.sup.3.2.2.1
denotes H or methyl; [0280] R.sup.3.2.2.2 denotes H or methyl; or
[0281] phenyl, which is optionally substituted by one or two
R.sup.3.2.3 [0282] R.sup.3.2.3 denotes a group selected from among
##STR36## [0283] R.sup.3.3 denotes H, C.sub.1-6-alkyl, optionally
substituted by one or more R.sup.3.3.1; [0284] R.sup.3.3.1 denotes
C.sub.5-6-cycloalkyl, C.sub.5-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2,
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1CONR.sup.3.3.1.2)NR.sup.3.3.1.3, NR.sup.3.3.1.3,
CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or het which is
optionally substituted by one or more groups selected from among
methyl, SO.sub.2H, SO.sub.2Me, SO.sub.2CH.sub.2phenyl; ##STR37##
[0285] R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 denote a
group selected from among C.sub.1-4alkyl, C.sub.7-11-aralkyl,
C.sub.1-4-alkyl-hetaryl, COC.sub.1-4-alkyl-hetaryl; [0286] R.sup.a
denotes H, methyl, ethyl, propyl, butyl, 3-methyl-butyl, propenyl,
cyclopropyl, cyclohexyl, CF.sub.3, COR.sup.8, NR.sup.9R.sup.10,
NO.sub.2, OR.sup.8, SR.sup.11, SOR.sup.11, SO.sub.2R.sup.11 or a
group selected from among ##STR38## [0287] or a group selected from
among ##STR39## [0288] which may optionally be substituted by one
or more Cl, [0289] or a group selected from among ##STR40## [0290]
which may optionally be substituted by one or more CH.sub.3,
COCF.sub.3, CH.sub.2NH.sub.2 or CH.sub.2NHCOOR.sup.12; [0291]
R.sup.8 denotes methyl, propyl, cyclopropyl, NH.sub.2, furanyl or
phenyl, optionally substituted by one or more chlorine; [0292]
R.sup.9 denotes H, COOR.sup.12 or piperidino, optionally
substituted by one or more CH.sub.3, or a group selected from among
methyl, ethyl and propyl, which may optionally be substituted by
one or more COOH, NMe.sub.2 or 4-methylpiperazine; [0293] R.sup.10
denotes H, methyl, COCH.sub.3, C.ident.CH or CH.sub.2C.ident.CH;
[0294] R.sup.11 denotes ethyl or propyl, optionally substituted by
one or more NMe.sub.2, [0295] R.sup.12 denotes butyl [0296] R.sup.b
denotes R.sup.4, CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NH.sub.2, NHCOOR.sup.4, NHCONR.sup.4R.sup.5 or
OH; [0297] R.sup.4 denotes H, methyl, ethyl, 2-hydroxyethyl,
propyl, C.ident.CH, CF.sub.3, phenyl, ##STR41## [0298] R.sup.5
denotes H, methyl or ethyl; [0299] R.sup.c denotes NHR.sup.6 or a
group selected from among ##STR42## [0300] wherein [0301] B denotes
a bond, methylene, ethylene, propylene or butynylene; [0302]
R.sup.6 denotes H, C.sub.1-4-alkyl, aryl, optionally substituted by
SO.sub.2CH.sub.3; [0303] R.sup.7 denotes H, NR.sup.7.1R.sup.7.2,
OR.sup.7.2, SR.sup.7.2 or a group selected from among ##STR43##
[0304] R.sup.7.1 denotes H, methyl, ethyl,
(CH.sub.2).sub.2R.sup.7.1.1 or COObutyl; [0305] R.sup.7.2 denotes
H, methyl or ethyl; [0306] R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); [0307] R.sup.7.1.1.1 denotes H or
C.sub.1-6-alkyl; [0308] R.sup.7.1.1.2 denotes H or C.sub.1-6-alkyl;
and the pharmacologically acceptable salts, diastereomers,
enantiomers, racemates, hydrates or solvates thereof, with the
proviso that R.sup.a cannot be H or Me if Y=nitrogen; Z=nitrogen;
j=2; k=0; R.sup.b=H and R.sup.c=NHCONH-Et.
[0309] Preferred compounds of formula 1 mentioned above are those
wherein [0310] R.sup.a denotes a group selected from among aryl,
C.sub.7-11-aralkyl and hetaryl, which may optionally be substituted
by one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; [0311] R.sup.1 and R.sup.2 independently of one another
denote C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkylene-COOH, C.sub.1-6-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SR.sup.1.1,
SOR.sup.1.1, SO.sub.2R.sup.1.1, het or hetaryl, [0312] R.sup.1.1
denotes OH, C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
NR.sup.1.1.1R.sup.1.1.2 [0313] R.sup.1.1.1 denotes H,
C.sub.1-6-alkyl, optionally substituted by a group selected from
among NH.sub.2, NHMe, NMe.sub.2; [0314] R.sup.1.1.2 denotes H,
C.sub.1-6-alkyl; [0315] or R.sup.1.1.1 and R.sup.1.1.2 together
form a five- or six-membered heterocyclic ring, which may
optionally be substituted by a group selected from among methyl,
ethyl, propyl; [0316] R.sup.3 denotes a group selected from among
##STR44## [0317] wherein [0318] X denotes a bond or
C.sub.1-4-alkylene; [0319] R.sup.3a denotes a group, which may be
identical or different, selected from among R.sup.3.1, R.sup.3.2
and R.sup.3.3; [0320] R.sup.3.1 denotes spiro or het, while het may
optionally be substituted by one or more R.sup.3.1.1; [0321]
R.sup.3.1.1 denotes C.sub.1-6alkyl, C.sub.2-6-alkenyl, OH,
C.sub.1-4-alkylene-OH,
C.sub.1-4-alkylene-NR.sup.3.1.1.1R.sup.3.1.1.2, COR.sup.3.1.1.1,
COOR.sup.3.1.1.1, CONR.sup.3.1.1.1R.sup.3.1.1.2,
NR.sup.3.1.1.1R.sup.3.1.1.2, het, hetaryl, NHCOR.sup.3.1.1.1 [0322]
R.sup.3.1.1.1 denotes a group selected from among H,
C.sub.1-4-alkyl, aryl and C.sub.7-11-aralkyl; optionally
substituted by a group selected from among halogen, OH and CN;
[0323] R.sup.3.1.1.2 denotes H, C.sub.1-4-alkyl; [0324] R.sup.3.2
denotes a group selected from among C.sub.3-6-cycloalkyl, het,
hetaryl and spiro which is optionally substituted by one or more
R.sup.3.2.1 [0325] R.sup.3.2.1 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, OH, NR.sup.3.2.1.1R.sup.3.2.1.2,
NHCOR.sup.3.2.1.3 or het, optionally substituted by one or more
groups selected from among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; [0326] R.sup.3.2.1 denotes
H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl; [0327] R.sup.3.2.1.2
denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl; [0328]
R.sup.3.2.1.3 denotes aryl, C.sub.7-11-aralkyl; or [0329]
C.sub.1-6-alkyl, which is optionally substituted by one or two
R.sup.3.2.2; [0330] R.sup.3.2.2 denotes C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2, NR.sup.3.2.2.1R.sup.3.2.2.2
NHCOR.sup.3.2.2.1, C.sub.1-6-haloalkyl, CN, OR.sup.3.2.2.1,
SO.sub.2R.sup.3.2.2.1, C.sub.3-6-cycloalkyl, CO-het,
C.sub.2-4-alkynyl-hetaryl, guanidine or a group selected from among
het, hetaryl and aryl, which is optionally substituted by one or
more groups selected from among halogen, C.sub.1-6-alkyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2, OH, imidazolidinone; [0331]
R.sup.3.2.2.1 denotes H or C.sub.1-6-alkyl, aryl,
C.sub.7-11-aralkyl [0332] R.sup.3.2.2.2 denotes H or
C.sub.1-6-alkyl; or [0333] aryl, which is optionally substituted by
one or two R.sup.3.2.3 [0334] R.sup.3.2.3 denotes a group selected
from among NH--C.sub.1-6-alkyl-N(C.sub.1-6-alkyl).sub.2 or het,
while het may optionally be substituted by a C.sub.1-6-alkyl group;
[0335] R.sup.3.3 denotes H or a group selected from among
C.sub.1-6alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-6-haloalkyl and aryl, which may optionally be substituted
by one or more groups R.sup.3.3.1; [0336] R.sup.3.3.1 denotes
C.sub.3-4-cycloalkyl, C.sub.3-4-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.2R.sup.3.3.1.2,
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, optionally substituted by one or more groups selected from
among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
SO.sub.2C.sub.1-4-alkyl, SO.sub.2C.sub.7-11-aralkyl,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; [0337] R.sup.3.3.1.1,
R.sup.3.3.1.2 and R.sup.3.3.1.3 denote a group selected from among
C.sub.1-6alkyl, C.sub.2-4-alkenyl, C.sub.2-6-alkynyl,
C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl, C.sub.2-4-alkynyl-aryl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-4-alkenyl-hetaryl,
C.sub.2-4-alkynyl-hetaryl, COC.sub.1-4-alkyl-hetaryl,
COC.sub.2-4-alkenyl-hetaryl, COC.sub.2-4-alkynyl-hetaryl; or [0338]
two of the groups R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3
together form a ring, consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur; [0339]
R.sup.b denotes R.sup.4, OR.sup.4, --CH.sub.2OR.sup.4, COR.sup.4,
COOR.sup.4, CONR.sup.4R.sup.5, NR.sup.4R.sup.5, NR.sup.5COR.sup.4,
NR.sup.5COOR.sup.4, NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; [0340] R.sup.4, R.sup.5 denote H,
C.sub.1-6alkyl, C.sub.1-6-haloalkyl, C.sub.1-6alkylene-OH,
C.sub.2-4-alkenyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
C.sub.2-4-alkynyl, optionally substituted by
Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected from
among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur; [0341]
R.sup.c denotes NHR.sup.6 or a group selected from among ##STR45##
[0342] wherein [0343] B denotes a bond, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl; [0344] R.sup.6 denotes H or
a group selected from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl,
het, aryl, hetaryl optionally substituted by one or more groups
R.sup.6.1; [0345] R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); [0346] R.sup.7 denotes H,
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2,
hetaryl, het, optionally substituted by C.sub.1-4-alkyl or
CONH.sub.2; [0347] R.sup.7.1 denotes H, C.sub.1-6alkyl,
(CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl; [0348] R.sup.7.2 denotes
H, C.sub.1-6-alkyl, optionally substituted by one or more OH;
[0349] R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2, het or
1-imidazolyl, 2-(N-ethylpyrrolidine); [0350] R.sup.7.1.1.1 denotes
H or C.sub.1-6-alkyl; [0351] R.sup.7.1.1.2 denotes H or
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0352] Preferred compounds of formula 1 mentioned above are those
wherein [0353] R.sup.a denotes a group selected from among aryl,
C.sub.7-11-aralkyl and hetaryl, which may optionally be substituted
by one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; [0354] R.sup.1 and R.sup.2 independently of one another
denote C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
C.sub.3-6-Cycloalkyl, C.sub.3-6-Cycloalkenyl, C: .sub.6-haloalkyl,
C.sub.1-6-alkylene-COOH, C.sub.1-6-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SR.sup.1.1,
SOR.sup.1.1, SO.sub.2R.sup.1.1, het or hetaryl, [0355] R.sup.1.1
denotes OH, C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
NR.sup.1.1.1R.sup.1.1.2 [0356] R.sup.1.1.1 denotes H,
C.sub.1-6-alkyl, optionally substituted by a group selected from
among NH.sub.2, NHMe, NMe.sub.2; [0357] R.sup.1.1.2 denotes H,
C.sub.1-6-alkyl; [0358] or R.sup.1.1.1 and R.sup.1.1.2 together
form a five- or six-membered heterocyclic ring, which may
optionally be substituted by a group selected from among methyl,
ethyl, propyl; [0359] R.sup.3 denotes a group selected from among
##STR46## [0360] wherein [0361] X denotes a bond or
C.sub.1-4-alkylene; [0362] R.sup.3a denotes a group, which may be
identical or different, selected from among R.sup.3.1, R.sup.3.2
and R.sup.3.3; [0363] R.sup.3.1 denotes spiro or het, while het may
optionally be substituted by one or more R.sup.3.1.1; [0364]
R.sup.3.1.1 denotes C.sub.1-6-alkyl, C.sub.2-6-alkenyl, OH,
C.sub.1-4-alkylene-OH,
C.sub.1-4-alkylene-NR.sup.3.1.1.1R.sup.3.1.1.2, COR.sup.3.1.1.1,
COOR.sup.3.1.1.1, CONR.sup.3.1.1.1R.sup.3.1.1.2,
NR.sup.3.1.1.1R.sup.3.1.1.2, het, hetaryl, NHCOR.sup.3.1.1.1 [0365]
R.sup.3.1.1.1 denotes a group selected from among H,
C.sub.1-4-alkyl, aryl and C.sub.7-11-aralkyl; optionally
substituted by a group selected from among halogen, OH and CN;
[0366] R.sup.3.1.1.2 denotes H, C.sub.1-4-alkyl; [0367] R.sup.3.2
denotes a group selected from among C.sub.3-6-cycloalkyl, het,
hetaryl and spiro which is optionally substituted by one or more
R.sup.3.2.1 [0368] R.sup.3.2.1 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, OH, --NR.sup.3.2.1.1R.sup.3.2.1.2,
NHCOR.sup.3.2.1.3 or het, optionally substituted by one or more
groups selected from among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
CH.sub.2--C.sub.3 cycloalkyl and aryl; [0369] R.sup.3.2.1.1 denotes
H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl; [0370] R.sup.3.2.1.2
denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl; [0371]
R.sup.3.2.1.3 denotes aryl, C.sub.7-11-aralkyl; or [0372]
--C.sub.1-6-alkyl, which is optionally substituted by one or two
R.sup.3.2.2; [0373] R.sup.3.2.2 denotes C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, COOR.sup.3.2.2,
CONR.sup.3.2.2.1R.sup.3.2.2.2, NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.2, C.sub.1-6-haloalkyl, CN, OR.sup.3.2.2.1,
SO.sub.2R.sup.3.2.2.1, C.sub.3-6-cycloalkyl, CO-het,
C.sub.2-4-alkynyl-hetaryl, guanidine or a group selected from among
het, hetaryl and aryl, which is optionally substituted by one or
more groups selected from among halogen, C.sub.1-6-alkyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2, OH, imidazolidinone; [0374]
R.sup.3.2.2.1 denotes H or C.sub.1-6-alkyl, aryl,
C.sub.7-11-aralkyl [0375] R.sup.3.2.2.2 denotes H or
C.sub.1-6-alkyl; or [0376] aryl, which is optionally substituted by
one or two R.sup.3.2.3 [0377] R.sup.3.2.3 denotes a group selected
from among NH--C.sub.1-6-alkyl-N(C.sub.1-6-alkyl).sub.2 or het,
while het may optionally be substituted by a C.sub.1-6-alkyl group;
[0378] R.sup.3.3 denotes H or a group selected from among
C.sub.1-6-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.1-4-haloalkyl and aryl, which may optionally be substituted
by one or more groups R.sup.3.3.1; [0379] R.sup.3.3.1 denotes
C.sub.5-6-cycloalkyl, C.sub.5-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3 OH, CN, halogen or het,
optionally substituted by one or more groups selected from among
C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1, SO.sub.2C.sub.1-4-alkyl,
SO.sub.2C.sub.7-11-aralkyl, CH.sub.2--C.sub.3-6-cycloalkyl and
aryl; [0380] R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 denote
a group selected from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
COC.sub.1-4-alkyl-hetaryl, COC.sub.2-4-alkenyl-hetaryl,
COC.sub.2-4-alkynyl-hetaryl; or [0381] two of the groups
R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 together form a
five-, six- or seven-membered ring, consisting of carbon atoms and
optionally a heteroatom selected from among oxygen, nitrogen and
sulphur; [0382] R.sup.b denotes R.sup.4, OR.sup.4,
--CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5,
NR.sup.4R.sup.5, NR.sup.5COR.sup.4, NR.sup.5COOR.sup.4,
NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; [0383] R.sup.4 denotes H, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH, C.sub.2-6-alkenyl,
C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl, C.sub.2-4-alkynyl-aryl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-4-alkenyl-hetaryl,
C.sub.2-4-alkynyl-hetaryl, C.sub.2-6-alkynyl, optionally
substituted by Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a
group selected from among aryl, het, hetaryl and optionally
substituted by C.sub.1-4-alkyl; [0384] R.sup.5 denotes H or
C.sub.1-6-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur; [0385]
R.sup.c denotes NHR.sup.6 or a group selected from among ##STR47##
wherein [0386] B denotes a bond, C.sub.1-4-alkyl or
C.sub.2-4-alkynyl; [0387] R.sup.6 denotes H or a group selected
from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, het, aryl, hetaryl
optionally substituted by one or more groups R.sup.6.1; [0388]
R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); [0389] R.sup.7 denotes H,
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2,
hetaryl, het, optionally substituted by C.sub.1-4-alkyl or
CONH.sub.2; [0390] R.sup.7.1 denotes H, C.sub.1-4-alkyl,
(CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl; [0391] R.sup.7.2 denotes
H, C.sub.1-6-alkyl, optionally substituted by one or more OH;
[0392] R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2, het or
1-imidazolyl, 2-(N-ethylpyrrolidine); [0393] R.sup.7.1.1.1 denotes
H or C.sub.1-6-alkyl; [0394] R.sup.7.1.1.2 denotes H or
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0395] Preferred compounds of formula 1 mentioned above are those
wherein [0396] R.sup.a denotes a group selected from among aryl,
C.sub.7-11-aralkyl and hetaryl, which may optionally be substituted
by one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; [0397] R.sup.1 and R.sup.2 independently of one another
denote C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkylene-COOH, C.sub.1-6-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SR.sup.1.1,
SOR.sup.1.1, SO.sub.2R.sup.1.1, het or hetaryl, [0398] R.sup.1.1
denotes OH, C.sub.1-6-alkyl, C.sub.2-6-alkenyl C.sub.2-6-alkynyl,
NR.sup.1.1.1R.sup.1.1.2 [0399] R.sup.1.1.1 denotes H,
C.sub.1-6-alkyl, optionally substituted by a group selected from
among NH.sub.2, NHMe, NMe.sub.2; [0400] R.sup.1.1.2 denotes H,
C.sub.1-6-alkyl; [0401] or R.sup.1.1.1 and R.sup.1.1.2 together
form a five- or six-membered heterocyclic ring, which may
optionally be substituted by a group selected from among methyl,
ethyl, propyl; [0402] R.sup.3 denotes a group selected from among
##STR48## [0403] wherein [0404] X denotes a bond or
C.sub.1-4-alkylene; [0405] R.sup.3a denotes a group, which may be
identical or different, selected from among R.sup.3.1, R.sup.3.2
and R.sup.3.3; [0406] R.sup.3.1 denotes spiro or het, while het may
optionally be substituted by one or more R.sup.3.1.1; [0407]
R.sup.3.1.1 denotes C.sub.1-6-alkyl, C.sub.2-6alkenyl, OH,
C.sub.1-4-alkylene-OH,
C.sub.1-4-alkylene-NR.sup.3.1.1.1R.sup.3.1.1.2, COR.sup.3.1.1.1,
COOR.sup.3.1.1.1 [0408] CONR.sup.3.1.1.1R.sup.3.1.1.2,
NR.sup.3.1.1.1R.sup.3.1.1.2, het, hetaryl, NHCOR.sup.3.1.1.1 [0409]
R.sup.3.1.1.1 denotes a group selected from among H,
C.sub.1-4-alkyl, aryl and C.sub.7-11-aralkyl; optionally
substituted by a group selected from among halogen, OH and CN;
[0410] R.sup.3.1.1.2 denotes H, C.sub.1-4-alkyl; [0411] R.sup.3.2
denotes a group selected from among C.sub.3-6cycloalkyl, het,
hetaryl and spiro which is optionally substituted by one or more
R.sup.3.2.1 [0412] R.sup.3.2.1 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, OH, --NR.sup.3.2.1.1R.sup.3.2.1.2,
NHCOR.sup.3.2.1.3 or het, optionally substituted by one or more
groups selected from among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; [0413] R.sup.3.2.1.1
denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl; [0414]
R.sup.3.2.1.2 denotes H, C.sub.1-4-alkyl or C.sub.7-11-aralkyl;
[0415] R.sup.3.2.1.3 denotes aryl, C.sub.7-11-aralkyl; or [0416]
C.sub.1-6-alkyl, which is optionally substituted by one or two
R.sup.3.2.2; [0417] R.sup.3.2.2 denotes C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2, NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, C.sub.1-6-haloalkyl, CN, OR.sup.3.2.2.1,
SO.sub.2R.sup.3.2.2.1, C.sub.3-16-cycloalkyl, CO-het,
C.sub.2-4-alkynyl-hetaryl, guanidine or a group selected from among
het, hetaryl and aryl, which is optionally substituted by one or
more groups selected from among halogen, C.sub.1-6-alkyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2, OH, imidazolidinone; [0418]
R.sup.3.2.2.1 denotes H or C.sub.1-6-alkyl, aryl,
C.sub.7-11-aralkyl [0419] R.sup.3.2.2.2 denotes H or
C.sub.1-6-alkyl; or [0420] aryl, which is optionally substituted by
one or two R.sup.3.2.3 [0421] R.sup.3.2.3 denotes a group selected
from among NH--C.sub.1-6-alkyl-N(C.sub.1-6-alkyl).sub.2 or het,
while het may optionally be substituted by a C.sub.1-6-alkyl group;
[0422] R.sup.3.3 denotes H or a group selected from among
C.sub.1-6-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl and aryl,
which may optionally be substituted by one or more groups
R.sup.3.3.1; [0423] R.sup.3.3.1 denotes C.sub.5-6-cycloalkyl,
C.sub.5-4-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2,
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, optionally substituted by one or more groups selected from
among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
SO.sub.2C.sub.1-4-alkyl, SO.sub.2C.sub.7-11-aralkyl,
CH.sub.2--C.sub.3-6-cycloalkyl and aryl; [0424] R.sup.3.3.1.1,
R.sup.3.3.1.2 and R.sup.3.3.1.3 denote a group selected from among
C.sub.1-4-alkyl, C.sub.7-11-aralkyl, C.sub.1-4-alkyl-hetaryl,
COC.sub.1-4-alkyl-hetaryl; or [0425] two of the groups
R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 together form a
five-, six- or seven-membered ring, consisting of carbon atoms and
optionally a heteroatom selected from among oxygen, nitrogen and
sulphur; [0426] R.sup.b denotes R.sup.4, OR.sup.4,
--CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5,
NH.sub.2, NR.sup.5COOR.sup.4, NR.sup.5CONR.sup.4R.sup.5 or
NR.sup.5SOR.sup.4; [0427] R.sup.4 denotes H, C.sub.1-alkyl,
C.sub.1-haloalkyl, C.sub.1-alkylene-OH, C.sub.2-4-alkenyl,
C.sub.7-11-aralkyl, C.sub.1-4-alkyl-hetaryl, C.sub.2-6-alkynyl,
optionally substituted by Si(C.sub.1-4-alkyl).sub.3, or R.sup.4
denotes a group selected from among aryl, het, hetaryl and
optionally substituted by C.sub.1-4-alkyl; [0428] R.sup.5 denotes H
or C.sub.1-6-alkyl; or R.sup.4 and R.sup.5 together form a five-,
six- or seven-membered ring consisting of carbon atoms and
optionally a heteroatom selected from among oxygen, nitrogen and
sulphur; [0429] R.sup.c denotes NHR.sup.6 or a group selected from
among ##STR49## wherein [0430] B denotes a bond, C.sub.1-4-alkyl or
C.sub.2-4-alkynyl; [0431] R.sup.6 denotes H or a group selected
from among C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, het, aryl,
hetaryl optionally substituted by one or more groups R.sup.6.1;
[0432] R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); [0433] R.sup.7 denotes H,
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2,
OR.sup.7.2, SR.sup.7.2, hetaryl, het, optionally substituted by
C.sub.1-4-alkyl or CONH.sub.2; [0434] R.sup.7.1 denotes H,
C.sub.1-4-alkyl, (CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl; [0435]
R.sup.7.2 denotes H, C.sub.1-6-alkyl, optionally substituted by one
or more OH; [0436] R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2,
het or 1-imidazolyl, 2-(N-ethylpyrrolidine); [0437] R.sup.7.1.1.1
denotes H or C.sub.1-6-alkyl; [0438] R.sup.7.1.1.2 denotes H or
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0439] Preferred compounds of formula 1 mentioned above are those
wherein [0440] R.sup.a denotes a group selected from among aryl and
C.sub.7-11-aralkyl, which may optionally be substituted by one or
more groups selected from among R.sup.1, R.sup.2 and R.sup.3; or
hetaryl optionally substituted by one or more C.sub.1-4-alkyl;
[0441] R.sup.1 denotes C.sub.1-4-alkyl, C.sub.1-4-haloalkyl,
C.sub.1-4-alkylene-COOH, C.sub.1-4-alkoxy, halogen, OH, CN,
COR.sup.1.1, O--C.sub.1-4-haloalkyl, NO.sub.2 or SO.sub.2R.sup.1.1;
[0442] R.sup.1.1 denotes OH, methyl, NH.sub.2, NHMe, NMe.sub.2,
##STR50## [0443] R.sup.2 denotes C.sub.1-4-alkyl, C.sub.1-4-alkoxy
or halogen; [0444] R.sup.3 denotes a group selected from among
##STR51## [0445] wherein [0446] n denotes 0 or 1; [0447] m denotes
0 or 1; [0448] o denotes 2; [0449] R.sup.3.1 denotes Spiro or het,
while het may optionally be substituted by one or more R.sup.3.1.1;
[0450] R.sup.3.1.1 denotes C.sub.1-4-alkyl, C.sub.2-4-alkenyl, OH,
C.sub.1-4-alkylene-OH, CH.sub.2NEt.sub.2, COMe, COOH, CONH.sub.2,
NH.sub.2, het, hetaryl, ##STR52## [0451] R.sup.3.2 denotes a group
selected from among C.sub.3-6-cycloalkyl, het, hetaryl and spiro
which is optionally substituted by one or two R.sup.3.2.1 [0452]
R.sup.3.2.1 denotes C.sub.1-4-alkyl, cyclopentyl, OH,
--NR.sup.3.2.1.1R.sup.3.2.1.2 or ##STR53## [0453] or het, is
optionally substituted by one or more groups selected from among
methyl, SO.sub.2R.sup.3.2.1.1, ##STR54## [0454] R.sup.3.2.1.1
denotes H, methyl or benzyl; [0455] R.sup.3.2.1.2 denotes H, methyl
or benzyl; or [0456] C.sub.1-6-alkyl, which is optionally
substituted by one or two R.sup.3.2.2; [0457] R.sup.3.2.2 denotes
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2, NR.sup.3.2.2.1R.sup.3.2.2.2,
NHCOR.sup.3.2.2.1, C.sub.1-14-haloalkyl, CN, OH,
SO.sub.2R.sup.3.2.2.1, C.sub.3-6-cycloalkyl or a group selected
from among ##STR55## [0458] or a group selected from among het,
hetaryl and aryl, which is optionally substituted by one or more
groups selected from among Cl, methyl,
CONR.sup.3.2.2.1R.sup.3.2.2.2 OH; [0459] R.sup.3.2.2.1 denotes H or
methyl; [0460] R.sup.3.2.2.2 denotes H or methyl; or [0461] aryl,
which is optionally substituted by one or two R.sup.3.2.3 [0462]
R.sup.3.2.3 denotes a group selected from among ##STR56## [0463]
R.sup.3.3 denotes H or a group selected from among C.sub.1-6-alkyl
and aryl, which may optionally be substituted by one or more groups
R.sup.3.3.1; [0464] R.sup.3.3.1 denotes C.sub.5-6-cycloalkyl,
C.sub.5-6-cycloalkenyl, OR.sup.3.3.1.1,
NR.sup.3.3.1.1R.sup.3.3.1.2, CONR.sup.3.3.1.1R.sup.3.3.1.2,
COOR.sup.3.3.1.1, NR.sup.3.3.1.1COR.sup.3.3.1.2, SOR.sup.3.3.1.1,
SO.sub.2R.sup.3.3.1.1,
C(NR.sup.3.3.1.1R.sup.3.3.1.2)NR.sup.3.3.1.3,
NR.sup.3.3.1.1CONR.sup.3.3.1.2R.sup.3.3.1.3, OH, CN, halogen or
het, optionally substituted by one or more groups selected from
among C.sub.1-4-alkyl, SO.sub.2R.sup.3.2.1.1,
SO.sub.2C.sub.1-4-alkyl, SO.sub.2C.sub.7-11-aralkyl, ##STR57##
[0465] R.sup.3.3.1.1, R.sup.3.3.1.2 and R.sup.3.3.1.3 denote a
group selected from among C.sub.1-4-alkyl, C.sub.7-11-aralkyl,
C.sub.1-4-alkyl-hetaryl, COC.sub.1-4-alkyl-hetaryl; [0466] R.sup.b
denotes R.sup.4 CH.sub.2OR, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NH.sub.2, NHCOOR.sup.4, NHCONR.sup.4R.sup.5 or
OH; [0467] R.sup.4 denotes H, C.sub.1-4-alkyl,
C.sub.1-4-alkylene-OH, C.sub.2-4-alkynyl, C.sub.1-6-haloalkyl,
aryl, het, hetaryl, ##STR58## [0468] R.sup.5 denotes H or
C.sub.1-4-alkyl; [0469] R.sup.c denotes NHR.sup.6 or a group
selected from among ##STR59## wherein [0470] B denotes a bond,
C.sub.1-4-alkyl or C.sub.2-4-alkynyl; [0471] R.sup.6 denotes H,
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, C.sub.7-11-aralkyl, aryl,
optionally substituted by SO.sub.2CH.sub.3; [0472] R.sup.7 denotes
H, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2, hetaryl, het,
optionally substituted by C.sub.1-4-alkyl or CONH.sub.2, or a group
selected from among ##STR60## [0473] R.sup.7.1 denotes H,
C.sub.1-4-alkyl, (CH.sub.2).sub.2R.sup.7.1.1 or COObutyl; [0474]
R.sup.7.2 denotes H, C.sub.1-4-alkyl; [0475] R.sup.7.1.1 denotes
NR.sup.7.1.1.2, het or 1-imidazolyl, 2-(N-ethylpyrrolidine); [0476]
R.sup.7.1.1.1 denotes H or C.sub.1-6-alkyl; [0477] R.sup.7.1.1.2
denotes H or C.sub.1-6-alkyl; and the pharmacologically acceptable
salts, diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0478] Particularly preferred are the above-mentioned compounds of
formula 1 wherein [0479] R.sup.a denotes phenyl or benzyl, in each
case optionally substituted by one or more groups selected from
among R.sup.1, R.sup.2 and R.sup.3; or ##STR61## [0480] R.sup.1
denotes methyl, ethyl, propyl, butyl, CF.sub.3, CH.sub.2COOH,
methoxy, F, Cl, Br, OH, CN, COR.sup.1.1, OCF.sub.3, NO.sub.2 or
SO.sub.2R.sup.1.1; [0481] R.sup.1.1 denotes OH, methyl, NH.sub.2,
NHMe, NMe.sub.2, ##STR62## [0482] R.sup.2 denotes methyl, methoxy,
F, Cl or Br; [0483] R.sup.3 denotes a group selected from among
##STR63## [0484] wherein [0485] n denotes 0 or 1; [0486] m denotes
0 or 1; [0487] o denotes 2; [0488] R.sup.3.1 denotes a group
selected from among ##STR64## [0489] or a group selected from among
##STR65## [0490] which may optionally be substituted by one or more
R.sup.3.1.1; [0491] R.sup.3.1.1 denotes methyl, ethyl, OH,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2NEt.sub.2, COMe, COOH,
CONH.sub.2, NH.sub.2, ##STR66## [0492] R.sup.3.2 denotes a group
selected from among ##STR67## [0493] which is optionally
substituted by one or more groups selected from among methyl,
ethyl, cyclopentyl, OH, NH.sub.2; or [0494] cyclohexyl, which is
optionally substituted by one or two R.sup.3.2.1 [0495] R.sup.3.2.1
denotes --NR.sup.3.2.1.1R.sup.3.2.1.2 or a group selected from
among ##STR68## [0496] or a group selected from among ##STR69##
[0497] which is optionally substituted by one or more groups
selected from among methyl, SO.sub.2R.sup.3.2.1.1, ##STR70## [0498]
R.sup.3.2.1.1 denotes H, methyl or benzyl; [0499] R.sup.3.2.1.2
denotes H, methyl or benzyl; or [0500] --C.sub.1-6-alkyl,
straight-chain or branched, which is optionally substituted by one
or two R.sup.3.2.2; [0501] R.sup.3.2.2 denotes C.dbd.CH.sub.2,
C.ident.CH, COOR.sup.3.2.2.1, CONR.sup.3.2.2.1R.sup.3.2.2.2,
NR.sup.3.2.2.1R.sup.3.2.2.2, N HCOR.sup.3.2.2.1, CF.sub.3, CN, OH,
SO.sub.2R.sup.3.2.2.1 or a group selected from among ##STR71##
[0502] or a group selected from among ##STR72## [0503] which is
optionally substituted by one or more groups selected from among
Cl, methyl, CONR.sup.3.2.2.1R.sup.3.2.2.2 OH; [0504] R.sup.3.2.2.1
denotes H or methyl; [0505] R.sup.3.2.2.2 denotes H or methyl; or
[0506] phenyl, which is optionally substituted by one or two
R.sup.3.2.3 [0507] R.sup.3.2.3 denotes a group selected from among
##STR73## [0508] R.sup.3.3 denotes H, methyl or ethyl; [0509]
R.sup.b denotes R.sup.4, CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NH.sub.2, NHCOOR.sup.4, NHCONR.sup.4R.sup.5 or
OH; [0510] R.sup.4 denotes H, methyl, ethyl, 2-hydroxyethyl,
propyl, C.ident.CH, CF.sub.3, phenyl, ##STR74## [0511] R.sup.5
denotes H, methyl or ethyl; [0512] R.sup.c denotes NHR.sup.6 or a
group selected from among ##STR75## wherein [0513] B denotes a
bond, methylene, ethylene, propylene or butynylene; [0514] R.sup.6
denotes H, phenyl, optionally substituted by SO.sub.2CH.sub.3;
[0515] R.sup.7 denotes H, NR.sup.7.1R.sup.7.2, OR.sup.7.2,
SR.sup.7.2 or a group selected from among ##STR76## [0516]
R.sup.7.1 denotes H, methyl, ethyl, (CH.sub.2).sub.2R.sup.7.1.1 or
COObutyl; [0517] R.sup.7.2 denotes H, methyl or ethyl; [0518]
R.sup.7.1.1 denotes NMe.sub.2 or 1-imidazolyl and the
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0519] Particularly preferred are the above-mentioned compounds of
formula 1 wherein [0520] R.sup.c denotes a group ##STR77## wherein
[0521] B denotes methylene, propylene; [0522] R.sup.7 denotes H,
NR.sup.7.1R.sup.7.2 or 1-imidazolyl; [0523] R.sup.7.1 denotes H or
methyl; [0524] R.sup.7.2 denotes H or methyl; and the
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0525] Particularly preferred are the above-mentioned compounds of
formula 1 wherein [0526] R.sup.a denotes phenyl, optionally
substituted by one or more groups selected from among R.sup.1,
R.sup.2 and R.sup.3; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0527] Particularly preferred are the above-mentioned compounds of
formula 1 wherein [0528] R.sup.a denotes phenyl, optionally
substituted by one or more groups selected from among R.sup.1 and
R.sup.3; [0529] R.sup.1 denotes methyl, ethyl, propyl, CF.sub.3,
methoxy, F, Cl or Br; [0530] R.sup.3 denotes a group ##STR78## and
the pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0531] Particularly preferred are the above-mentioned compounds of
formula 1 wherein [0532] R.sup.a denotes phenyl, optionally
substituted by one or more groups selected from among R.sup.1 and
R.sup.3; [0533] R.sup.1 denotes methyl, ethyl, propyl, CF.sub.3,
methoxy, F, Cl or Br; [0534] R.sup.3 denotes a group ##STR79## and
the pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0535] Particularly preferred of the above-mentioned compounds of
formula 1 are the compounds of formula 1.1 ##STR80## wherein
R.sup.a, R.sup.b and R.sup.c have the meanings given above, and the
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0536] Particularly preferred are the above-mentioned compounds of
formula 1.1; wherein [0537] R.sup.a denotes phenyl, optionally
substituted by one or more groups selected from among R.sup.1,
R.sup.2 and R.sup.3; or ##STR81## [0538] R.sup.1 denotes methyl,
ethyl, propyl, CF.sub.3, CH.sub.2COOH, methoxy, F, Cl, Br, CN,
COR.sup.1.1 or SO.sub.2R.sup.1.1; [0539] R.sup.1.1 denotes OH,
methyl, NH.sub.2, NHMe, NMe.sub.2 or ##STR82## [0540] R.sup.2
denotes methyl, F, Cl or Br; [0541] R.sup.3 denotes a group
selected from among ##STR83## [0542] wherein [0543] n denotes 0 or
1; [0544] m denotes 0 or 1; [0545] o denotes 2; [0546] R.sup.3.1
denotes a group selected from among ##STR84## [0547] or a group
selected from among ##STR85## [0548] which may optionally be
substituted by one or more R.sup.3.1.1; [0549] R.sup.3.1.1 denotes
methyl, OH, CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2NEt.sub.2,
COMe, COOH, CONH.sub.2, ##STR86## [0550] R.sup.3.2 denotes a group
selected from among ##STR87## [0551] which is optionally
substituted by one or more groups selected from among methyl,
ethyl, cyclopentyl, OH, NH.sub.2; or [0552] cyclohexyl, which is
optionally substituted by one or two R.sup.3.2.1 [0553] R.sup.3.2.1
denotes --NR.sup.3.2.1.1R.sup.3.2.1.2 or a group selected from
among ##STR88## [0554] or a group selected from among ##STR89##
[0555] which is optionally substituted by one or more methyl groups
[0556] R.sup.3.2.1.1 denotes H or methyl; [0557] R.sup.3.2.1.2
denotes H or methyl; or [0558] --Cl-alkyl, straight-chain or
branched, which is optionally substituted by one or two
R.sup.3.2.2; [0559] R.sup.3.2.2 denotes C.dbd.CH.sub.2, C.ident.CH,
COOR.sup.3.2.2.1, CONR.sup.3.2.2.1R.sup.3.2.2.2,
NR.sup.3.2.2.1R.sup.3.2.2.2, CN, OH or a group selected from among
##STR90## [0560] or a group selected from among ##STR91## [0561]
which is optionally substituted by one or more groups selected from
among methyl, CONR.sup.3.2.2.1R.sup.3.2.2.2, OH; [0562]
R.sup.3.2.2.1 denotes H or methyl; [0563] R.sup.3.2.2.2 denotes H
or methyl; or [0564] phenyl, which is optionally substituted by one
or two R.sup.3.2.3 [0565] R.sup.3.2.3 denotes a group selected from
among ##STR92## [0566] R.sup.3.3 denotes H, methyl or ethyl; [0567]
R.sup.b R.sup.4, CH.sub.2OCH.sub.3, COR.sup.4, COOH, COOCH.sub.3
CONR.sup.4R.sup.5, NH.sub.2, NHCOOR.sup.4 or OH; [0568] R.sup.4
denotes H, methyl, propyl, C.ident.CH, phenyl, ##STR93## [0569]
R.sup.5 denotes H or methyl; [0570] R.sup.c denotes a group
##STR94## wherein [0571] B denotes methylene, propylene; [0572]
R.sup.7 denotes H, NR.sup.7.1R.sup.7.2 or 1-imidazolyl; [0573]
R.sup.7.1 denotes H or methyl; [0574] R.sup.7.2 denotes H or
methyl; and the pharmacologically acceptable salts, diastereomers,
enantiomers, racemates, hydrates or solvates thereof.
[0575] Most preferred are the above-mentioned compounds of formula
1.1; wherein [0576] R.sup.a denotes phenyl, optionally substituted
by one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; or ##STR95## [0577] R.sup.1 denotes methyl, CF.sub.3,
methoxy, F, Cl, Br, COR.sup.1.1 or SO.sub.2R.sup.1.1; [0578]
R.sup.1.1 denotes OH, NH.sub.2, NHMe or NMe.sub.2; [0579] R.sup.2
denotes Cl; [0580] R.sup.3 denotes a group selected from among
##STR96## [0581] wherein [0582] n denotes 0 or 1; [0583] m denotes
0 or 1; [0584] R.sup.3.1 denotes a group selected from among
##STR97## [0585] or a group selected from among ##STR98## [0586]
which may optionally be substituted by one or more R.sup.3.1.1;
[0587] R.sup.3.1.1 denotes OH, CONH.sub.2 or 4-pyridinyl, [0588]
R.sup.3.2 denotes a group selected from among ##STR99## [0589]
which is optionally substituted by one or more methyl groups; or
[0590] cyclohexyl, which is optionally substituted by one or two
R.sup.3.2.1 [0591] R.sup.3.2.1 denotes a group selected from among
##STR100## [0592] --C.sub.1-6alkyl, straight-chain or branched,
which is optionally substituted by one or two R.sup.3.2.2; [0593]
R.sup.3.2.2 denotes COOR.sup.3.2.2.1,
CONR.sup.3.2.2.1R.sup.3.2.2.2, 4-pyrdinyl or a group selected from
among ##STR101## [0594] which is optionally substituted by one or
more groups selected from among methyl; [0595] R.sup.3.2.2.1
denotes H or methyl; [0596] R.sup.3.2.2.2 denotes H or methyl; or
[0597] R.sup.3.3 denotes H, methyl or ethyl; [0598] R.sup.b denotes
R.sup.4, CH.sub.2OCH.sub.3 or OH; [0599] R.sup.4 denotes H,
C.ident.CH, ##STR102## [0600] R.sup.c denotes a group ##STR103##
wherein [0601] B denotes methylene, propylene; [0602] R.sup.7
denotes H or NR.sup.7.1R.sup.7.2; [0603] R.sup.7.1 denotes H or
methyl; [0604] R.sup.7.2 denotes H or methyl; and the
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0605] Particularly preferred of the above-mentioned compounds of
formula 1 are the compounds of formula 1.2 ##STR104## wherein
R.sup.a, R.sup.b and R.sup.c have the meanings given above, and the
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0606] Particularly preferred are the above-mentioned compounds of
formula 1.2; wherein R.sup.b and R.sup.c have the meanings given
above and [0607] R.sup.a denotes aryl, optionally substituted by
one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; [0608] R.sup.1 and R.sup.2 independently of one another
denote C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-alkoxy,
halogen, COR.sup.1.1, SO.sub.2R.sup.1.1, [0609] R.sup.1.1 denotes
C.sub.1-6-alkyl, NR.sup.1.1.1R.sup.1.1.2l [0610] R.sup.1.1.1
denotes H, C.sub.1-6-alkyl, optionally substituted by a group
selected from among NH.sub.2, NHMe, NMe.sub.2; [0611] R.sup.1.1.2
denotes H, C.sub.1-6-alkyl; [0612] or R.sup.1.1.1 and R.sup.1.1.2
together form a five- or six-membered heterocyclic ring, which may
optionally be substituted by a group selected from among methyl,
ethyl, propyl; [0613] R.sup.3 denotes a group selected from among
##STR105## [0614] wherein [0615] X denotes a bond or
C.sub.1-4-alkylene; [0616] R.sup.3a denotes a group, which may be
identical or different, selected from among R.sup.3.1, R.sup.3.2
and R.sup.3.3; [0617] R.sup.3.1 denotes spiro or het, while het may
optionally be substituted by one or more R.sup.3.1.1; [0618]
R.sup.3.1.1 denotes NR.sup.3.1.1.1R.sup.3.1.1.2; [0619]
R.sup.3.1.1.1 denotes H, C.sub.1-4-alkyl; [0620] R.sup.3.1.1.2
denotes H, C.sub.1-4-alkyl; and the pharmacologically acceptable
salts, diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0621] Particularly preferred are the above-mentioned compounds of
formula 1.2; wherein [0622] R.sup.a denotes phenyl, optionally
substituted by one or more groups selected from among R.sup.1,
R.sup.2 and R.sup.3; [0623] R.sup.1 and R.sup.2 independently of
one another denote C.sub.1-6-alkyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkoxy, halogen, COR.sup.1.1, SO.sub.2R.sup.1.1, [0624]
R.sup.1.1 denotes methyl ethyl, propyl, NR.sup.1.1.1R.sup.1.1.2
[0625] R.sup.1.1.1 denotes H, methyl ethyl, propyl; [0626]
R.sup.1.1.2 denotes H, methyl ethyl, propyl; [0627] or R.sup.1.1.1
and R.sup.1.1.2 together form a five- or six-membered heterocyclic
ring, which may optionally be substituted by a group selected from
among methyl, ethyl, propyl; [0628] R.sup.3 denotes a group
selected from among ##STR106## [0629] wherein [0630] X denotes a
bond or methylene, ethylene, propylene; [0631] R.sup.3a denotes a
group, which may be identical or different, selected from among
R.sup.3.1, R.sup.3.2 and R.sup.3.3; [0632] R.sup.3.1 denotes spiro
or het, while het may optionally be substituted by one or more
R.sup.3.1.1; [0633] R.sup.3.1.1 denotes
NR.sup.3.1.1.1R.sup.3.1.1.2; [0634] R.sup.3.1.1.1 denotes H, methyl
ethyl, propyl; [0635] R.sup.3.1.1.2 denotes H, methyl ethyl,
propyl; [0636] R.sup.b denotes R.sup.4; [0637] R.sup.4 denotes H;
[0638] R.sup.c denotes NHR.sup.6 or a group ##STR107## wherein
[0639] B denotes a bond, methylene, ethylene or propylene; [0640]
R.sup.6 denotes H; [0641] R.sup.7 denotes H or NR.sup.7.1R.sup.7.2,
##STR108## [0642] R.sup.7.1 denotes H, methyl, ethyl,
(CH.sub.2).sub.2R.sup.7.1.1 or COObutyl; [0643] R.sup.7.2 denotes
H, methyl or ethyl; [0644] R.sup.7.1.1 denotes NMe.sub.2 or
1-imidazolyl and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0645] Particularly preferred are the above-mentioned compounds of
formula 1.2; wherein [0646] R.sup.a denotes phenyl, optionally
substituted by one or more groups selected from among R.sup.1 and
R.sup.2; [0647] R.sup.1 denotes methyl, ethyl, propyl, CF.sub.3, F,
Cl, COR.sup.1.1 or SO.sub.2R.sup.1.1; [0648] R.sup.1.1 denotes
methyl; [0649] R.sup.2 denotes methyl, F or Cl; [0650] R.sup.b
denotes R.sup.4; [0651] R.sup.4 denotes H; [0652] R.sup.c denotes
NHR.sup.6 or a group ##STR109## wherein [0653] B denotes a bond,
methylene, ethylene or propylene; [0654] R.sup.6 denotes H; [0655]
R.sup.7 denotes H or NR.sup.7.1R.sup.7.2; ##STR110## [0656]
R.sup.7.1 denotes H, methyl, ethyl, (CH.sub.2).sub.2R.sup.7.1.1 or
COObutyl; [0657] R.sup.7.2 denotes H, methyl or ethyl; [0658]
R.sup.7.1.1 denotes NMe.sub.2 or 1-imidazolyl and the
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0659] Most preferred are the above-mentioned compounds of formula
1.2; wherein [0660] R.sup.a denotes phenyl, optionally substituted
by R.sup.1; [0661] R.sup.1 denotes methyl, F, Cl, Br or
COR.sup.1.1; [0662] R.sup.1.1 denotes methyl; [0663] R.sup.b
denotes R.sup.4; [0664] R.sup.4 denotes H; [0665] R.sup.c denotes a
group ##STR111## wherein [0666] B denotes a bond, methylene or
propylene; [0667] R.sup.7 denotes H or NR.sup.7.1R.sup.7.2, [0668]
R.sup.7.1 denotes H or methyl; [0669] R.sup.7.2 denotes methyl; and
the pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0670] Particularly preferred of the above-mentioned compounds of
formula 1 are the compounds of formula 1.3 ##STR112## wherein
R.sup.a, R.sup.b and R.sup.c have the meanings given above, and the
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0671] Particularly preferred are the above-mentioned compounds of
formula 1.3; wherein R.sup.b and R.sup.c have the meanings given
above and [0672] R.sup.a denotes aryl, optionally substituted by
one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3, or hetaryl; [0673] R.sup.1 and R.sup.2 independently of
one another denote C.sub.1-6-alkyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkoxy, halogen, COR.sup.1.1; [0674] R.sup.1.1 denotes
OH, C.sub.1-6alkyl, NR.sup.1.1.1R.sup.1.1.2 [0675] R.sup.1.1.1
denotes H, C.sub.1-6-alkyl, optionally substituted by a group
selected from among NH.sub.2, NHMe, NMe.sub.2; [0676] R.sup.1.1.2
denotes H, C.sub.1-alkyl; [0677] or R.sup.1.1.1 and R.sup.1.1.2
together form a five- or six-membered heterocyclic ring, which may
optionally be substituted by a group selected from among methyl,
ethyl, propyl; [0678] R.sup.3 denotes a group selected from among
##STR113## [0679] wherein [0680] X denotes a bond or
C.sub.1-4-alkylene; [0681] R.sup.3a denotes a group, which may be
identical or different, selected from among R.sup.3.1, R.sup.3.2
and R.sup.3.3; [0682] R.sup.3.1 denotes spiro or het, while het may
optionally be substituted by one or more R.sup.3.1.1; [0683]
R.sup.3.1.1 denotes NR.sup.3.1.1R.sup.3.1.1.2; [0684] R.sup.3.1.1.1
denotes H, C.sub.1-4-alkyl; [0685] R.sup.3.1.1.2 denotes H,
C.sub.1-4-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0686] Particularly preferred are the above-mentioned compounds of
formula 1.3; wherein [0687] R.sup.a denotes phenyl, optionally
substituted by one or more groups selected from among R.sup.1,
R.sup.2 and R.sup.3, pyrazolyl or pyridinyl; [0688] R.sup.1 and
R.sup.2 independently of one another denote C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-alkoxy, halogen, COR.sup.1.1, [0689]
R.sup.1.1 denotes methyl ethyl, propyl, NR.sup.1.1.1R.sup.1.1.2
[0690] R.sup.1.1.1 denotes H, methyl ethyl, propyl; [0691]
R.sup.1.1.2 denotes H, methyl ethyl, propyl; [0692] or R.sup.1.1.1
and R.sup.1.1.2 together form a five- or six-membered heterocyclic
ring, which may optionally be substituted by a group selected from
among methyl, ethyl, propyl; [0693] R.sup.3 denotes a group
selected from among ##STR114## [0694] wherein [0695] X denotes a
bond or C.sub.1-4-alkylene; [0696] R.sup.3a denotes a group, which
may be identical or different, selected from among R.sup.3.1,
R.sup.3.2 and R.sup.3.3; [0697] R.sup.3.1 denotes spiro or het,
while het may optionally be substituted by one or more R.sup.3.1.1;
[0698] R.sup.3.1.1 denotes NR.sup.3.1.1.1R.sup.3.1.1.2; [0699]
R.sup.3.1.1.1 denotes H, methyl ethyl, propyl; [0700] R.sup.3.1.1.2
denotes H, methyl ethyl, propyl; [0701] R.sup.b denotes R.sup.4 or
OH; [0702] R.sup.4 denotes H; [0703] R.sup.c denotes NHR.sup.6 or a
group ##STR115## wherein [0704] B denotes a bond, methylene,
ethylene or propylene; [0705] R.sup.6 denotes H; [0706] R.sup.7
denotes H, NR.sup.7.1R.sup.7.2 or a group selected from among
##STR116## [0707] R.sup.7.1 denotes H, methyl or
(CH.sub.2).sub.2R.sup.7.1.1; [0708] R.sup.7.2 denotes H, methyl or
ethyl; [0709] R.sup.7.1.1 denotes NMe.sub.2; and the
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0710] Particularly preferred are the above-mentioned compounds of
formula 1.3; wherein [0711] R.sup.a denotes phenyl, optionally
substituted by one or more groups selected from among R.sup.1 and
R.sup.2; or ##STR117## [0712] R.sup.1 denotes methyl, methoxy, Cl,
OH or COR.sup.1.1; [0713] R.sup.1.1 denotes NH.sub.2, NHMe or
NMe.sub.2; [0714] R.sup.2 denotes methoxy or Cl; [0715] R.sup.b
denotes R.sup.4 or OH; [0716] R.sup.4 denotes H; [0717] R.sup.c
denotes NHR.sup.6 or a group ##STR118## wherein [0718] B denotes a
bond, methylene, ethylene or propylene; [0719] R.sup.6 denotes H;
[0720] R.sup.7 denotes H, NR.sup.7.1R.sup.7.2 or a group selected
from among ##STR119## [0721] R.sup.7.1 denotes H, methyl or
(CH.sub.2).sub.2R.sup.7.1.1; [0722] R.sup.7.2 denotes H, methyl or
ethyl; [0723] R.sup.7.1.1 denotes NMe.sub.2; and the
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0724] Most preferred are the above-mentioned compounds of formula
1.3; wherein [0725] R.sup.a denotes phenyl, optionally substituted
by one or more groups selected from among R.sup.1, R.sup.2 and
R.sup.3; or [0726] R.sup.1 denotes Cl or COR.sup.1.1; [0727]
R.sup.1.1 denotes NH.sub.2; [0728] R.sup.2 denotes Cl; [0729]
R.sup.b denotes R.sup.4 or OH; [0730] R.sup.4 denotes H; [0731]
R.sup.c denotes NHR.sup.6 or a group ##STR120## wherein [0732] B
denotes methylene; [0733] R.sup.6 denotes H; [0734] R.sup.7 denotes
H; and the pharmacologically acceptable salts, diastereomers,
enantiomers, racemates, hydrates or solvates thereof.
[0735] Particularly preferred of the above-mentioned compounds of
formula 1 are the above-mentioned compounds of formula 1.4
##STR121## wherein R.sup.a, R.sup.b and R.sup.c have the meanings
given above, and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0736] Particularly preferred are the above-mentioned compounds of
formula 1.4; wherein [0737] R.sup.a denotes phenyl, optionally
substituted by one or more groups selected from among R.sup.1 and
R.sup.3; or [0738] R.sup.1 denotes methyl, F, Cl or Br; [0739]
R.sup.3 denotes a group selected from among ##STR122## [0740]
wherein [0741] m denotes 1; [0742] R.sup.3.2 denotes a group
##STR123## [0743] which is optionally substituted by a group
selected from among methyl and cyclopentyl; [0744] cyclohexyl,
which is optionally substituted by a R.sup.3.2.1 [0745] R.sup.3.2.1
denotes a group ##STR124## [0746] R.sup.3.3 denotes H; [0747]
R.sup.b denotes R.sup.4; [0748] R.sup.4 denotes a group selected
from among ##STR125## [0749] R.sup.c denotes a group ##STR126##
wherein [0750] B denotes methylene; [0751] R.sup.7 denotes H; and
the pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof.
[0752] Most preferred are the above-mentioned compounds of formula
1.4; wherein [0753] R.sup.a denotes phenyl, optionally substituted
by one or more groups selected from among R.sup.1 and R.sup.3; or
[0754] R.sup.1 denotes Cl; [0755] R.sup.3 denotes a group selected
from among ##STR127## [0756] wherein [0757] m denotes 0; [0758]
R.sup.3.2 denotes a group ##STR128## [0759] which is optionally
substituted by methyl; or [0760] cyclohexyl, which is optionally
substituted by a R.sup.3.2.1 [0761] R.sup.3.2.1 denotes a group
##STR129## [0762] R.sup.3.3 denotes H; [0763] R.sup.b denotes
R.sup.4; [0764] R.sup.4 denotes a group ##STR130## [0765] R.sup.c
denotes a group ##STR131## wherein [0766] B denotes methylene;
[0767] R.sup.7 denotes H; and the pharmacologically acceptable
salts, diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0768] Also preferred are the above-mentioned compounds of formula
1; wherein [0769] R.sup.a denotes H, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl,
C.sub.1-6-haloalkyl, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2,
OR.sup.8, SR.sup.11, SOR.sup.11, SO.sub.2R.sup.11,
NHCO--C.sub.1-6-alkyl-NH.sub.2, spiro or a group selected from
among C.sub.7-11-aralkyl, CH.sub.2--O-aryl and het which may
optionally be substituted by one or more halogens, C.sub.1-6-alkyl,
CO--C.sub.1-4-haloalkyl, C.sub.1-4-alkyl-NH.sub.2 or
CH.sub.2NHCOOR.sup.12; [0770] R.sup.8 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl, optionally
substituted by one or more halogens or C.sub.1-4-alkyl; [0771]
R.sup.9 denotes H, COOR.sup.12, CONR.sup.12 or C.sub.1-6-alkyl,
optionally substituted by one or more COOH,
N(C.sub.1-6-alkyl).sub.2 or het, optionally substituted by one or
more C.sub.1-6-alkyl; or R.sup.9 denotes het, optionally
substituted by one or more C.sub.1-4-alkyl; [0772] R.sup.10 denotes
H, C.sub.1-6-alkyl, CO--C.sub.1-6-alkyl or C.sub.2-6-alkynyl;
[0773] R.sup.11 denotes C.sub.1-6-alkyl, optionally substituted by
one or more N(C.sub.1-4-alkyl).sub.2; [0774] R.sup.12 denotes H,
C.sub.1-6-alkyl; [0775] R.sup.b denotes R.sup.4, OR.sup.4,
--CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4, CONR.sup.4R.sup.5,
NR.sup.4R.sup.5, NR.sup.5COR.sup.4, NR.sup.5COOR.sup.4,
NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; [0776] R.sup.4, R.sup.5 denote H,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH,
C.sub.2-4-alkenyl, C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl,
C.sub.2-4-alkynyl-aryl, C.sub.1-4-alkyl-hetaryl,
C.sub.2-4-alkenyl-hetaryl, C.sub.2-4-alkynyl-hetaryl,
C.sub.2-4-alkynyl, optionally substituted by
Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected from
among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur; [0777]
R.sup.c denotes NHR.sup.6 or a group selected from among ##STR132##
wherein [0778] B denotes a bond, C.sub.1-6alkyl, C.sub.2-4-alkenyl
or C.sub.2-6-alkynyl; [0779] R.sup.6 denotes H or a group selected
from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, het, aryl, hetaryl
optionally substituted by one or more groups R.sup.6.1; [0780]
R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); [0781] R.sup.7 denotes H,
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2,
hetaryl, het, optionally substituted by C.sub.1-4-alkyl or
CONH.sub.2; [0782] R.sup.7.1 denotes H, C.sub.1-6alkyl,
(CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl; [0783] R.sup.7.2 denotes
H, C.sub.1-6alkyl, optionally substituted by one or more OH; [0784]
R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2, het or
1-imidazolyl, 2-(N-ethylpyrrolidine); [0785] R.sup.7.1.1.1 denotes
H or C.sub.1-6-alkyl; [0786] R.sup.7.1.1.2 denotes H or
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof, with the proviso that R.sup.a cannot be H or Me if
Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0787] Preferred compounds of formula 1 mentioned above are those
wherein [0788] R.sup.a denotes H, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.3-8-cycloalkyl, C.sub.3-8-cycloalkenyl,
C.sub.1-6-haloalkyl, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2,
OR.sup.8, SR.sup.11, SOR.sup.11, SO.sub.2R.sup.11,
NHCO--C.sub.1-6-alkyl-NH.sub.2, spiro or a group selected from
among C.sub.7-11-aralkyl, CH.sub.2--O-aryl and het which may
optionally be substituted by one or more halogens, C.sub.1-6-alkyl,
CO--C.sub.1-4-haloalkyl, C.sub.1-4-alkyl-NH.sub.2 or
CH.sub.2NHCOOR.sup.12; [0789] R.sup.8 denotes C.sub.1-6alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl, optionally
substituted by one or more halogens or C.sub.1-4-alkyl; [0790]
R.sup.9 denotes H, COOR.sup.12 or C.sub.1-4-alkyl, optionally
substituted by one or more COOH, N(C.sub.1-4-alkyl).sub.2 or het,
optionally substituted by one or more C.sub.1-4-alkyl; or R.sup.9
denotes het, optionally substituted by one or more C.sub.1-4-alkyl;
[0791] R.sup.10 denotes H, C.sub.1-6-alkyl, CO--C.sub.1-4-alkyl or
C.sub.2-6-alkynyl; [0792] R.sup.11 denotes C.sub.1-6-alkyl,
optionally substituted by one or more N(C.sub.1-4-alkyl).sub.2;
[0793] R.sup.12 denotes C.sub.1-6alkyl; [0794] R.sup.b denotes
R.sup.4, OR.sup.4, --CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NR.sup.4R.sup.5, NR.sup.5COR.sup.4,
NR.sup.5COOR.sup.4, NR.sup.5CONR.sup.4R.sup.5, NR.sup.5SOR.sup.4 or
NR.sup.5SO.sub.2R.sup.4; [0795] R.sup.4 denotes H, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-alkylene-OH, C.sub.2-4-alkenyl,
C.sub.7-11-aralkyl, C.sub.2-4-alkenyl-aryl, C.sub.2-4-alkynyl-aryl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-4-alkenyl-hetaryl,
C.sub.2-4-alkynyl-hetaryl, C.sub.2-4-alkynyl, optionally
substituted by Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a
group selected from among aryl, het, hetaryl and optionally
substituted by C.sub.1-4-alkyl; [0796] R.sup.5 denotes H or
C.sub.1-6-alkyl; or R.sup.4 and R.sup.5 together form a five-, six-
or seven-membered ring consisting of carbon atoms and optionally a
heteroatom selected from among oxygen, nitrogen and sulphur; [0797]
R.sup.c denotes NHR.sup.6 or a group selected from among ##STR133##
wherein [0798] B denotes a bond, C.sub.1-4-alkyl or
C.sub.2-4-alkynyl; [0799] R.sup.6 denotes H or a group selected
from among C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl, het, aryl, hetaryl
optionally substituted by one or more groups R.sup.6.1; [0800]
R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); [0801] R.sup.7 denotes H,
C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl,
C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2,
hetaryl, het, optionally substituted by C.sub.1-4-alkyl or
CONH.sub.2; [0802] R.sup.7.1 denotes H, C.sub.1-4-alkyl,
(CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl; [0803] R.sup.7.2 denotes
H, C.sub.1-6-alkyl, optionally substituted by one or more OH;
[0804] R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2, het or
1-imidazolyl, 2-(N-ethylpyrrolidine); [0805] R.sup.7.1.1.1 denotes
H or C.sub.1-6-alkyl; [0806] R.sup.7.1.1.2 denotes H or
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof, with the proviso that R.sup.a cannot be H or Me if
Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0807] Preferred compounds of formula 1 mentioned above are those
wherein [0808] R.sup.a denotes H, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl,
C.sub.1-6-haloalkyl, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2,
OR.sup.8, SR.sup.11, SOR.sup.11, SO.sub.2R.sup.11,
NHCO--C.sub.1-6-alkyl-NH.sub.2, spiro or a group selected from
among C.sub.7-11-aralkyl, CH.sub.2--O-aryl and het which may
optionally be substituted by one or more halogens, C.sub.1-6-alkyl,
CO--C.sub.1-4-haloalkyl, C.sub.1-4-alkyl-NH.sub.2 or
CH.sub.2NHCOOR.sup.12; [0809] R.sup.8 denotes C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl or aryl, optionally
substituted by one or more halogens or C.sub.1-4-alkyl; [0810]
R.sup.9 denotes H, COOR.sup.12 or C.sub.1-4-alkyl, optionally
substituted by one or more COOH, N(C.sub.1-4-alkyl).sub.2 or het,
optionally substituted by one or more C.sub.1-4-alkyl; or R.sup.9
denotes het, optionally substituted by one or more C.sub.1-4-alkyl;
[0811] R.sup.10 denotes H, C.sub.1-6alkyl, CO--C.sub.1-4-alkyl or
C.sub.2-4-alkynyl; [0812] R.sup.11 denotes C.sub.1-6alkyl,
optionally substituted by one or more N(C.sub.1-4-alkyl).sub.2;
[0813] R.sup.12 denotes C.sub.1-6alkyl; [0814] R.sup.b denotes
R.sup.4, OR.sup.4, --CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NH.sub.2, NR.sup.5COOR.sup.4,
NR.sup.5CONR.sup.4R.sup.5 or NR.sup.5SOR.sup.4; [0815] R.sup.4
denotes H, C.sub.1-6-alkyl, C.sub.1-6-haloalkyl,
C.sub.1-6-alkylene-OH, C.sub.2-4-alkenyl, C.sub.7-11-aralkyl,
C.sub.1-4-alkyl-hetaryl, C.sub.2-4-alkynyl, optionally substituted
by Si(C.sub.1-4-alkyl).sub.3, or R.sup.4 denotes a group selected
from among aryl, het, hetaryl and optionally substituted by
C.sub.1-4-alkyl; [0816] R.sup.5 denotes H or C.sub.1-6alkyl; or
R.sup.4 and R.sup.5 together form a five-, six- or seven-membered
ring consisting of carbon atoms and optionally a heteroatom
selected from among oxygen, nitrogen and sulphur; [0817] R.sup.c
denotes NHR.sup.6 or a group selected from among ##STR134## wherein
[0818] B denotes a bond, C.sub.1-4-alkyl or C.sub.2-4-alkynyl;
[0819] R.sup.6 denotes H or a group selected from among
C.sub.1-4-alkyl, C.sub.3-4-cycloalkyl, het, aryl, hetaryl
optionally substituted by one or more groups R.sup.6.1; [0820]
R.sup.6.1 denotes halogen, CF.sub.3, OH, CN, OMe,
SO.sub.2(C.sub.1-4-alkyl); [0821] R.sup.7 denotes H,
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, NR.sup.7.1R.sup.7.2,
OR.sup.7.2, SR.sup.7.2, hetaryl, het, optionally substituted by
C.sub.1-4-alkyl or CONH.sub.2; [0822] R.sup.7.1 denotes H,
C.sub.1-4-alkyl, (CH.sub.2).sub.2-4R.sup.7.1.1 or COObutyl; [0823]
R.sup.7.2 denotes H, C.sub.1-6-alkyl, optionally substituted by one
or more OH; [0824] R.sup.7.1.1 denotes NR.sup.7.1.1.1R.sup.7.1.1.2,
het or 1-imidazolyl, 2-(N-ethylpyrrolidine); [0825] R.sup.7.1.1.1
denotes H or C.sub.1-6-alkyl; [0826] R.sup.7.1.1.2 denotes H or
C.sub.1-6-alkyl; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof, with the proviso that R.sup.a cannot be H or Me if
Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0827] Preferred compounds of formula 1 mentioned above are those
wherein [0828] R.sup.a denotes H, C.sub.1-6-alklyl,
C.sub.2-4-alkenyl, C.sub.3-6-cycloalkyl, CF.sub.3, COR.sup.8,
NR.sup.9R.sup.10, NO.sub.2, S(O).sub.nR.sup.11, or a group selected
from among ##STR135## [0829] or a group selected from among
##STR136## [0830] which may optionally be substituted by one or
more Cl; [0831] or a group selected from among ##STR137## [0832]
which may optionally be substituted by one or more CH.sub.3,
COCF.sub.3, CH.sub.2NH.sub.2 or CH.sub.2NHCOOR.sup.12; [0833]
R.sup.8 denotes C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2,
furanyl or phenyl, optionally substituted by one or more chlorine;
[0834] R.sup.9 denotes H, COOR.sup.12 or piperidino, optionally
substituted by one or more CH.sub.3, or a group selected from among
C.sub.1-4-alkyl, which may optionally be substituted by one or more
COOH, NMe.sub.2 or 4-methylpiperazine; [0835] R.sup.10 denotes H,
C.sub.1-4-alkyl, C.sub.2-4-alkynyl or COCH.sub.3; [0836] R.sup.11
denotes C.sub.1-4-alkyl, optionally substituted by one or more
NMe.sub.2, [0837] R.sup.12 denotes C.sub.1-4-alkyl; [0838] R.sup.b
denotes R.sup.4, CH.sub.2OR.sup.4, COR.sup.4, COOR.sup.4,
CONR.sup.4R.sup.5, NH.sub.2, NHCOOR.sup.4, NHCONR.sup.4R.sup.5 or
OH; [0839] R.sup.4 denotes H, C.sub.1-4-alkyl,
C.sub.1-4-alkylene-OH, C.sub.2-4-alkynyl, C.sub.1-6-haloalkyl,
aryl, het, hetaryl, ##STR138## [0840] R.sup.5 denotes H or
C.sub.1-4-alkyl; [0841] R.sup.c denotes NHR.sup.6 or a group
selected from among ##STR139## wherein [0842] B denotes a bond,
C.sub.1-4-alkyl or C.sub.2-4-alkynyl; [0843] R.sup.6 denotes H,
C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, C.sub.7-11-aralkyl, aryl,
optionally substituted by SO.sub.2CH.sub.3; [0844] R.sup.7 denotes
H, NR.sup.7.1R.sup.7.2, OR.sup.7.2, SR.sup.7.2, hetaryl, het,
optionally substituted by C.sub.1-4-alkyl or CONH.sub.2, or a group
selected from among ##STR140## [0845] R.sup.7.1 denotes H,
C.sub.1-4-alkyl, (CH.sub.2).sub.2R.sup.7.1.1 or COObutyl; [0846]
R.sup.7.2 denotes H, C.sub.1-4-alkyl; [0847] R.sup.7.1.1 denotes
NR.sup.7.1.1.1R.sup.7.1.1.2, het or 1-imidazolyl,
2-(N-ethylpyrrolidine); [0848] R.sup.7.1.1.1 denotes H or
C.sub.1-alkyl; [0849] R.sup.7.1.1.2 denotes H or C.sub.1-alkyl; and
the pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof, with the proviso that
R.sup.a cannot be H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0;
R.sup.b=H and R.sup.c=NHCONH-Et.
[0850] Particularly preferred are the above-mentioned compounds of
formula 1 wherein [0851] R.sup.a denotes H, C.sub.1-alklyl,
C.sub.2-6-alkenyl, C.sub.3-6-cycloalkyl, C.sub.3-6-cycloalkenyl,
CF.sub.3, COR.sup.8, NR.sup.9R.sup.10, NO.sub.2,
S(O).sub.nR.sup.11, spiro, NHCO--C.sub.1-1-alkyl-NH.sub.2 or a
group selected from among C.sub.7-11-aralkyl and CH.sub.2O-aryl,
which may optionally be substituted by one or more Cl; or a group
selected from among het, which may optionally be substituted by one
or more C.sub.1-4-alkyl, COCF.sub.3, CH.sub.2NH.sub.2 or
CH.sub.2NHCOOR.sup.12; [0852] R.sup.8 denotes C.sub.1-4-alkyl,
C.sub.3-6-cycloalkyl, NH.sub.2, hetaryl, aryl, optionally
substituted by one or more chlorine; [0853] R.sup.9 denotes H,
COOR.sup.12 or het, optionally substituted by one or more
C.sub.1-4-alkyl, or a group selected from among C.sub.1-4-alkyl,
which may optionally be substituted by one or more COOH,
N(C.sub.1-4-alkyl).sub.2 or 4-methylpiperazine; [0854] R.sup.10
denotes H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl or COCH.sub.3; [0855]
R.sup.11 denotes C.sub.1-4-alkyl, optionally substituted by one or
more N(C.sub.1-4-alkyl).sub.2, [0856] R.sup.12 denotes
C.sub.1-4-alkyl; [0857] n denotes 0 or 2; [0858] R.sup.b denotes H,
OH or COOEt; [0859] R.sup.c denotes NH.sub.2 or NHCOR.sup.13;
[0860] R.sup.13 denotes C.sub.1-4-alkyl, or NR.sup.13.1R.sup.13.2,
[0861] R.sup.13.1 denotes H or C.sub.1-4-alkyl; [0862] R.sup.13.2
denotes H or C.sub.1-4-alkyl; and the pharmacologically acceptable
salts, diastereomers, enantiomers, racemates, hydrates or solvates
thereof, with the proviso that R.sup.a cannot be H or Me if
Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0863] Particularly preferred are the above-mentioned compounds of
formula 1 wherein [0864] R.sup.a denotes H, C.sub.1-alklyl,
C.sub.2-6-alkenyl, C.sub.3-6-cycloalkyl, CF.sub.3, COR.sup.8,
NR.sup.9R.sup.10, NO.sub.2, S(O).sub.nR.sup.11, or a group selected
from among ##STR141## [0865] or a group selected from among
##STR142## [0866] which may optionally be substituted by one or
more Cl; [0867] or a group selected from among ##STR143## [0868]
which may optionally be substituted by one or more CH.sub.3,
COCF.sub.3, CH.sub.2NH.sub.2 or CH.sub.2NHCOOR.sup.12; [0869]
R.sup.8 denotes C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, NH.sub.2,
furanyl or phenyl, optionally substituted by one or more chlorine;
[0870] R.sup.9 denotes H, COOR.sup.12 or piperidino, optionally
substituted by one or more CH.sub.3, or a group selected from among
C.sub.1-4-alkyl, which may optionally be substituted by one or more
COOH, NMe.sub.2 or 4-methylpiperazine; [0871] R.sup.10 denotes H,
C.sub.1-4-alkyl, C.sub.2-4-alkynyl or COCH.sub.3; [0872] R.sup.11
denotes C.sub.1-4-alkyl, optionally substituted by one or more
NMe.sub.2, [0873] R.sup.12 denotes C.sub.1-4-alkyl; [0874] R.sup.b
denotes H, OH or COOEt; [0875] R.sup.c denotes NH.sub.2 or
NHCOR.sup.13; [0876] R.sup.13 denotes C.sub.1-4-alkyl, or
NR.sup.13.1R.sup.13.2, [0877] R.sup.13.1 denotes H or
C.sub.1-4-alkyl; [0878] R.sup.13.2 denotes H or C.sub.1-4-alkyl;
and the pharmacologically acceptable salts, diastereomers,
enantiomers, racemates, hydrates or solvates thereof, with the
proviso that R.sup.a cannot be H or Me if Y=nitrogen; Z=nitrogen;
j=2; k=0; R.sup.b=H and R.sup.c=NHCONH-Et.
[0879] Particularly preferred are the above-mentioned compounds of
formula 1 wherein [0880] R.sup.a denotes H, methyl, ethyl, propyl,
butyl, 3-methyl-butyl, propenyl, cyclopropyl, cyclohexyl, CF.sub.3,
COR.sup.8, NR.sup.9R.sup.10, NO.sub.2, S(O).sub.nR.sup.11, or a
group selected from among ##STR144## [0881] or a group selected
from among ##STR145## [0882] which may optionally be substituted by
one or more Cl; [0883] or a group selected from among ##STR146##
[0884] which may optionally be substituted by one or more CH.sub.3,
COCF.sub.3, CH.sub.2NH.sub.2 or CH.sub.2NHCOOR.sup.12; [0885]
R.sup.8 denotes methyl, propyl, cyclopropyl, NH.sub.2, furanyl or
phenyl, optionally substituted by one or more chlorine; [0886]
R.sup.9 denotes H, COOR.sup.12 or piperidino, optionally
substituted by one or more CH.sub.3, or a group selected from among
methyl, ethyl and propyl, which may optionally be substituted by
one or more COOH, NMe.sub.2 or 4-methylpiperazine; [0887] R.sup.10
denotes H, methyl, COCH.sub.3, C.ident.CH or CH.sub.2C.ident.CH;
[0888] R.sup.11 denotes ethyl or propyl, optionally substituted by
one or more NMe.sub.2, [0889] R.sup.12 denotes butyl [0890] R.sup.b
denotes H, OH or COOEt; [0891] R.sup.c denotes NH.sub.2 or
NHCOR.sup.13; [0892] R.sup.13 denotes methyl or
NR.sup.13.1R.sup.13.2, [0893] R.sup.13.1 denotes H or methyl;
[0894] R.sup.13.2 denotes H or methyl. and the pharmacologically
acceptable salts, diastereomers, enantiomers, racemates, hydrates
or solvates thereof, with the proviso that R.sup.a cannot be H or
Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R.sup.b=H and
R.sup.c=NHCONH-Et.
[0895] Most preferred are the above-mentioned compounds of formula
1; wherein R.sup.a denotes propyl, COR.sup.8, NR.sup.9R.sup.10,
S(O).sub.nR.sup.11 and ##STR147## R.sup.8 denotes furanyl; R.sup.9
denotes methyl; R.sup.10 denotes methyl; R.sup.11 denotes ethyl; n
denotes 0; R.sup.b denotes H or OH; R.sup.c denotes NH.sub.2 or
NHCOCH.sub.3; and the pharmacologically acceptable salts,
diastereomers, enantiomers, racemates, hydrates or solvates
thereof.
[0896] Particularly preferred are the above compounds, and also
pharmacologically acceptable salts, diastereomers, enantiomers,
racemates, hydrates or solvates thereof, with the proviso that
R.sup.a cannot be H or Me if Y and Z=nitrogen; j=2; k=0; R.sup.b=H
and R.sup.c=NHCONH-Et denotes and that R.sup.c cannot be NH.sub.2
if Y and Z=nitrogen; j=2; k=1; R.sup.b=H and R.sup.a= ##STR148##
Terms and Definitions Used
[0897] By the term "C.sub.1-6-alkyl" (including those which are
part of other groups) are meant branched and unbranched alkyl
groups with 1 to 6 carbon atoms, and by the term "C.sub.1-4-alkyl"
are meant branched and unbranched alkyl groups with 1 to 4 carbon
atoms. Alkyl groups with 1 to 4 carbon atoms are preferred.
Examples of these include: methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,
neo-pentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu,
i-Bu, t-Bu, etc. may optionally also be used for the
above-mentioned groups. Unless stated otherwise, the definitions
propyl, butyl, pentyl and hexyl include all the possible isomeric
forms of the groups in question. Thus, for example, propyl includes
n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and
tert-butyl etc.
[0898] By the term "C.sub.1-6-alkylene" (including those which are
part of other groups) are meant branched and unbranched alkylene
groups with 1 to 6 carbon atoms and by the term
"C.sub.1-4-alkylene" are meant branched and unbranched alkylene
groups with 1 to 4 carbon atoms. Alkylene groups with 1 to 4 carbon
atoms are preferred. Examples include: methylene, ethylene,
propylene, 1-methylethylene, butylene, 1-methylpropylene,
1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,
1,1-dimethylpropylene, 2,2-dimethylpropylene,
1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless
stated otherwise, the definitions propylene, butylene, pentylene
and hexylene also include all the possible isomeric forms of the
relevant groups with the same number of carbons. Thus for example
propyl also includes 1-methylethylene and butylene includes
1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.
[0899] The term "C.sub.2-6-alkenyl" (including those which are part
of other groups) denotes branched and unbranched alkenyl groups
with 2 to 6 carbon atoms and the term "C.sub.2-4-alkenyl" denotes
branched and unbranched alkenyl groups with 2 to 4 carbon atoms,
provided that they have at least one double bond. Preferred are
alkenyl groups with 2 to 4 carbon atoms. Examples include: ethenyl
or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise
stated, the definitions propenyl, butenyl, pentenyl and hexenyl
include all possible isomeric forms of the groups in question.
Thus, for example, propenyl includes 1-propenyl and 2-propenyl,
butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl,
1-methyl-2-propenyl etc.
[0900] By the term "C.sub.2-6-alkenylene" (including those which
are part of other groups) are meant branched and unbranched
alkenylene groups with 2 to 6 carbon atoms and by the term
"C.sub.2-4-alkenylene" are meant branched and unbranched alkylene
groups with 2 to 4 carbon atoms. Alkenylene groups with 2 to 4
carbon atoms are preferred. Examples include: ethenylene,
propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene,
1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene,
1,1-dimethylpropenylene, 2,2-dimethylpropenylene,
1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene.
Unless stated otherwise, the definitions propenylene, butenylene,
pentenylene and hexenylene include all the possible isomeric forms
of the respective groups with the same number of carbons. Thus, for
example, propenyl also includes 1-methylethenylene and butenylene
includes 1-methylpropenylene, 1,1-dimethylethenylene,
1,2-dimethylethenylene.
[0901] By the term "C.sub.2-6-alkynyl" (including those which are
part of other groups) are meant branched and unbranched alkynyl
groups with 2 to 6 carbon atoms and by the term "C.sub.2-4-alkynyl"
are meant branched and unbranched alkynyl groups with 2 to 4 carbon
atoms, provided that they have at least one triple bond. Alkynyl
groups with 2 to 4 carbon atoms are preferred. Examples include:
ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless stated
otherwise, the definitions propynyl, butynyl, pentynyl and hexynyl
include all the possible isomeric forms of the respective groups.
Thus, for example, propynyl includes 1-propynyl and 2-propynyl,
butynyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl,
1-methyl-2-propynyl etc.
[0902] By the term "C.sub.2-6-alkynylene" (including those which
are part of other groups) are meant branched and unbranched
alkynylene groups with 2 to 6 carbon atoms and by the term
"C.sub.2-4-alkynylene" are meant branched and unbranched alkylene
groups with 2 to 4 carbon atoms. Alkynylene groups with 2 to 4
carbon atoms are preferred. Examples include: ethynylene,
propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene,
1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene,
1,1-dimethylpropynylene, 2,2-dimethylpropynylene,
1,2-dimethylpropynylene, 1,3-dimethylpropynylene or hexynylene.
Unless stated otherwise, the definitions propynylene, butynylene,
pentynylene and hexynylene include all the possible isomeric forms
of the respective groups with the same number of carbons. Thus for
example propynyl also includes 1-methylethynylene and butynylene
includes 1-methylpropynylene, 1,1-dimethylethynylene,
1,2-dimethylethynylene.
[0903] By the term "C.sub.1-6-alkoxy" (including those which are
part of other groups) are meant branched and unbranched alkoxy
groups with 1 to 6 carbon atoms and by the term "C.sub.1-4-alkoxy"
are meant branched and unbranched alkoxy groups with 1 to 4 carbon
atoms. Alkoxy groups with 1 to 4 carbon atoms are preferred.
Examples include: methoxy, ethoxy, propoxy, butoxy or pentoxy. The
abbreviations OMe, OEt, OPr, etc. may optionally be used for the
above-mentioned groups. Unless stated otherwise, the definitions
propoxy, butoxy and pentoxy include all the possible isomeric forms
of the respective groups. Thus for example propoxy includes
n-propoxy and iso-propoxy, butoxy includes iso-butoxy, sec-butoxy
and tert-butoxy etc.
[0904] By the term "C.sub.3-8-cycloalkyl" (including those which
are part of other groups) are meant cyclic alkyl groups with 3 to 8
carbon atoms, by the term "C.sub.3-6-cycloalkyl" are meant cyclic
alkyl groups with 3 to 8 carbon atoms and by the term
"C.sub.5-6-cycloalkyl" are meant cyclic alkyl groups with 5 to 6
carbon atoms. Examples include: cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
[0905] By the term "C.sub.3-6-cycloalkenyl" (including those which
are part of other groups) are meant cyclic alkyl groups with 5 or 6
carbon atoms which contain one or two double bonds. Examples
include: cyclopentenyl, cyclopentadienyl, cyclohexenyl or
cyclohexadienyl.
[0906] By the term "C.sub.1-6-haloalkyl" (including those which are
part of other groups) are meant branched and unbranched alkyl
groups with 1 to 6 carbon atoms wherein one or more hydrogen atoms
are replaced by a halogen atom selected from among fluorine,
chlorine or bromine, preferably fluorine and chlorine, particularly
preferably fluorine. By the term "C.sub.1-4-haloalkyl" are meant
correspondingly branched and unbranched alkyl groups with 1 to 4
carbon atoms, wherein one or more hydrogen atoms are replaced
analogously to what was stated above. C.sub.1-4-haloalkyl is
preferred. Examples include: CH.sub.2F, CHF.sub.2, CF.sub.3,
[0907] By the term "C.sub.7-11-aralkyl" (including those which are
part of other groups) are meant branched and unbranched alkyl
groups with 1 to 4 carbon atoms which are substituted by an
aromatic ring system with 6 carbon atoms. Examples include: benzyl,
1- or 2-phenylethyl. Unless otherwise stated, the aromatic groups
may be substituted by one or more groups selected from among
methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine,
bromine and iodine.
[0908] By the term "aryl" (including those which are part of other
groups) are meant aromatic ring systems with 6 or 10 carbon atoms.
Examples include: phenyl or naphthyl, the preferred aryl group
being phenyl.
[0909] By the term heterocyclic rings ("het") are meant five-, six-
or seven-membered, saturated or unsaturated heterocyclic rings or
5-10 membered, bicyclic hetero rings which may contain one, two or
three heteroatoms, selected from among oxygen, sulphur and
nitrogen; the ring may be linked to the molecule by a carbon atom
or, if present, by a nitrogen atom. The following are examples of
five-, six- or seven-membered, saturated or unsaturated
heterocyclic rings: ##STR149##
[0910] Unless stated otherwise, a heterocyclic ring may be provided
with a keto group. Examples include: ##STR150##
[0911] Examples of 5- 10-membered bicyclic heterorings are
pyrrolizine, indole, indolizine, isoindole, indazole, purine,
quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran,
benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine,
pyrimidopyrimidine, ##STR151##
[0912] Although the term heterocyclic rings includes ("hetaryl"),
the term heterocyclic aromatic groups denotes five- or six-membered
heterocyclic aromatic groups or 5-10 membered, bicyclic hetaryl
rings which may contain one, two or three heteroatoms, selected
from among oxygen, sulphur and nitrogen, which contain sufficient
conjugated double bonds that an aromatic system is formed. The ring
may be linked to the molecule through a carbon atom or if present
through a nitrogen atom. The following are examples of five- or
six-membered heterocyclic aromatic groups: ##STR152##
[0913] Examples of 5- 10-membered bicyclic hetaryl rings include
pyrrolizine, indole, indolizine, isoindole, indazole, purine,
quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran,
benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine,
pyrimidopyrimidine.
[0914] By the term heterocyclic spiro rings ("spiro") are meant
5-10 membered, spirocyclic rings which may optionally contain one,
two or three heteroatoms, selected from among oxygen, sulphur and
nitrogen, while the ring may be connected to the molecule via a
carbon atom or, if present, via a nitrogen atom. Unless otherwise
stated, a spirocyclic ring may be provided with a keto group.
Examples include: ##STR153##
[0915] By the term "optionally substituted" is meant within the
scope of the invention the above-mentioned group, optionally
substituted by a lower-molecular group. Examples of lower-molecular
groups regarded as chemically meaningful are groups consisting of
1-200 atoms. Preferably such groups have no negative effect on the
pharmacological efficacy of the compounds.
[0916] For example the groups may comprise: [0917] Straight-chain
or branched carbon chains, optionally interrupted by heteroatoms,
optionally substituted by rings, heteroatoms or other common
functional groups. [0918] Aromatic or non-aromatic ring systems
consisting of carbon atoms and optionally heteroatoms, which may in
turn be substituted by functional groups. [0919] A number of
aromatic or non-aromatic ring systems consisting of carbon atoms
and optionally heteroatoms which may be linked by one or more
carbon chains, optionally interrupted by heteroatoms, optionally
substituted by heteroatoms or other common functional groups.
Synthesis of the Reagents
IMIDAZOL-1-YL-[1-(2-TRIMETHYLSILANYL-ETHOXYMETHYL)-1H-IMIDAZOL-4-YL]-METHA-
NONE
[0920] ##STR154##
[0921] A suspension of 1.5 g (63 mmol) sodium hydride (60%
suspension in mineral oil) in 80 ml DMF is combined batchwise with
8 g (63 mmol) methyl imidazole-4-carboxylate and the resulting
solution is stirred for 1 hour. The reaction mixture is cooled to
5.degree. C. and 12 ml (70 mmol) [2-(trimethylsilyl)-ethoxy]methyl
chloride are added. After 12 hours the suspension is combined with
100 ml of water and extracted with ethyl acetate. The combined
organic phases are washed with sodium chloride solution, dried and
evaporated down.
[0922] Yield: 16 g
[0923] 16 g (62 mmol) of the intermediate described above is
dissolved in 20 ml dioxane and 66 ml 2 N sodium hydroxide solution
and refluxed for 1.5 hours. The reaction mixture is acidified with
2 N hydrochloric acid and the precipitated solid is suction
filtered, washed with water and diethyl ether and dried.
[0924] Yield: 13 g
[0925] 13 g (55 mmol) of the intermediate described above are
placed in 150 ml dichloromethane and combined with 22.4 g (138
mmol) carbonyldiimidazole. The reaction mixture is stirred for 1
hour at ambient temperature and then washed with semisaturated
sodium chloride solution. The organic phase is dried and evaporated
to dryness. Yield: 15 g
IMIDAZOL-1-YL(1-METHYL-1H-IMIDAZOL-4-YL)-METHANONE
[0926] ##STR155##
[0927] 39.5 g (0.31 mol) 1-methyl-1H-imidazol-4-carboxylic acid are
placed in 400 ml dichloromethane and 115.6 g (0.71 mol)
carbonyldiimidazole are added. The suspension is stirred for 3
hours at ambient temperature, then extracted with saturated sodium
chloride solution. The aqueous phase is extracted with
dichloromethane, the combined organic phases are dried and
evaporated to dryness. Yield: 60.6 g
1-IMIDAZOL-1-YL-2-METHYL-PROPAN-1-ONE
[0928] ##STR156##
[0929] 12.0 g (0.18 mol) imidazole are placed in 200 ml chloroform
at 0.degree. C. and then combined with 10.8 ml (0.10 mol) isobutyl
chloride. The mixture is stirred for 1 hour at ambient temperature.
Then the reaction mixture is washed with water, the organic phase
is dried and evaporated to dryness. Yield: 10.7 g
(R)-IMIDAZOL-1-YL-(TETRAHYDROFURAN-2-YL)-METHANONE
[0930] ##STR157##
[0931] 21.8 g (32 mmol) imidazole are placed in 400 ml chloroform
and cooled to .sup.0.degree. C. 21.3 g (15.0 mol)
(R)-tetrahydrofuran-2-carbonyl chloride are added dropwise, is then
the mixture is stirred for 1.5 hours at ambient temperature. After
cooling again to 0.degree. C. the reaction mixture is extracted
with semisaturated sodium chloride solution. The organic phase is
dried and evaporated to dryness. Yield: 24.0 g
(S)-IMIDAZOL-1-YL-(TETRAHYDROFURAN-2-YL)-METHANONE
[0932] ##STR158##
[0933] 21.8 g (32.0 mmol) imidazole are placed in 400 ml chloroform
and cooled to .sup.0.degree. C. 21.5 g (15.0 mmol)
(S)-tetrahydrofuran-2-carbonyl chloride are added dropwise, then
stirred for 1.5 hours at ambient temperature. After cooling again
to 0.degree. C. the reaction mixture is extracted with
semisaturated sodium chloride solution. The organic phase is dried
and evaporated to dryness. Yield: 23.5 g
1-IMIDAZOL-1-YL-2-METHOXY-ETHANONE
[0934] ##STR159##
[0935] Analogously to the method described above 5.6 g of the
desired product are obtained from 14.9 g (219 mmol) imidazole and
10 ml (109 mmol) methoxyacetic acid chloride.
1-IMIDAZOL-1-YL-3-TRIMETHYLSILANYL-PROPYNONE
[0936] ##STR160##
[0937] 0.5 g (3.5 mmol) 3-trimethylsilylpropynoic acid are
dissolved in 10 ml THF and combined with 1.7 g (10.6 mmol)
carbonyldiimidazole. The reaction mixture is stirred overnight at
ambient temperature and then filtered. The filtrate is diluted with
diethyl ether and washed twice with cold water. The organic phase
is dried over magnesium sulphate and evaporated down. Yield: 0.4
g
(4-HYDRAZINO-PHENYL)-ACETIC ACID HYDROCHLORIDE
[0938] ##STR161##
[0939] 15.1 g (10.0 mmol) 4-aminophenylacetic acid are placed in a
solution of 10.6 g (10.0 mmol) sodium carbonate in 100 ml of water.
The mixture is cooled to .sup.0.degree. C., then 6.9 g (10.0 mmol)
sodium nitrite in 50 ml of water are added. This mixture is added
dropwise to 100 ml of conc. hydrochloric acid while being cooled,
then stirred for 0.1 hours. 45.1 g (20.0 mmol) tin(II)-chloride in
40 ml of conc. hydrochloric acid are added dropwise with vigorous
stirring, during which time a precipitate is formed. The reaction
mixture is stirred for 1 hour at ambient temperature, then suction
filtered. The precipitate is washed with water and dried. Yield:
22.0 g
3-CHLORO-5-HYDRAZINO-PHENOL
[0940] ##STR162##
[0941] 2.1 g (14.3 mmol) 3-amino-5-chloro-phenol are dissolved in
20 ml of conc. hydrochloric acid and 20 ml of water and cooled to
0.degree. C. 1.0 g (15.0 mmol) sodium nitrite in 4 ml of water are
added. Then a solution of 12.1 g (53.5 mmol) tin(II)-chloride in 16
ml hydrochloric acid is slowly added dropwise at -5.degree. C. It
is stirred for 1 hour at 0.degree. C., then adjusted to pH7 with
sodium hydrogen carbonate. The precipitate formed is suction
filtered and washed with water. The filtrate is extracted with
diethyl ether. The organic phase is dried and evaporated to
dryness. The residue is extracted with hexane.
[0942] Yield: 1.2 g
2-CHLORO-4-HYDRAZINO-PHENOL
[0943] ##STR163## analogously to the method described above 2.3 g
hydrazine are obtained from 2.2 g (15 mmol)
4-amino-2-chloro-phenol.
METHYL 3-CHLORO-4--HYDRAZINO-BENZOATE
[0944] ##STR164##
[0945] 3.0 g (16.0 mmol) methyl 4-amino-3-chlorobenzoate are
suspended in 15 ml of conc. hydrochloric acid and cooled to
-10.degree. C. First a solution of 1.1 g (16.0 mmol) sodium nitrite
in 15 ml of water is added dropwise, then a solution of 16.1 g
(71.0 mmol) tin(II)-chloride in 13.5 ml hydrochloric acid. A
precipitate settles out. The reaction mixture is made basic with 3
molar sodium hydroxide solution, then suction filtered. The
precipitate is extracted with dichloromethane and water, the
organic phase is dried, combined with activated charcoal and
evaporated to dryness. The residue is purified by chromatography.
Yield: 1.4 g (M.p.: 120.degree. C.)
3-CHLORO-4--HYDRAZINO-BENZOIC ACID
[0946] ##STR165##
[0947] 4.0 g (20.0 mmol) methyl 3-chloro-4-hydrazino-benzoate are
taken and 75 ml 3 molar sodium hydroxide solution are added
thereto. This is stirred for 16 hours at ambient temperature. Then
the reaction mixture is adjusted to pH 6 with glacial acetic acid
and the precipitated solid is suction filtered. This is extracted
with diethyl ether. Yield: 2.4 g
(4-BROMO-2-TRIFLUOROMETHYL-PHENYL)-HYDRAZINE
[0948] ##STR166##
[0949] A suspension of 25.6 g (0.11 mol)
4-bromo-2-(trifluoromethyl)-aniline in 125 ml of conc. hydrochloric
acid is cooled to -10.degree. C. and a solution of 7.7 g (0.11 mol)
sodium nitrite in 125 ml of water is added. The reaction mixture is
stirred for 3 hours at -10 to -5.degree. C., then a solution of 103
g (0.46 mol) tin-(II)-chloride-dihydrate in 125 ml of conc.
hydrochloric acid is added dropwise. The mixture is stirred for 1
hour at -5.degree. C. The precipitate formed is suction filtered
and washed with water. The aqueous mother liquor is extracted with
petroleum ether, then made basic with sodium hydroxide. The
precipitate formed is extracted with diethyl ether. The organic
phase is dried and evaporated to dryness. Yield: 12.9 g
2,2,2-TRIFLUORO-1-(4-HYDRAZINO-PIPERIDIN-1-YL)-ETHANONE-TRIFLUOROACETATE
[0950] ##STR167##
[0951] 100 g (0.65 mol) 4-piperdinone-hydrate-hydrochloride and
274.6 ml (1.97 mol) triethylamine are placed in 1000 ml
dichloromethane and then cooled to 0.degree. C. 182.1 ml (1.31 mol)
trifluoroacetic anhydride are slowly added and the mixture is
stirred for 0.5 hours. The reaction mixture is washed with water
and sodium bicarbonate solution, the organic phase is dried and
evaporated to dryness. The residue is stirred with
methyl-tert-butylether, the precipitate is suction filtered, washed
and dried. Yield: 106.0 g
[0952] 106.0 g (0.54 mol)
1-(2,2,2-trifluoro-acetyl)-piperidin-4-one are dissolved in 1000 ml
of ethanol and combined with 71.8 g (0.54 mol) tert-butyl
hydrazinoformate. The reaction mixture is stirred for 3.5 hours at
ambient temperature, then evaporated to dryness. Yield: 172.0 g
[0953] 172.0 g (0.56 mol) tert-butyl
N'-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-ylidene]-hydrazine-carboxylate
are dissolved in 2000 ml of methanol. 17.0 g palladium on charcoal
(10%) are added and the mixture is hydrogenated at 1 bar hydrogen.
After the hydrogen uptake has ended the catalyst is suction
filtered and the mother liquor concentrated by evaporation. The
residue crystallises out overnight. Yield: 168.0 g
[0954] 5.0 g (16.1 mmol) tert-butyl
N'-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-hydrazine-carboxylate
are dissolved in 50 ml dichloromethane and combined with 6.0 ml
(77.9 mmol) trifluoroacetic acid. The reaction mixture is stirred
for 5 hours at ambient temperature, then concentrated by
evaporation. Yield: 6.70 g
4-(4-METHYL-PIPERAZIN-1-YL)-PHENYLAMINE
[0955] ##STR168##
[0956] 18.1 g (0.18 mol) 1-methyl-piperazine, 25.5 g (0.18 mol)
1-fluoro-4-nitrobenzene and 50 g (0.36 mol) potassium carbonate are
placed in 200 ml of dimethylformamide and stirred for 15 hours at
130.degree. C. After cooling 300 ml of water are added, during
which time a precipitate is formed. The aqueous phase with the
precipitate is cooled, then suction filtered and washed with water.
The precipitate is recrystallised from ethanol.
[0957] Yield: 23.2 g
[0958] 10.0 g (45 mmol) 1-methyl-4-(4-nitro-phenyl)-piperazine are
dissolved in 250 ml of ethanol, then combined with 2 g
palladium/charcoal (10%) and hydrogenated at 5 bar hydrogen for 2
hours. Then the reaction mixture is suction filtered and the
filtrate is concentrated by evaporation. The residue is
recrystallised from cyclohexane. Yield: 7.7 g
4-(1-METHYL-PIPERIDIN-4-YL)-PHENYLAMINE
[0959] ##STR169##
[0960] 125 g (0.78 mol) 4-phenylpiperidine are dissolved in 1300 ml
dichloromethane and combined with 149 ml (0.85 mol)
diisopropylethylamine. The reaction mixture is cooled to -5.degree.
C., then within 2 hours 120 ml (0.85 mol) trifluoroacetic anhydride
are added dropwise. The mixture is then stirred for 1 hour while
cooling with ice and for 16 hours at ambient temperature. 400 ml of
water are added and the phases are separated. The organic phase is
washed with water, dried and evaporated to dryness. Yield: 193
g
[0961] 80 g (0.31 mol)
2,2,2-trifluoro-1-(4-phenyl-piperidin-1-yl)-ethanone are dissolved
in 400 ml glacial acetic acid and 200 ml acetic anhydride and
cooled to 0.degree. C. 1.6 g sodium nitrite are added, then 52 ml
(1.24 mol) fuming nitric acid are added dropwise. The reaction
mixture is stirred for 16 hours at ambient temperature. Then the
reaction mixture is poured onto 1200 ml ice water and adjusted to
pH 8 with 8 N sodium hydroxide solution (temp. <20.degree. C.).
After the addition of dichloromethane the phases are separated and
the aqueous phase is extracted with dichloromethane. The combined
organic phases are washed with 0.1 N sodium hydroxide solution and
water, dried and evaporated to dryness. The product is
recrystallised from cyclohexane/ethyl acetate. Yield: 47 g
[0962] 20 g (66.2 mmol)
2,2,2-trifluoro-1-[4-(4-nitro-phenyl)-piperidin-1yl]-ethanone and
32 g (23.2 mmol) potassium carbonate are placed in 400 ml of
methanol and stirred for 48 hours at ambient temperature. Then the
reaction mixture is concentrated by evaporation, the residue is
extracted with water and dichloromethane. The organic phase is
dried and evaporated to dryness. The hydrochloride is precipitated.
Yield: 15 g
[0963] 6.0 g (24.7 mmol)
4-(4-nitro-phenyl)-piperidine-hydrochloride are placed in 300 ml of
tetrahydrofuran and combined successively with 11 ml (61.8 mmol)
diisopropylethylamine, 5 ml (49.4 mmol) formaldehyde (37% in water)
and 13 g (61.8 mmol) sodium triacetoxyborohydride. The reaction
mixture is stirred for 16 hours at ambient temperature, then poured
onto water and concentrated by evaporation. The aqueous residue is
made basic with 2 N sodium hydroxide solution and extracted with
dichloromethane. The combined organic phases are dried and
evaporated to dryness. Yield: 4.5 g
[0964] 4.3 g (19.5 mmol) 1-methyl-4-(4-nitro-phenyl)-piperidine are
dissolved in a mixture of 60 ml of ethanol and 60 ml THF, combined
with 2 g palladium/charcoal (10%) and hydrogenated at 1 bar
hydrogen. Then the reaction mixture is suction filtered and the
filtrate is concentrated by evaporation. Yield: 3.5 g
4-(1-CYCLOPROPYLMETHYL-PIPERIDIN-4-YL)-PHENYLAMINE
[0965] ##STR170##
[0966] 6.0 g (24.7 mmol) of the intermediate described above,
4-(4-nitro-phenyl)-piperidine-hydrochloride, are placed in 300 ml
of tetrahydrofuran and combined successively with 11 ml (61.8 mmol)
diisopropylethylamine, 3.7 ml (49.4 mmol) cyclopropane
carboxaldehyde and 13 g (61.8 mmol) sodium triacetoxyborohydride.
The reaction mixture is stirred for 3 hours at ambient temperature,
then poured onto water and concentrated by evaporation. The aqueous
residue is extracted with dichloromethane, the organic phase is
dried and evaporated to dryness. The aqueous phase is made basic
with 2 N sodium hydroxide solution, then extracted with
dichloromethane. The organic phase is dried and evaporated to
dryness. Yield: 5.6 g
[0967] 3.3 g (12.5 mmol)
1-cyclopropylmethyl-4-(4-nitro-phenyl)-piperidine are dissolved in
a mixture of 40 ml of ethanol and 40 ml THF, combined with 1.3 g
palladium/charcoal (10%) and hydrogenated at 1 bar hydrogen. Then
the reaction mixture is suction filtered and the filtrate is
concentrated by evaporation. Yield: 2.7 g
1,1-DIMETHYL-2-DIMETHYLAMINO-1-YL-ETHYLAMINE AND
1,1-DIMETHYL-2-PIPERIDIN-1-YL-ETHYLAMINE
[0968] ##STR171##
[0969] The compounds were prepared according to the following
references: a) S. Schuetz et al. Arzneimittel-Forschung 1971, 21,
739-763 b) V. M. Belikov et al. Tetrahedron 1970, 26, 1199-1216. c)
E. B. Butler and McMillan J. Amer. Chem. Soc. 1950, 72, 2978.
[0970] Other amines were prepared as follows according to a
modification of the literature mentioned above.
1,1-DIMETHYL-2-MORPHOLIN-1-YL-ETHYLAMINE
[0971] ##STR172##
[0972] 8.7 ml morpholine and 9.3 ml 2-nitropropane are taken, while
cooling with ice, and 7.5 ml formaldehyde (37% in water) and 4 ml
of a 0.5 mol/L NaOH solution are slowly added dropwise
(<10.degree. C.). Then the mixture is stirred for 1 h at
25.degree. C. and for 1 h at 50.degree. C. The solution is treated
with water and ether and the aqueous phase is extracted 3.times.
with ether. The combined organic phases are dried over sodium
sulphate and combined with hydrochloric acid in dioxane (4 mol/L),
the precipitate formed is suction filtered.
[0973] Yield: 21.7 g of colourless powder
[0974] 5 g of the white powder are dissolved in 80 ml of methanol
and with the addition of 2 g RaNi treated with hydrogen at
35.degree. C. and 50 psi for 40 minutes. This yields 3.6 g of
1,1-dimethyl-2-morpholin-1-yl-ethylamine.
[0975] The following amine is prepared analogously to this
method:
1,1-DIMETHYL-N-METHYLPIPERAZIN-1-YL-ETHYLAMINE
[0976] ##STR173##
1,3-DIMORPHOLIN-2-AMINO-PROPANE
[0977] ##STR174##
[0978] 5 g 1,3-dimorpholine-2-nitropropane are dissolved in 80 ml
of methanol and with the addition of 2 g RaNi treated with hydrogen
at 30.degree. C. and 50 psi for 5.5 h. This yields 4.2 g
1,3-dimorpholin-2-amino-propane.
TRANS-N,N-DIBENZYL-CYCLOHEXANE-1,4-DIAMINE
[0979] ##STR175##
[0980] 33 g (112 mmol) 4-dibenzylaminocyclohexanone are dissolved
in 300 ml of methanol, combined with 17.4 g (250 mmol)
hydroxylamine hydrochloride and stirred for 4 h at 60.degree. C.
The solvent is evaporated down in vacuo, combined with 500 ml of
water and 50 g potassium carbonate and extracted twice with 300 ml
dichloromethane. The organic phase is dried, evaporated down in
vacuo, the residue is crystallised from petroleum ether, dissolved
in 1.5 L ethanol and heated to 70.degree. C. 166 g sodium are added
batchwise and the mixture is refluxed until the sodium dissolves.
The solvent is eliminated in vacuo, the residue is combined with
100 ml of water and extracted twice with 400 ml ether. The org.
phase is washed with water, dried, evaporated down in vacuo and the
trans-isomer is isolated through a column (approx. 1.5 L silica
gel; approx. 2 L ethyl acetate 80/methanol 20+2% conc. ammonia).
Yield: 12.6 g
TRANS-N,N-DIMETHYL-CYCLOHEXANE-1,4-DIAMINE
(DIMETHANESULPHONATE)
[0981] ##STR176##
[0982] 4 g (13.6 mmol) trans-N,N-dibenzyl-cyclohexane-1,4-diamine
are placed in 8.1 g (100 mmol) formalin solution (37% in water) and
20 ml (43.4 mmol) formic acid and refluxed for 2 hours. The
reaction mixture is added to ice water and combined with conc.
ammonia. It is extracted with ethyl acetate. The organic phase is
washed with water, dried and evaporated to dryness. The residue is
crystallised from acetone and methanesulphonic acid. Yield: 6 g
(M.p.: 203-204.degree. C. 6 g (11,7 mmol)
trans-N,N-dibenzyl-N',N'-dimethyl-cyclohexane-1,4-diamine-dimethane-
sulphonate are placed in 120 ml of methanol, 1.2 g
palladium/charcoal (10%) are added and then the mixture is
hydrogenated at 50 psi and 20.degree. C. The reaction mixture is
suction filtered through kieselguhr, the mother liquor is
concentrated by evaporation. The residue is crystallised from
acetone. Yield: 3.5 g
CIS- AND TRANS-4-MORPHOLINO-CYCLOHEXYLAMINE
[0983] ##STR177##
[0984] 3.9 g (30 mmol) 4-dibenzylaminocyclohexanone are dissolved
in 100 ml dichloromethane and stirred with 3.9 g (45 mmol)
morpholine and 9.5 g (45 mmol) sodium triacetoxyborohydride for 12
h at RT. Then the mixture is combined with water and potassium
carbonate, the organic phase is separated off, dried and the
solvent is eliminated in vacuo. The residue is purified through a
silica gel column (approx 20 ml silica gel; approx 500 ml of ethyl
acetate 90/methanol 10+1% conc. ammonia). The required fractions
are evaporated down in vacuo.
[0985] Yield: 6.6 g cis-isomer and 2 g trans-isomer.
[0986] Alternatively the
trans-dibenzyl-4-morpholino-cyclohexylamine may be prepared as
follows:
[0987] 6.8 g (23 mmol) trans-N,N-dibenzyl-cyclohexane-1,4-diamine
are dissolved in 90 ml DMF and stirred with 5 ml (42 mmol)
2,2'-dichloroethylether and 5 g potassium carbonate for 8 h at
100.degree. C. After cooling the mixture is combined with 30 ml of
water, precipitated crystals are suction filtered and purified
through a short column (approx. 20 ml silica gel, approx. 100 ml of
ethyl acetate). The residue is crystallised from methanol and conc.
HCl as the dihydrochloride. Yield: 7.3 g
[0988] 7.2 g (16.4 mmol)
trans-dibenzyl-4-morpholino-cyclohexylamine are dissolved in 100 ml
of methanol and hydrogenated on 1.4 g Pd/C (10%) at 30-50.degree.
C. The solvent is eliminated in vacuo and the residue crystallised
from ethanol and conc. HCl.
[0989] Yield: 3.9 g (M.p. 312.degree. C.). The cis-isomer may be
prepared analogously.
CIS- AND TRANS-4-PIPERIDINO-CYCLOHEXYLAMINE
[0990] ##STR178##
[0991] 2.0 g (6.8 mmol) trans-1-amino-4-dibenzylaminocyclohexane
(see preceding Example) are dissolved in 50 ml DMF and stirred with
1.6 g (7 mmol) 1,5-dibromopentane and 2 g potassium carbonate 48 h
at RT. It is cooled, combined with water, extracted twice with 100
ml dichloromethane, dried and the solvent is eliminated in vacuo.
The residue is purified through a column (approx. 100 ml silica
gel, approx. 500 ml of ethyl acetate 80/methanol 20+1% conc.
ammonia). The required fractions are evaporated down in vacuo and
crystallised from petroleum ether. Yield: 1.2 g
[0992] 1.7 g (4.8 mmol) trans-dibenzyl-4-piperidino-cyclohexylamine
are dissolved in 35 ml of methanol and hydrogenated on 350 mg Pd/C
(10%) at 20.degree. C. The solvent is eliminated in vacuo and the
residue is crystallised from ethanol and conc. HCl. Yield: 1.1 g.
The cis-isomer may be prepared analogously.
CIS- AND TRANS-4-(4-PHENYL-PIPERAZIN-1-YL)-CYCLOHEXYLAMINE
[0993] ##STR179##
[0994] 4.1 g (25.3 mmol) 4-dibenzylaminocyclohexanone are dissolved
in 50 ml dichloromethane and stirred with 7.4 g (25.3 mmol)
N-phenylpiperazine and 7.4 g (35 mmol) sodium triacetoxyborohydride
for 12 h at RT. Then the mixture is combined with water and
potassium carbonate, the organic phase is separated off, dried and
the solvent is eliminated in vacuo. The residue is purified through
a silica gel column (ethyl acetate 80/methanol 20+0.5% conc.
ammonia). Yield: 1.7 g cis-isomer and 0.27 g trans-isomer.
[0995] 270 mg (0.61 mmol)
trans-dibenzyl-[4-(4-phenyl-piperazin-1-yl)-cyclohexyl]-amine are
dissolved in 5 ml of methanol and hydrogenated on 40 mg Pd/C (10%)
at 20-30.degree. C. The solvent is eliminated in vacuo and the
residue is crystallised from ethanol and conc. HCl. Yield: 110 mg.
The cis-isomer may be prepared analogously.
CIS-4-(4-CYCLOPROPYLMETHYL-PIPERAZIN-1-YL)-CYCLOHEXYLAMINE
[0996] ##STR180##
[0997] 9.8 g (33.4 mmol) 4-dibenzylcyclohexanone are dissolved in
100 ml dichloromethane and stirred with 5.6 g (40 mmol)
N-cyclopropylmethylpiperazine and 8.5 g (40 mmol) sodium
triacetoxyborohydride for 12 h at RT. Then the mixture is combined
with water and potassium carbonate, the organic phase is separated
off, dried and the solvent is eliminated in vacuo. The residue is
purified through a silica gel column (approx. 50 ml silica gel,
approx. 3 L ethyl acetate 95/methanol 5+0.25% conc. ammonia). The
required fractions are evaporated down in vacuo.
[0998] Yield: 8.5 g cis-isomer and 2.2 trans-isomer.
[0999] 8.5 g (20 mmol)
cis-dibenzyl-[4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-amine
are dissolved in 170 ml of methanol and hydrogenated on 1.7 g Pd/C
(10%) at 30-50.degree. C. The solvent is eliminated in vacuo and
the residue is crystallised from ethanol and conc. HCl. Yield: 4.4
g
4-(4,4-DIMETHYL-PIPERIDIN-1YL)-CYCLOHEXYLAMINE
[1000] ##STR181##
[1001] 8.8 g (30 mmol) 4-dibenzylamino-cyclohexanone, 6.7 g (45
mmol) 4,4-dimethyl-piperidine-hydrochloride and 9.5 g (45 mmol)
sodium triacetoxyborohydride are stirred in 100 ml dichloromethane
for 16 hours at ambient temperature. 200 ml of water and 20 g
potassium carbonate are added, the organic phase is separated off
and evaporated to dryness. The residue is purified by
chromatography.
[1002] Yield: 0.7 g cis-isomer (M.p.: 125-126.degree. C.) and 0.4 g
trans-isomer.
[1003] 0.7 g (1.8 mmol)
cis-dibenzyl-[4-(4,4-dimethyl-piperidin-1yl)-cyclohexyl]-amine are
placed in 14 ml of methanol, 0.14 g palladium/charcoal (10%) are
added and the mixture is hydrogenated at 50 psi and 20.degree. C.
Then the catalyst is suction filtered and the mother liquor is
concentrated by evaporation. Yield: 0.3 g
CIS- AND TRANS-4-PYRROLIDIN-1-YL-CYCLOHEXYLAMINE
(HYDROCHLORIDE)
[1004] ##STR182##
[1005] 0.8 g (21 mmol) lithium aluminium hydride are placed in 50
ml of tetrahydrofuran and 6.2 g (20 mmol)
4-dibenzylamino-cyclohexanone oxime (for preparation see above)
dissolved in 62 ml of tetrahydrofuran are added dropwise. Then the
reaction mixture is refluxed for 3 hours with stirring. After
cooling 0.8 ml of water and 2.4 ml 15% sodium hydroxide solution
are added dropwise. The precipitate formed is suction filtered and
washed with tetrahydrofuran. The mother liquor is evaporated to
dryness.
[1006] Yield: 4.9 g (cis/trans-mixture)
[1007] 2.9 g (10 mmol)
cis/trans-N,N-dibenzyl-cyclohexane-1,4-diamine, 2.4 g (11 mmol))
1,4-dibromobutane and 2.7 g potassium carbonate are placed in 70 ml
of dimethylformamide and stirred for 48 hours at ambient
temperature. Then the reaction mixture is concentrated by
evaporation, the residue is extracted with water and
dichloromethane. The organic phase is washed with water, dried and
evaporated to dryness. The residue is purified by chromatography,
corresponding is fractions are combined, concentrated by
evaporation and crystallised from petroleum ether.
[1008] Yield: 0.8 g cis-isomer (M.p.: 81-82.degree. C.) and 0.9 g
trans-isomer (122-124.degree. C.).
[1009] 2.2 g (6.1 mmol)
trans-dibenzyl-(4-pyrrolidin-1-yl-cyclohexyl)-amine are placed in
40 ml of methanol and 0.4 g palladium/charcoal (10%) are added. The
mixture is hydrogenated at 5 bar and 20.degree. C. Then the
catalyst is suction filtered, the mother liquor is combined with
conc. hydrochloric acid and concentrated by evaporation. The
residue is stirred out with acetone.
[1010] Yield: 1.20 g. The cis isomer may be prepared
analogously.
TRANS-4-(4-METHANESULPHONYL-PIPERAZIN-1-YL)-CYCLOHEXYLAMINE
[1011] ##STR183##
[1012] 14 g (47 mmol) 4-dibenzylamino-cyclohexanone, 8.5 g (51
mmol) 1-methanesulphonyl-piperazine and 17.5 g (78 mmol) sodium
triacetoxyborohydride are stirred in 250 ml dichloromethane for 4
hours at ambient temperature. Then the reaction mixture is combined
with 200 ml of water and 20 g potassium carbonate. The organic
phase is separated off, dried and evaporated to dryness. The
residue is purified by chromatography. Yield: 4.8 g
trans-isomer
[1013] 4.8 g (11 mmol)
trans-dibenzyl-[4-(4-methanesulphonyl-piperazin-1yl)-cyclohexyl]-amine
are dissolved in 100 ml of methanol and 2 g palladium/charcoal
(10%) are added. The mixture is hydrogenated at 50 psi and
50.degree. C. Then the catalyst is suction filtered, the mother
liquor is concentrated by evaporation. The precipitate formed is
suction filtered and washed with diethyl ether. Yield: 2.4 g
CIS- AND
TRANS-4-(2,6-DIMETHYL-MORPHOLIN-4-YL)-CYCLOHEXYLAMINE-DIHYDROCHLO-
RIDE
[1014] ##STR184##
[1015] 9 g (31 mmol) 4-dibenzylamino-cyclohexanone, 7.5 g (65 mmol)
cis-2,6-dimethyl-morpholine and 9.5 g (45 mmol) sodium
triacetoxyborohydride are stirred in 100 ml dichloromethane for 2
hours at ambient temperature. Then 200 ml of water are added and
the mixture is made basic with potassium carbonate. The organic
phase is separated off, dried and evaporated to dryness. The
residue is purified by chromatography. Corresponding fractions are
combined and concentrated by evaporation, then the hydrochloride is
precipitated.
[1016] Yield: 10 g cis-isomer (M.p.: 304-305.degree. C.) and 3.5 g
trans-isomer (334-335.degree. C.).
[1017] 9.8 g (21 mmol)
cis-dibenzyl-[4-(2,6-dimethyl-morpholin-4-yl)-cyclohexyl]-amine-dihydroch-
loride are placed in 150 ml of methanol and 2 g palladium/charcoal
(10%) are added. The mixture is hydrogenated at 50 psi and
50.degree. C. Then the catalyst is suction filtered, the mother
liquor is concentrated by evaporation. The precipitate formed is
suction filtered and washed with diethyl ether. Yield: 5.5 g. The
trans isomer may be prepared analogously.
CIS- AND TRANS-4-(4-METHYL-PIPERAZIN-1YL)-CYCLOHEXYLAMINE
[1018] ##STR185##
[1019] 14.7 g (50 mmol) 4-dibenzylamino-cyclohexanone, 15.8 g (100
mmol) ethyl piperazine-N-carboxylate and 10.6 g (50 mmol) sodium
triacetoxyborohydride are stirred in 200 ml dichloromethane for 16
hours at ambient temperature. Then the reaction mixture is combined
with 200 ml of water and 20 g potassium carbonate. The organic
phase is separated off and evaporated to dryness. The residue is
purified by chromatography. Yield: 12 g cis-isomer (M.p.:
143-144.degree. C.) and 4 g trans-isomer (281-282.degree. C.).
[1020] 12 g (27.5 mmol) ethyl
cis-4-(4-dibenzylamino-cyclohexyl)-piperazin-1-carboxylate are
placed in 50 ml of water and 50 ml of conc. hydrochloric acid, then
refluxed for 72 hours. Then the reaction mixture is concentrated by
evaporation, the residue is combined with 200 ml of water and 20 g
potassium carbonate and extracted with dichloromethane. The organic
phase is separated off, dried and evaporated to dryness. The
residue is crystallised from ethyl acetate. Yield: 8.6 g (M.p.:
100-101.degree. C.)
[1021] 4 g (11 mmol)
cis-dibenzyl-(4-piperazin-1-yl-cyclohexyl)-amine are placed in 5 ml
(16.7 mmol) formalin solution (37% in water) and 10 ml (22 mmol)
formic acid, then refluxed for 2 hours with stirring. The reaction
mixture is added to ice water and combined with conc. ammonia. It
is extracted with diethyl ether. The organic phase is washed with
water, dried and evaporated to dryness. The residue is stirred out
with petroleum ether, suction filtered and dried. Yield: 4.10 g
(M.p.: 93-94.degree. C.)
[1022] 4.1 g (11 mmol)
cis-dibenzyl-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-amine are
placed in 80 ml of methanol, 0.8 g palladium/charcoal (10%) are
added and then the mixture is hydrogenated at 50 psi and 20.degree.
C. The reaction mixture is suction filtered through kieselguhr, the
mother liquor is concentrated by evaporation. Yield: 1.90 g. The
trans-isomer may be prepared analogously.
Synthesis of the Intermediate Compounds
INTERMEDIATE COMPOUND 1.
N-(7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE
[1023] ##STR186##
[1024] 112 g (1.0 mol) 1,3-cyclohexanedione are suspended in 700 ml
ice water and 51.6 ml (1.0 mol) bromine are added dropwise at
0.degree. C. within 45 minutes. The suspension is stirred for 3.5
hours at max. 10.degree. C. Then it is suction filtered and the
solid is stirred out in 800 ml of water, suction filtered, washed
with 3 L water and dried. The solid obtained is recrystallised from
ethanol. Yield: 37 g Z2a (m.p.: 159-160.degree. C.)
[1025] 15.5 g (0.2 mol) thiourea are placed in 200 ml of ethanol at
ambient temperature. 37.1 g (0.2 mol) Z2a are added batchwise to
this suspension, then it is rinsed with 60 ml of ethanol. The
solution gradually formed is refluxed for 2 hours with stirring and
then concentrated by evaporation. The residue is extracted with
water and diethyl ether, the aqueous phase is made basic with
sodium carbonate solution. The resulting solid is suction filtered,
washed with water, then stirred out with methanol and evaporated to
dryness. Yield: 22 g Z3a (m.p.: 265-268.degree. C.)
[1026] 230 ml (2.4 mol) acetic anhydride are taken at ambient
temperature, 22 g (0.13 mol) Z3a are added and the mixture is
refluxed for 3 hours with stirring. The suspension goes partially
into solution. After cooling with ice/saline bath the solid is
suction filtered, decocted 2.times. in 150 ml acetone, suction
filtered and dried.
[1027] Yield: 25 g Z4a (m.p.: 268-272.degree. C.)
INTERMEDIATE COMPOUND 2.
N-(6-FORMYL-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE
[1028] ##STR187##
[1029] 20 g (0.37 mol) sodium methoxide are suspended in 50 ml of
dimethylformamide, a suspension of 21 g (0.1 mol) intermediate
compound 1 in 100 ml of dimethylformamide is added dropwise. The
mixture is stirred for 15 minutes, then cooled to 0.degree. C. A
mixture of 29.9 ml (0.37 mol) ethyl formate and 60 ml benzene is
added dropwise and the reaction mixture is diluted with another 100
ml benzene. Gradually a precipitate is formed and stirring is
continued at 0.degree. C. for 3.5 hours. The suspension is
hydrolysed with 370 ml 1 molar hydrochloric acid, the solid thus
precipitated is suction filtered. The two phases of the mother
liquor are separated, the aqueous phase is extracted with
dichloromethane. The resulting organic phase is dried and
evaporated to dryness. The solid and the residue from the
extraction are recrystallised from acetonitrile.
[1030] Yield: 20 g Z5a
INTERMEDIATE COMPOUND 3.
N-(6-DIMETHYLAMINOMETHYLENE-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-A-
CETAMIDE
[1031] ##STR188##
[1032] 30 g (0.13 mol) intermediate compound 2 are suspended in 750
ml dichloromethane and while cooling with ice combined with 1 ml
glacial acetic acid and 30 ml dimethylamine (33% solution in THF).
The reaction mixture is stirred overnight at ambient temperature,
evaporated down and the solid remaining is extracted with
cyclohexane. Yield: 33 g Z5b
INTERMEDIATE COMPOUND 4.
N-[6-(FURAN-2-CARBONYL)-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETA-
MIDE
[1033] ##STR189##
[1034] Analogously to the preparation of intermediate compound 21.7
g product Z5c are obtained from 2 g (10 mmol) intermediate compound
1, 1.6 g (30 mmol) sodium methoxide and 3.8 g (30 mmol) methyl
2-furanoate. (m.p.: 255-256.degree. C.)
INTERMEDIATE COMPOUND 5.
N-(6-BENZOYL-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE
[1035] ##STR190##
[1036] Analogously to the preparation of intermediate compound 23.6
g product Z5d are obtained from 10 g (50 mmol) intermediate
compound 1, 7.8 g (140 mmol) sodium methoxide and 17.9 ml (140
mmol) methyl benzoate.
INTERMEDIATE COMPOUND 6.
N-[6-(FURAN-3-CARBONYL)-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETA-
MIDE
[1037] ##STR191##
[1038] Analogously to the preparation of intermediate compound 24.8
g product Z5e are obtained from 7.5 g (40 mmol) intermediate
compound 1, 7.7 g (110 mmol) sodium methoxide and 15.1 ml (110
mmol) ethyl furan-3-carboxylate.
INTERMEDIATE COMPOUND 7. METHYL
(2-ACETYLAMINO-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-6-YL)-OXO-ACETATE
[1039] ##STR192##
[1040] Analogously to the preparation of intermediate compound 2 52
g product Z5f.sup.Me are obtained from 40 g (190 mmol) intermediate
compound 1, 38 g (0.7 mol) sodium methoxide and 84 g (0.7 mol)
dimethyl oxalate.
INTERMEDIATE COMPOUND 8. ETHYL
(2-ACETYLAMINO-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-6-YL)-OXO-ACETATE
[1041] ##STR193##
[1042] Analogously to the preparation of intermediate compound 2 78
g product Z5f.sup.Et are obtained from 73 g (348 mmol) intermediate
compound 1, 54 g (1 mol) sodium methoxide and 152 g (1 mol) diethyl
oxalate.
INTERMEDIATE COMPOUND 9.
N-[7-OXO-6-(PYRIDINE-3-CARBONYL)-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-AC-
ETAMIDE
[1043] ##STR194##
[1044] Analogously to the preparation of intermediate compound 2
3.1 g product Z5g are obtained from 4 g (19 mmol) intermediate
compound 1, 3.9 g (57 mmol) sodium ethoxide and 7.9 g (57 mmol)
methyl nicotinate.
INTERMEDIATE COMPOUND 10.
N-(6-ACETYL-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE
[1045] ##STR195##
[1046] 1 g (4.8 mmol) intermediate compound 1 are dissolved in 20
ml THF, cooled to -20.degree. C. and combined with 12 ml (12 mmol)
of a 1 N solution of lithium hexamethyl disilazide in hexane. After
45 minutes at -20.degree. C. 0.8 g (7.2 mmol)
1-imidazol-1-yl-ethanone are added and the reaction mixture is
slowly heated to ambient temperature. After one hour at this
temperature the pH is adjusted to 6 with 2 N hydrochloric acid and
the mixture is extracted with ethyl acetate. The combined organic
phases are dried and evaporated down. Yield: 1.2 g Z5h
INTERMEDIATE COMPOUND 11.
N-[6-(1-METHYL-1H-IMIDAZOL-4-CARBONYL)-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIA-
ZOL-2-YL]-ACETAMIDE
[1047] ##STR196##
[1048] Analogously to the preparation of intermediate compound 10
57 g product Z5i are obtained from 50 g (0.24 mol) intermediate
compound 1, 714 ml (0.71 mol) LiHMDS (1 M in THF) and 55 g (0.31
mol) imidazol-1-yl-(1-methyl-1H-imidazol-4-yl)-methanone.
INTERMEDIATE COMPOUND 12.
N-(6-ISOBUTYRYL-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE
[1049] ##STR197##
[1050] Analogously to the preparation of intermediate compound
104.4 g product Z5j are obtained from 4.8 g (23 mmol) intermediate
compound 1, 71 ml (71 mmol) LiHMDS (1 M in hexane) and 6.3 g (46
mmol) 1-imidazol-1-yl-2-methyl-propan-1-one.
INTERMEDIATE COMPOUND 13.
N-[6-(2-METHOXY-ACETYL)-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETA-
MIDE
[1051] ##STR198##
[1052] Analogously to the preparation of intermediate compound
101.8 g product Z5k are obtained from 4.2 g (20 mmol) intermediate
compound 1, 60 ml (60 mmol) LiHMDS (1 M in hexane) and 5.6 g (40
mmol) 1-imidazol-1-yl-2-methoxy-ethanone.
INTERMEDIATE COMPOUND 14.
(R)-N-[7-OXO-6-(TETRAHYDRO-FURAN-2-CARBONYL)-4,5,6,7-TETRAHYDRO-BENZOTHIA-
ZOL-2-YL]-ACETAMIDE
[1053] ##STR199##
[1054] Analogously to the preparation of intermediate compound 10 1
g product Z5l are obtained from 10 g (48 mmol) intermediate
compound 1, 145 ml (145 mmol) LiHMDS (1 M in hexane) and 23.5 g (52
mmol) (R)-imidazol-1-yl-(tetrahydro-furan-2-yl)-methanone.
INTERMEDIATE COMPOUND 15.
(S)-N-[7-OXO-6-(TETRAHYDRO-FURAN-2-CARBONYL)-4,5,6,7-TETRAHYDRO-BENZOTHIA-
ZOL-2-YL]-ACETAMIDE
[1055] ##STR200##
[1056] Analogously to the preparation of intermediate compound
103.1 g product Z5m are obtained from 19.4 g (92 mmol) intermediate
compound 1, 277 ml (277 mmol) LiHMDS (1 M in hexane) and 23.5 g
(141 mmol) (S)-imidazol-1-yl-(tetrahydrofuran-2-yl)-methanone.
INTERMEDIATE COMPOUND 16.
N-[7-OXO-6-(3-TRIMETHYLSILANYL-PROPYNOYL)-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-
-2-YL]-ACETAMIDE
[1057] ##STR201##
[1058] Analogously to the preparation of intermediate compound
101.1 g product Z5n are obtained from 1.1 g (5.7 mmol) intermediate
compound 1, 17.5 ml (17.5 mmol) LiHMDS (1 M in hexane) and 4.6 g
(8.4 mmol) 1-imidazol-1-yl-3-trimethylsilanyl-propynone.
INTERMEDIATE COMPOUND 17.
N{7-OXO-6-[1-(2-TRIMETHYLSILANYL-ETHOXYMETHYL)-1H-IMIDAZOL-4-CARBONYL]-4,-
5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL}-ACETAMIDE
[1059] ##STR202##
[1060] A solution of 125 ml (0.125 mol) LHMDS (lithium hexamethyl
disilazide) in 100 mL tetrahydrofuran is combined with 10.5 g (50
mmol) intermediate compound 1 at -20.degree. C. and stirred for
0.75 hours. 15.6 g (53 mmol)
imidazol-1-yl-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-meth-
anone dissolved in 80 ml of tetrahydrofuran are added. The
resulting suspension is stirred for 16 hours at ambient
temperature. Then it is hydrolysed with 2 N hydrochloric acid and
extracted with methyl-tert-butylether. The organic phase is dried
and evaporated to dryness. The residue is purified by
chromatography. Yield: 1.5 g
INTERMEDIATE COMPOUND 18. ETHYL
2-ACETYLAMINO-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-6-CARBOXYLATE
[1061] ##STR203##
[1062] 4.0 g (19 mmol) intermediate compound 1 are placed in 120 ml
of tetrahydrofuran and cooled to -50.degree. C. 80 ml (60 mmol) of
a 1 molar solution of lithium bis(trimethylsilylamide) in
tetrahydrofuran are added and the mixture is stirred for 5 hours at
-30.degree. C. to -50.degree. C. Then the reaction mixture is
combined with 6.5 ml (80 mmol) chloroethyl formate, then stirred
for 1 hour. 50 ml of water are added, the mixture is acidified with
2 N hydrochloric acid and extracted with ethyl acetate. The organic
phase is dried and evaporated to dryness. The residue is purified
by chromatography, corresponding fractions are combined and
concentrated by evaporation. The crude product is triturated with
diethyl ether and suction filtered.
[1063] Yield: 2.3 g Z5o
INTERMEDIATE COMPOUND 19.
N-[7-OXO-6-(2,2,2-TRIFLUORO-ACETYL)-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-
-ACETAMIDE
[1064] ##STR204##
[1065] 140 g (1.25 mol) 1,3-cyclohexanedione are dissolved in 625
ml chloroform, then 145 ml (2.49 mol) ethanol and 3.4 g (18 mmol)
p-toluenesulphonic acid are added. The reaction mixture is refluxed
for 72 hours with stirring, while the resulting water is separated
off using the water separator. Then the mixture is concentrated by
evaporation and the residue is combined with diethyl ether, dried
and evaporated to dryness. The residue is purified by distillation.
Yield: 166 g
[1066] 4.6 g (0.115 mol) sodium hydride are suspended in 250 ml
diethyl ether and heated to 40.degree. C. Then a solution of 17 ml
(0.14 mol) ethyl trifluoroacetate and 10 g (71 mmol) of the
intermediate described above in 50 ml diethyl ether is added
dropwise. The mixture is refluxed for 24 hours with stirring. After
cooling to ambient temperature 150 ml of water are added and the
mixture is stirred for 0.1 hour at ambient temperature. The phases
are separated, the organic phase is extracted with 5% sodium
hydroxide solution. The combined basic aqueous phases are acidified
and extracted with ethyl acetate. The ethyl acetate phases are
dried and evaporated to dryness. The crude product is purified by
chromatography. Yield: 4.1 g
[1067] 0.4 g (1.7 mmol) of the intermediate described above are
dissolved in 10 ml dioxane and 10 ml of water, cooled to
-10.degree. C. and then combined with 0.3 g (1.9 mmol)
N-bromosuccinimide. The mixture is stirred for 1 hour at ambient
temperature and then 0.13 g (1.7 mmol) thiourea are added. The
mixture is stirred for 0.5 hours at ambient temperature and for 3
hours at 80.degree. C. After cooling the reaction mixture is made
basic and extracted with dichloromethane. The organic phase is
dried and evaporated to dryness. Yield: 0.2 g
[1068] 0.2 g (0.76 mmol) of the intermediate described above are
suspended in 10 ml (0.1 mol) acetic anhydride and then heated to
100.degree. C. The mixture is stirred for 3 hours at 100.degree. C.
and for 16 hours at ambient temperature. Then the reaction mixture
is concentrated by evaporation, the residue is combined with
glacial acetic acid and concentrated by evaporation. Yield: 0.3 g
Z5p
INTERMEDIATE COMPOUND 20.
1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YLAMINE
[1069] ##STR205##
[1070] 650 ml 37% hydrochloric acid are placed in 650 ml of water
and 99 g (0.27 mol) N-(1-phenyl-4,5-dihydro-1H-pyrazolo
[3',4':3,4]benzo[1,2-d]thiazol-7-yl)-acetamide (prepared
analogously to Example 1) are dissolved therein. The solution is
refluxed for 2 hours with stirring. After cooling to ambient
temperature the mixture is carefully made basic (pH 10-11) with
sodium hydroxide solution. The precipitate formed is suction
filtered and stirred out with methanol. Yield: 66 g (m.p.:
307-308.degree. C.)
INTERMEDIATE COMPOUND 21.
N-(6-BROMO-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE
[1071] ##STR206##
[1072] A solution of 2 g (9.5 mmol) intermediate compound 1 in 60
ml glacial acetic acid is combined at ambient temperature with a
solution of 1.5 g (9.5 mmol) bromine in 10 ml glacial acetic acid.
The reaction mixture is slowly heated to 75.degree. C., during
which time rapid decolorisation sets in. It is evaporated to
dryness, the residue is dissolved in methanol and the product is
precipitated by the addition of water.
[1073] Yield: 2.2 g (M.p.: 180-182.degree. C.)
INTERMEDIATE COMPOUND 22.
N-(5-FORMYL-6-OXO-4,5,6,6A-TETRAHYDRO-3AH-CYCLOPENTATHIAZOL-2-YL)-ACETAMI-
DE
[1074] ##STR207## 100 g (0.36 mol) 2-bromo-cyclopentane-1,3-dione
(see M. Vanderwalle et al., Bull. Soc. Chim. Belg. 1966, 75,
648-654) are dissolved in 370 ml of dimethylformamide and combined
with 43 g (0.36 mol) N-acetylthiourea. The mixture is stirred for 3
hours at 75.degree. C., then at 50.degree. C. 15 g activated
charcoal are added. After filtration through kieselguhr the
filtrate is cooled to 10.degree. C. and combined with 1200 ml of
water. The precipitate formed is stirred for 16 hours at ambient
temperature, suction filtered and dried.
[1075] Yield: 20.4 g Z4b (m.p.: 270-272.degree. C.)
[1076] 27.6 g (0.51 mol) sodium methoxide are suspended in 50 ml of
dimethylformamide and at ambient temperature a suspension of 20.0 g
(0.10 mol) Z4b in 350 ml of dimethylformamide is added dropwise in
batches within 0.25 hours. The reaction mixture is stirred for 1
hour at ambient temperature, then heated to an internal temperature
of 60.degree. C. A solution of 41 ml (0.51 mol) ethyl formate in 40
ml benzene is added dropwise and the mixture is stirred for 2
hours. After cooling to 5.degree. C. 100 ml semiconcentrated
hydrochloric acid are added and the mixture is diluted with water
to 3000 ml. A precipitate is formed which is suction filtered. The
filtrate is extracted with dichloromethane, the organic phase is
dried and evaporated to dryness. The residue is stirred with
dichloromethane/diethyl ether 1:5, suction filtered and dried.
[1077] Yield: 12.3 g Z5q
INTERMEDIATE COMPOUND 23.
N-(7-FORMYL-8-OXO-5,6,7,8-TETRAHYDRO-4H-CYCLOHEPTATHIAZOL-2-YL)-ACETAMIDE
[1078] ##STR208##
[1079] A solution of 7.4 g (90 mmol) sodium acetate and 9.9 g (79
mmol) 1,3-cycloheptadiene in 300 ml glacial acetic acid is combined
at 15.degree. C. with 12.6 g (79 mmol) bromine and stirred for 30
min. Then 6.0 g (79 mmol) thiourea are added and the suspension is
refluxed for 5 hours. The acetic acid is eliminated in vacuo and
the residue is taken up in saturated saline solution. Insoluble
constituents are suction filtered and the aqueous phase is first of
all extracted with ether and then made alkaline with ammonia. The
precipitated solid is suction filtered and dried.
[1080] Yield: 3.7 g Z3b
[1081] 3.7 g (20 mmol) of compound Z3b are refluxed in 50 ml acetic
anhydride for 1 hour. The solid precipitated after cooling is
suction filtered and stirred with ether.
[1082] Yield: 2.4 g Z4c
[1083] 1.7 g (31 mmol) sodium methoxide are suspended in 20 ml DMF
and combined batchwise with 2.4 g (11 mmol) of compound Z4c. After
30 min the mixture is cooled to -5.degree. C., a solution of 2.5 ml
(31 mmol) ethyl formate in 10 ml benzene is added dropwise and the
resulting mixture is stirred overnight at ambient temperature. It
is combined with 70 ml 1N hydrochloric acid, the precipitate formed
is suction filtered and washed with water. Yield: 2 g Z5r
Synthesis of Compounds of Formula 1
EXAMPLE 1
N-(1-P-TOLYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL)-A-
CETAMIDE
[1084] ##STR209##
[1085] 0.5 g (2 mmol) intermediate compound 2 are placed in 7.5 ml
glacial acetic acid, combined with 0.32 g (2 mmol)
p-tolylhydrazine-hydrochloride and heated to 60.degree. C. for 3.5
hours. The precipitate formed after the addition of 20 ml of water
is suction filtered and recrystallised from acetonitrile with the
addition of activated charcoal.
[1086] Yield: 0.32 g (m.p.: 240-242.degree. C.)
EXAMPLE 2
N-[1-(5-FLUORO-2-METHYL-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,-
2-d]THIAZOL-7-YL]-ACETAMIDE
[1087] ##STR210##
[1088] 8.8 mg (0.05 mmol)
5-Fluoro-2-methyl-phenylhydrazine-hydrochloride are placed in 2.5
ml of ethanol and combined with 13.3 mg (0.05 mmol) intermediate
compound 3, dissolved in 2.5 ml of ethanol. The reaction mixture is
heated overnight to 50.degree. C., evaporated down and the residue
is purified by RP-HPLC.
[1089] Yield: 13.3 mg
EXAMPLE 3
7-ACETYLAMINO-4,5-DIHYDRO-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOLE-1-CARBOX-
YLIC ACID AMIDE
[1090] ##STR211##
[1091] 14 g (59 mmol) intermediate compound 2 and 6.7 g (60 mmol)
semicarbazide are suspended in 130 ml of water and refluxed for 1
hour. The solid is suction filtered and purified by chromatography.
Yield: 5.6 g (M.p.: 265-270.degree. C.)
EXAMPLE 4
1-(4-NITRO-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-
-YLAMINE
[1092] ##STR212##
[1093] Analogously to Example 1 14 g product are obtained from 15 g
(63 mmol) intermediate compound 2 and 9.8 g (64 mmol)
4-nitrophenylhydrazine (M.p.: 300-310.degree. C.).
[1094] 7 g (20 mmol) of this intermediate are saponified with 90 ml
semiconcentrated hydrochloric acid as described for intermediate
20.
[1095] 5.2 g product are obtained (M.p.: 273-278.degree. C.).
EXAMPLE 5
N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO
[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL)-FORMAMIDE
[1096] ##STR213##
[1097] A mixture of 0.25 g (0.9 mmol) intermediate compound 20 in 8
ml phenyl formate is stirred for 4 hours at 60.degree. C. After
cooling to ambient temperature the precipitate is suction filtered
and washed with a little acetone. The crude product is
recrystallised from acetonitrile with the addition of activated
charcoal. Yield: 0.11 g (m.p.: 273-277.degree. C.)
EXAMPLE 6
METHYL
(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-Y-
L)-CARBAMOYLATE
[1098] ##STR214##
[1099] 0.50 g (1.9 mmol) intermediate compound 20 are suspended in
10 ml of pyridine and heated to 50.degree. C. 0.6 ml (7.6 mmol)
chloroethyl formate are slowly added and the reaction mixture is
then stirred for 48 hours at 50.degree. C. During this time a
further 2.times.0.6 ml of chloroethyl formate are added. The
mixture is stirred for another 72 hours at ambient temperature. The
suspension is filtered, the filtrate is combined with 130 ml of
water. The precipitate formed is suction filtered, washed and
dried. The crude product is recrystallised from methanol. Yield:
0.15 g (m.p.: 283-287.degree. C.)
EXAMPLE 7
4-DIMETHYLAMINO-N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO-[3',4':3,4]BENZO[1,2-D-
]THIAZOL-7-YL)-BUTYRAMIDE
[1100] ##STR215##
[1101] In a sealable pressure tube 0.9 g (4.8 mmol) freshly
prepared 4-(dimethylamino)-butyric acid chloride-hydrochloride are
suspended in 30 ml of tetrahydrofuran and heated to 50.degree. C.
0.6 ml triethylamine are added, followed by 0.5 g (1.9 mmol)
intermediate compound 20 added batchwise. The reaction mixture is
stirred for 71 hours at 70.degree. C. After cooling to ambient
temperature the precipitate formed is suction filtered, washed and
taken up in saturated sodium hydrogen carbonate solution and
chloroform. The organic phase is washed with water, dried and
evaporated to dryness. The crude product is recrystallised from
acetonitrile with the addition of activated charcoal. Yield: 0.2 g
(m.p.: 165-166.degree. C.)
EXAMPLE 8
S-ETHYL
(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-7--
YL)-THIOCARBAMOYLATE
[1102] ##STR216##
[1103] 2.7 g (9.9 mmol) intermediate compound 20 are placed in 70
ml of pyridine and heated to 50.degree. C. 1.6 ml (15 mmol) ethyl
thiochloroformate are added to this suspension. The resulting
solution is stirred for 2 hours at 50.degree. C. After cooling to
ambient temperature the solution is added to 700 ml of water, the
precipitate formed is suction filtered, washed and dried. Yield:
2.2 g
EXAMPLE 9
(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL)-UREA
[1104] ##STR217##
[1105] In a sealable pressure tube 7 ml (14 mmol) 2 molar ethanolic
ammonia solution are added to a suspension of 0.5 g (1.4 mmol) of
the compound described in Example 8 in 9 ml of ethanol. The tube is
sealed and the reaction mixture is stirred for a total of 24 hours
at 80.degree. C. After 5 hours reaction a further 3 ml (6 mmol) of
the ammonia solution are added. After cooling to ambient
temperature the precipitate formed is suction filtered, washed and
dried. The crude product is recrystallised from isopropanol with
the addition of activated charcoal. Yield: 0.16 g (m.p.:
321-325.degree. C.)
EXAMPLE 10
3-METHANESULPHONYL-PHENYL-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZ-
O[1,2-d]THIAZOL-7-YL)-AMINE
[1106] ##STR218##
[1107] A mixture of 0.5 g (2 mmol) intermediate compound 20, 0.5 g
(2 mmol) 1-bromo-3-methanesulphonylbenzene, 0.13 g (0.4 mmol)
tri-tert-butylphosphine tetrafluoroborate, 0.2 g (0.2 mmol)
tris(dibenzylideneacetone)-dipalladium (0) and 0.2 g (2 mmol)
sodium carbonate in 10 ml DMF is stirred for 48 hours at 90.degree.
C. The reaction mixture is combined with dichloromethane and water
and the aqueous phase is extracted with dichloromethane. The
combined organic phases are dried, evaporated down and the residue
remaining is purified by column chromatography. Yield: 25 mg
EXAMPLE 11
1-TERT-BUTYL-3-{4-[3-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-
-d]THIAZOL-7-YL)-UREIDO]-BUT-2-YNYL}-UREA
[1108] ##STR219##
[1109] A solution of 0.4 g (1.5 mmol) intermediate compound 20 in
0.5 ml of pyridine, 3 ml dichloromethane and 0.5 ml THF is combined
with 0.4 g (2 mmol) 4-nitrophenyl chloroformate and stirred for 2
hours at ambient temperature. Then the reaction mixture is combined
with 0.5 g (2.7 mmol) tert-butyl (4-amino-but-2-ynyl)-carbamoylate
and 1 ml of pyridine and stirred for a further 24 hours. After the
addition of dichloromethane and water the aqueous phase is
extracted with dichloromethane. The combined organic phases are
evaporated down and the residue remaining is purified by column
chromatography. Yield: 0.2 g (M.p.: 196.degree. C.)
EXAMPLE 12
1-(4-AMINO-BUT-2-YNYL)-3-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO-
[1,2-d]THIAZOL-7-YL)-UREA
[1110] ##STR220##
[1111] 0.1 g (0.2 mmol) of the compound obtained in Example 11 are
suspended in 0.5 ml trifluoroacetic acid and 2 ml dichloromethane
and stirred overnight at ambient temperature. The reaction mixture
is evaporated down, the residue taken up in acetone and the product
is precipitated by the addition of ethereal hydrochloric acid.
[1112] Yield: 0.1 g (M.p.: 232.degree. C.)
EXAMPLE 13
2-[(1-ETHYL-PYRROLIDIN-2-YLMETHYL)-AMINO]-N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZ-
OLO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDE
[1113] ##STR221##
[1114] 0.8 g (6.2 mmol) bromoacetic acid are dissolved in 20 ml
DMF, combined with 4.9 g
N-cyclohexylcarbodiimide-N'-methyl-polystyrene HL (1.9 mmol/g) and
stirred for 30 minutes at ambient temperature. Then a solution of
0.83 g (3.1 mmol) intermediate compound 20 is added and the mixture
is stirred overnight. The polymer is suction filtered and washed
with DMF. The filtrate is evaporated down and the residue is
triturated in ethyl acetate/diisopropylether. Yield: 1 g
[1115] 6 mg (0.048 mmol) C-(1-ethyl-pyrrolidin-2-yl)-methylamine
are dissolved in 0.4 ml DMF and combined with 0.02 ml (0.12 mmol)
triethylamine, dissolved in 0.1 ml DMF. Then 16 mg (0.04 mmol) of a
solution of the bromide intermediate described above in 0.5 ml DMF
are added. The reaction mixture is stirred overnight and then
evaporated down. Yield: 4 mg.
EXAMPLE 14
2-AMINO-N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO-[3',4':3,4]BENZO[1,2-d]THIAZOL-
-7-YL)-ACETAMIDE
[1116] ##STR222##
[1117] 26 mg of the bromide intermediate obtained in the first part
of Example 13 are suspended in 3 ml 33% aqueous ammonia solution
and stirred overnight at ambient temperature. The reaction mixture
is extracted with dichloromethane and the combined organic phases
are evaporated down. The residue is purified by RP-HPLC. Yield: 8
mg
EXAMPLE 15
2-HYDROXY-N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZO-
L-7-YL)-ACETAMIDE
[1118] ##STR223##
[1119] 26 mg of the bromide intermediate obtained in the first part
of Example 13 are suspended in 2 ml of water and 1 ml DMF and
stirred for 48 hours at 100.degree. C. The reaction mixture is
purified by RP-HPLC. Yield: 9 mg
EXAMPLE 16
N-{1-[4-(MORPHOLIN-4-CARBONYL)-PHENYL]-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]B-
ENZO[1,2-d]THIAZOL-7-YL}-ACETAMIDE
[1120] ##STR224##
[1121] A solution of 3.5 mg (0.01 mmol)
4-(7-acetylamino-4,5-dihydro-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-1-yl)-
-benzoic acid (prepared analogously to Example 1) in 0.5 ml DMF is
combined with 4 .mu.L (0.03 mmol) triethylamine and 4 mg (0.01
mmol) O-pentafluorophenyl-1,1,3,3-tetramethyluronium
hexafluorophosphate (PFTU) and stirred for 15 minutes. A solution
of 1 mg (0.01 mmol) morpholine in 0.5 ml DMF is added to this
mixture and it is shaken for 12 hours at ambient temperature. Then
3 mg polyamine resin HL (0.01 mmol, 200-400 mesh) are added and the
mixture is shaken for a further 8 hours. The resin is filtered off
and the filtrate is evaporated to dryness in vacuo.
EXAMPLE 17
N-{1-[4-(4-AMINO-PIPERIDINE-1-CARBONYL)-PHENYL]-4,5-DIHYDRO-1H-PYRAZOLO[3'-
,4':3,4]BENZO[1,2-d]THIAZOL-7-YL}-ACETAMIDE
[1122] ##STR225##
[1123] A solution of 0.3 g (0.85 mmol))
4-(7-acetylamino-4,5-dihydro-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-1-yl)-
-benzoic acid (prepared analogously to Example 1), 0.32 g (1.00
mmol) TBTU and 0.75 ml (4.38 mmol) diisopropylethylamine in 25 ml
dichloromethane is stirred for 15 minutes at ambient temperature
and then combined with 0.17 g (0.86 mmol) 4-N-Boc-aminopiperidine.
After 2.5 hours the reaction mixture is poured onto 25 ml 5%
potassium carbonate solution. The organic phase is dried and
evaporated down. The residue is triturated with ethyl
acetate/ether.
[1124] Yield: 0.43 mg (M.p.: 230.degree. C.)
[1125] 0.40 g (0.75 mmol) of the compound described previously are
suspended in 10 ml ethereal hydrochloric acid and stirred for 72
hours at ambient temperature. The solid is suction filtered and
washed with ether. Yield: 0.35 mg (M.p.: 269-270.degree. C.)
EXAMPLE 18
N-{1-[4-(7-ACETYLAMINO-4,5-DIHYDRO-PYRAZOLO[3',4':3,4]-BENZO[1,2-d]THIAZOL-
-1-YL)-BENZOYL]-PIPERIDIN-4-YL}-2-PHENYL-ACETAMIDE
[1126] ##STR226##
[1127] A solution of 12 mg (0.09 mmol) phenylacetic acid, 33 mg
(0.09 mmol) TBTU and 80 .mu.L (0.47 mmol) diisopropylethylamine in
2 ml dichloromethane is stirred for 15 minutes at ambient
temperature and then combined with 40 mg (0.09 mmol) of the
compound described in Example 17. After 2.5 hours the reaction
mixture is poured onto 5% potassium carbonate solution. The organic
phase is dried and evaporated down. The residue is triturated with
ethyl acetate. Yield: 34 mg (M.p.: 271-272.degree. C.)
EXAMPLE 19
N-[1-(4-METHYLSULPHAMOYL-PHENYL)-4,5-DIHYDRO-PYRAZOLO[3',4':3,4]BENZO[1,2--
d]THIAZOL-7-YL]-ACETAMIDE
[1128] ##STR227##
[1129] 3.0 g (7.7 mmol)
4-(7-acetylamino-4,5-dihydro-pyrazolo[3',4':3,4]benzo[1,2-d]thiazol-1-yl)-
-benzenesulphonic acid (prepared analogously to Example 1) are
placed in 180 ml phosphorus oxychloride, and 1.6 g (7.7 mmol)
phosphorus pentachloride are added with cooling. The suspension is
stirred for 3 hours at 90.degree. C. and for 16 hours at ambient
temperature, then cooled to 5.degree. C. Within 0.75 hours the
reaction solution is added dropwise to ice, then extracted with
chloroform. The organic phase is dried and evaporated to dryness.
Yield: 1.3 g
[1130] 0.15 g (0.37 mmol) of the sulphonic acid chloride described
previously and 2 ml (4.0 mmol) methylamine (2 M in THF) are placed
In a pressurised reaction vessel, then the mixture is stirred for 1
hour at ambient temperature. The solution is concentrated by
evaporation, the residue is crystallised from ethanol. The crude
product is recrystallised from methanol. Yield: 0.02 g (m.p.:
>260.degree. C.)
EXAMPLE 20
N-(1-CYCLOHEX-2-ENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-
-7-YL)-ACETAMIDE
EXAMPLE 21
N-(2-CYCLOHEX-2-ENYL-4,5-DIHYDRO-2H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-
-7-YL)-ACETAMIDE
[1131] ##STR228##
[1132] 4.0 g (16.8 mmol) intermediate compound 2 are suspended in
50 ml glacial acetic acid and combined with 1.6 g (16.8 mol)
hydrazine-acetate. The mixture is stirred for 3.5 hours at
60.degree. C. stirred and then 150 ml of water are added. The
precipitate formed is suction filtered, washed and dried. Yield:
2.8 g (m.p.: 261-264.degree. C.)
[1133] 0.2 g (0.85 mmol) of the intermediate described above are
dissolved in 2 ml dimethylacetamide and combined with 0.1 g (2.5
mmol) sodium hydroxide (ground). It is stirred for 0.5 hours at
ambient temperature. Then 12 mg (0.035 mmol) tetrabutylammonium
hydrogen sulphate and 0.09 ml (0.9 mmol) 3-bromocyclohexene are
added. The reaction mixture is stirred for 3 hours at 120.degree.
C. It is concentrated by evaporation, the residue is extracted with
water and dichloromethane. The combined organic phases are dried
and evaporated to dryness. The crude product is purified by
chromatography.
[1134] Yield: 0.020 g (m.p.: 247-249.degree. C., Example 21);
[1135] Yield: 0.060 g (m.p.: 213-214.degree. C., Example 20)
EXAMPLE 22
N-(1-BENZOYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL)-A-
CETAMIDE
EXAMPLE 23
N-(2-BENZOYL-4,5-DIHYDRO-2H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL)-A-
CETAMIDE
[1136] ##STR229##
[1137] 0.2 g (0.85 mmol) of the intermediate described in Example
20/21 are suspended in 2 ml benzene and combined with 0.25 ml (1.80
mmol) triethylamine and 0.18 ml (1.55 mmol) benzoyl chloride. The
reaction mixture is stirred for 2 hours at 75.degree. C. Then the
suspension is suction filtered, the precipitate is washed with
ethyl acetate and water. Yield: 0.12 g (m.p.: 266-267.degree. C.,
Example 23)
[1138] The mother liquor is concentrated by evaporation and the
residue is purified by chromatography.
[1139] Yield: 7 mg (Example 22)
EXAMPLE 24
N-[1-(2-CHLORO-PHENYL)-3-FURAN-2-YL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZ-
O[1,2-d]THIAZOL-7-YL]-ACETAMIDE
EXAMPLE 25
N-[2-(2-CHLORO-PHENYL)-3-FURAN-2-YL-4,5-DIHYDRO-2H-PYRAZOLO[3',4':3,4]BENZ-
O[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1140] ##STR230##
[1141] 220 mg (0.7 mmol) intermediate compound 4 are placed in 3 ml
glacial acetic acid and combined with 179 mg (0.7 mmol)
2-chloro-phenylhydrazine-hydrochloride. The suspension is heated
overnight to 50.degree. C., then combined with 20 ml of water and
the precipitate formed is suction filtered. The solid is purified
by column chromatography (eluant: dichloromethane/methanol
98:2).
[1142] Yield: 120 mg (yellow solid, m.p.: 265-266.degree. C.,
Example 24); 38 mg (m.p.: >300.degree. C., Example 25)
EXAMPLE 26
4-(7-ACETYLAMINO-3-FURAN-2-YL-4,5-DIHYDRO-PYRAZOLO[3',4':3,4]BENZO[1,2-d]T-
HIAZOL-1-YL)-3-CHLORO-N-(1-METHYL-PIPERIDIN-4-YL)-BENZAMIDE
[1143] ##STR231##
[1144] Analogously to Example 1 a mixture of the two possible
pyrazole isomers is obtained from 3.3 g (11 mmol) intermediate
compound 4 and 2.1 g (11 mmol) methyl
3-chloro-4-hydrazino-benzoate, and these are separated by column
chromatography.
[1145] Yield: 0.6 g isomer A; 0.7 g isomer B
[1146] 0.7 g (1.5 mmol) of the isomer B described above are
dissolved in 8 ml dioxane and combined with a solution of 0.1 g
(4.4 mmol) lithium hydroxide in 1 ml of water. After 1.5 hours the
reaction mixture is acidified with 2 N hydrochloric acid and the
precipitated solid is suction filtered. The product is stirred with
ether. Yield: 0.5 g
[1147] 40 mg (0.09 mmol) of the acid described previously, 33 mg
(0.09 mmol) HATU and 46 .mu.L diisopropylethylamine are dissolved
in 3 ml DMF and stirred for 10 minutes. Then a solution of 10 mg
(0.09 mmol) methylaminopiperidine in 2 ml DMF is added and the
mixture is stirred for 2 hours. The reaction mixture is diluted
with 15 ml 5% potassium hydrogen carbonate solution and extracted
with dichloromethane. The combined organic phases are washed with
water, dried and evaporated down. The crude product is purified by
column chromatography. Yield: 24 mg
EXAMPLE 27
N-[1-(2-CHLORO-PHENYL)-3-FURAN-3-YL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZ-
O[1,2-d]THIAZOL-7-YL]-ACETAMIDE
EXAMPLE 28
N-[2-(2-CHLORO-PHENYL)-3-FURAN-3-YL-4,5-DIHYDRO-2H-PYRAZOLO[3',4':3,4]BENZ-
O[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1148] ##STR232##
[1149] Analogously to Example 1,102 mg (M.p. 265-266.degree. C.,
Example 27); 12 mg (m.p.: >300.degree. C., Example 28) are
obtained from 0.5 g (1.2 mmol) intermediate compound 6 and 0.2 g
(1.2 mmol) 2-chloro-phenylhydrazine-hydrochloride after
purification by column chromatography.
EXAMPLE 29
N-[1-(2-CHLORO-PHENYL)-3-ISOPROPYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO-
[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1150] ##STR233##
[1151] Analogously to Example 1, 0.22 g product are obtained from
0.2 g (0.7 mmol) intermediate compound 13 and 0.13 g (0.7 mmol)
2-chloro-phenylhydrazine hydrochloride.
EXAMPLE 30
4-(7-ACETYLAMINO-3-METHOXYMETHYL-4,5-DIHYDRO-PYRAZOLO[3',4':3,4]BENZO[1,2--
d]THIAZOL-1-YL)-3-CHLORO-N-(1-METHYL-PIPERIDIN-4-YL)-BENZAMIDE
[1152] ##STR234##
[1153] Analogously to Example 1, 1.2 g of product, whose ester
function is saponified with 0.2 g (8.4 mmol) lithium hydroxide
analogously to Example 26, is obtained from 0.9 g (3.2 mmol)
intermediate compound 13 and 0.7 g (3.2 mmol) methyl
3-chloro-4-hydrazino-benzoate. Then 50 mg of the acid obtained are
subjected to amide coupling with methylaminopiperidine as described
in Example 26.
EXAMPLE 31
METHYL
7-ACETYLAMINO-1-(2-CHLORO-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4-
]BENZO[1,2-d]THIAZOLE-3-CARBOXYLATE
[1154] ##STR235##
[1155] Analogously to Example 1, 0.8 g product (M.p.:
294-297.degree. C.) are obtained from 1.0 g (3.4 mmol) intermediate
compound 7 and 0.6 g (3.4 mmol) 2-chloro-phenylhydrazine
hydrochloride.
EXAMPLE 32
7-ACETYLAMINO-1-(2-CHLORO-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[-
1,2-d]THIAZOLE-3-CARBOXYLIC ACID
[1156] ##STR236##
[1157] 24 g (1 mol) of the compound described in Example 31 are
placed in 250 ml dioxane and a solution of 4 g (10 mmol) lithium
hydroxide in 35 ml of water is is added. The mixture is stirred for
16 hours at ambient temperature. Then the solution is acidified
slightly and the dioxane is concentrated by evaporation. The
suspension is diluted with water, then suction filtered. The
precipitate is dried.
[1158] Yield: 23 g
EXAMPLE 33
7-ACETYLAMINO-1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZ-
OLE-3-CARBOXYLIC ACID
[1159] ##STR237##
[1160] Analogously to Example 1, 27 g product (M.p.:
298-300.degree. C.) are obtained from 30 g (0.1 mol) intermediate
compound 7 and 10.3 ml (0.1 mol) phenylhydrazine. Of this, 0.1 g
(0.3 mmol) are suspended in 12 ml of methanol/water (1:1) and
combined with 0.4 ml 10% potassium hydroxide solution. After 1.5
hours the reaction mixture is evaporated down and the solution is
acidified with dilute hydrochloric acid. The precipitate formed is
recrystallised from acetonitrile. Yield: 0.1 g (M.p.:
>300.degree. C.)
EXAMPLE 34
N-[3-AMINO-1-(2-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE[3',4':3,4]BENZO[1,2--
d]THIAZOL-7-YL]-ACETAMIDE
[1161] ##STR238##
[1162] 0.1 g (0.26 mmol) of the compound described in Example 32,
0.06 ml (0.27 mmol) diphenyl phosphate azide (DPPA) and 0.04 ml
(0.29 mmol) triethylamine are placed in 5 ml dimethylacetamide and
stirred for 2 hours at 50.degree. C. 0.05 g (0.29 mmol)
p-toluenesulphonic acid and 0.10 ml of water are added and the
mixture is stirred for 16 hours at 50.degree. C. Then the reaction
mixture is purified by chromatography, corresponding fractions are
combined and concentrated by evaporation. The residue is
crystallised from ethyl acetate/petroleum ether. Yield: 0.02 g
EXAMPLE 35
N-(3-AMINO-1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOL--
7-YL)-ACETAMIDE
[1163] ##STR239##
[1164] Analogously to Example 34, 0.5 g product is obtained from
1.5 g of the acid described in Example 33, 1 ml (4.6 mmol) DPPA and
0.6 ml (4.4 mmol) triethylamine in 20 ml dimethylacetamide and
subsequent reaction with 2 g p-toluenesulphonic acid and 10 ml of
water.
EXAMPLE 36
N-[1-(2-CHLOROPHENYL)-3-(3-ISOPROPYL-UREIDO)-4,5-DIHYDRO-1H-PYRAZOLE[3',4'-
:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1165] ##STR240##
[1166] 1.0 g (3.1 mmol) of the compound described in Example 35 and
1.0 ml (12.1 mmol) pyridine are suspended in 10 ml dichloromethane
and 2 ml of tetrahydrofuran and combined with a solution of 0.8 g
(4.0 mmol) 4-nitrophenyl chloroformate in 5 ml dichloromethane. The
mixture is stirred for 0.5 hours at ambient temperature. 1.8 ml of
this solution is combined with 0.05 ml (0.53 mmol) isopropylamine.
It is stirred for 16 hours at ambient temperature, then extracted
with dichloromethane and water. The organic phase is dried and
evaporated to dryness. The residue is purified by chromatography,
corresponding fractions are combined and concentrated by
evaporation. The residue is dissolved in water, made basic with
sodium hydrogen carbonate solution and precipitated crystals are
suction filtered. Yield: 0.010 g
EXAMPLE 37
N-[1-(2-CHLORO-PHENYL)-3-(3-METHYL-UREIDO)-4,5-DIHYDRO-1H-PYRAZOLO[3',
4':3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1167] ##STR241##
[1168] Analogously to Example 36 the desired product is obtained by
using methylamine.
EXAMPLE 38
ISOPROPYL
[7-ACETYLAMINO-1-(2-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE[3',4':-
3,4]BENZO[1,2-d]THIAZOLE-73-YL]-CARBAMATE
[1169] ##STR242##
[1170] 10 g (25 mmol) of the compound described in Example 32, 6.0
ml (27 mmol) diphenyl phosphate azide (DPPA) and 4.0 ml (29 mmol)
triethylamine are placed in 80 ml dimethylacetamide and stirred for
2 hours at 50.degree. C. 9 ml of this solution are combined with 2
ml isopropanol and stirred for 48 hours at 50.degree. C. Then the
mixture is diluted with dichloromethane, then washed with potassium
hydrogen sulphate solution and sodium hydrogen carbonate solution.
The organic phase is dried and evaporated to dryness. The residue
is dissolved in dichloromethane and shaken with 0.3 g anhydride
catching resin (MP anhydride resin) for 3 hours. Then the resin is
suction filtered, washed with dichloromethane and the organic phase
is concentrated by evaporation. The residue is purified by
chromatography, corresponding fractions are combined and
concentrated by evaporation. Yield: 0.09 g (m.p.: 196.degree.
C.)
EXAMPLE 39
N-[1-(2-CHLORO-PHENYL)-3-(MORPHOLINE-4-CARBONYL)-4,5-DIHYDRO-1H-PYRAZOLO[3-
',4':3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1171] ##STR243##
[1172] 0.1 g (0.26 mmol) of the compound described in Example 32
are placed in 5 ml dichloromethane and 0.1 g (0.28 mmol) HATU
(o-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophospha-
te) are added. Then the mixture is combined with 0.09 ml (0.53
mmol) diisopropylethylamine and 0.03 ml (0.28 mmol) morpholine. The
reaction mixture is stirred for 4 hours at ambient temperature,
then extracted with dichloromethane and water. The organic phase is
dried and evaporated to dryness. The residue is purified by
chromatography. Corresponding fractions are combined, concentrated
by evaporation, dissolved in water and made basic with sodium
hydrogen carbonate solution. The precipitated solid is suction
filtered and dried. Yield: 0.02 g
EXAMPLE 40
7-ACETYLAMINO-1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZ-
OLE-3-CARBOXYLIC ACID (2-HYDROXY-ETHYL)-METHYLAMIDE
[1173] ##STR244##
[1174] 0.09 g (0.25 mmol) of the compound described in Example 33
are placed in 5 ml of dimethylformamide, and 0.1 ml (0.75 mmol)
triethylamine and 0.1 g (0.25 mmol)
(dimethylamino-pentafluorophenyloxymethylene)-dimethyl-ammonium-hexafluor-
ophosphate are added. The mixture is stirred for 0.1 hours at
ambient temperature, then 0.02 g (0.25 mmol) 2-methylamino-ethanol
are added. The reaction mixture is stirred for 16 hours at ambient
temperature and 24 hours at 70.degree. C. Then it is concentrated
by evaporation, the residue is purified by chromatography.
Corresponding fractions are combined and freeze-dried. Yield: 0.04
g
EXAMPLE 41
ETHYL
7-ACETYLAMINO-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2-d]THIAZOLE-
-3-CARBOXYLATE
[1175] ##STR245##
[1176] Analogously to Example 16.4 g product are obtained from 10 g
(32 mmol) intermediate compound 8 and 1.7 g (33 mmol)
hydrazine-hydrate.
EXAMPLE 42
N-[1-(2-CHLORO-PHENYL)-3-(1-METHYL-1H-IMIDAZOL-4-YL)-4,5-DIHYDRO-1H-PYRAZO-
LO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
EXAMPLE 43
N-[2-(2-CHLORO-PHENYL)-3-(1-METHYL-1H-IMIDAZOL-4-YL)-4,5-DIHYDRO-2H-PYRAZO-
LO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1177] ##STR246##
[1178] Analogously to Example 1, 100 mg (M.p.: >300.degree. C.,
Example 42) and 4 mg (Example 43) are obtained from 0.25 g (0.8
mmol) intermediate compound 11 and 0.14 g (0.8 mmol)
2-chloro-phenylhydrazine-hydrochloride after purification by column
chromatography.
EXAMPLE 44
N-[1-(2-CHLORO-PHENYL)-3-ISOPROPYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO-
[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1179] ##STR247##
[1180] Analogously to Example 1, 0.2 g product are obtained from
0.25 g (0.9 mmol) intermediate compound 12 and 0.16 g (0.9 mmol)
2-chloro-phenylhydrazin-hydrochloride after purification by column
chromatography.
EXAMPLE 45
4-(7-ACETYLAMINO-3-ISOPROPYL-4,5-DIHYDRO-PYRAZOLO-[3',4':3,4]BENZO[1,2-d]T-
HIAZOL-1-YL)-3-CHLORO-N-(1-METHYL-PIPERIDIN-4-YL)-BENZAMIDE
[1181] ##STR248##
[1182] Analogously to Example 1, 0.68 g product, the ester function
of which is saponified with 0.1 g lithium hydroxide analogously to
Example 26, is obtained from 3.25 g (10.7 mmol) intermediate
compound 12 and 2.14 g (10.7 mmol) methyl
3-chloro-4-hydrazinebenzoate. Then 40 mg of the acid obtained are
subjected to amide is coupling with methylaminopiperidine as
described in Example 26.
EXAMPLE 46
N-[1-(2-CHLORO-PHENYL)-3-METHYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,-
2-d]THIAZOL-7-YL]-ACETAMIDE
[1183] ##STR249##
[1184] Analogously to Example 10.16 g product are obtained from
0.25 g (1.0 mmol) intermediate compound 10 and 0.18 g (1.0 mmol)
2-chloro-phenylhydrazine-hydrochloride.
EXAMPLE 47
N-[1-(2-CHLORO-PHENYL)-3-PYRIDIN-3-YL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BE-
NZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1185] ##STR250##
[1186] Analogously to Example 10.06 g product are obtained from 0.1
g (0.3 mmol) intermediate compound 9 and 0.06 g (0.3 mmol)
2-chloro-phenylhydrazine-hydrochloride after purification by column
chromatography.
EXAMPLE 48
N-[1-(2-CHLORO-PHENYL)-3-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,-
2-d]THIAZOL-7-YL]-ACETAMIDE
[1187] ##STR251##
[1188] Analogously to Example 1, 0.2 g product (M.p.:
232-234.degree. C.) are obtained from 0.3 g (1.0 mmol) intermediate
compound 5 and 0.18 g (1.0 mmol)
2-chloro-phenylhydrazine-hydrochloride.
EXAMPLE 49
N-[1-(2-CHLORO-PHENYL)-3-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,-
2-d]THIAZOL-7-YL]-4-DIMETHYLAMINO-BUTYRAMIDE
[1189] ##STR252##
[1190] A mixture of 0.5 g (1.2 mmol) of the compound obtained in
Example 48 in 5 ml of water and 5 ml hydrochloric acid is refluxed
for 2 hours. The solid precipitated after the solution is cooled is
suction filtered and dried. Yield: 0.4 g (M.p.: 182-185.degree.
C.)
[1191] 0.1 g of the intermediate compound described previously are
suspended in 5 ml dichloromethane, combined with 0.16 ml (1.2 mmol)
triethylamine and stirred for 15 minutes at ambient temperature,
forming a solution. This is heated to 40.degree. C. and 0.17 g (0.9
mmol) 4-dimethylamino-butanoic acid chloride are added. The
reaction mixture is stirred for 3 hours at 40.degree. C. and then
washed with 5% sodium carbonate solution and water. The organic
phase is dried, evaporated down and the residue is recrystallised
from isopropanol. Yield: 11 mg (M.p. 290-291.degree. C.)
EXAMPLE 50
N-[3-(1H-IMIDAZOL-4-YL)-1-(2-TRIFLUOROMETHYL-PHENYL)-4,5-DIHYDRO-1H-PYRAZO-
LO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1192] ##STR253##
[1193] Analogously to Example 11.26 g intermediate product are
obtained from 1.36 g (3.1 mmol) intermediate compound 17 and 0.55 g
(3.1 mmol) 2-trifluoromethyl-phenylhydrazine. Of this, 75 mg (0.13
mmol) are suspended in 0.65 ml (0.65 mmol) tetrabutylammonium
fluoride solution (1 M in THF) and refluxed for 5.5 hours. The
solution is combined with 5 ml pH 7-buffer solution, diluted with
10 ml of water and extracted with ethyl acetate. The organic phase
is washed with buffer solution, dried and evaporated to dryness.
The residue is purified by chromatography, the corresponding
fraction is stirred out with diethyl ether. Yield: 5 mg (M.p.:
>300.degree. C.)
EXAMPLE 51
N-[1-(2-CHLORO-PHENYL)-3-(1H-IMIDAZOL-4-YL)-4,5-DIHYDRO-1H-PYRAZOLO[3',4':-
3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1194] ##STR254##
[1195] Analogously to Example 1, 0.5 g intermediate product are
obtained from 0.6 g (1.4 mmol) intermediate compound 17 and 0.3 g
(1.4 mmol) 2-chlorophenylhydrazine hydrochloride. This is converted
into the desired product with 1.7 ml (1.7 mmol) tetrabutylammonium
fluoride solution (1 M in THF) as described in Example 50.
[1196] Yield: 35 mg (M.p.: 287-288.degree. C.)
EXAMPLE 52
(R)-N-[1-(2-CHLORO-PHENYL)-3-(TETRAHYDRO-FURAN-2-YL)-4,5-DIHYDRO-1H-PYRAZO-
LO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1197] ##STR255##
[1198] Analogously to Example 10.23 g product are obtained from
0.25 g (0.8 mmol) intermediate compound 14 and 0.15 g (0.8 mmol)
2-chloro-phenylhydrazine-hydrochloride after purification by column
chromatography.
EXAMPLE 53
(R)-4-[7-ACETYLAMINO-3-(TETRAHYDRO-FURAN-2-YL)-4,5-DIHYDRO-PYRAZOLO[3',4':-
3,4]BENZO[1,2-d]THIAZOL-1-YL]-3-CHLORO-N-PYRIDIN-4-YLMETHYL-BENZAMIDE
[1199] ##STR256##
[1200] Analogously to Example 11.16 g product, the ester function
of which is saponified with 0.2 g lithium hydroxide analogously to
Example 26, is obtained from 1.25 g (4.1 mmol) intermediate
compound 14 and 0.82 g (4.1 mmol) methyl 3-chloro-4-hydrazine
benzoate. Then 50 mg of the acid obtained are subjected to amide
coupling with 4-picolylamine as described in Example 26.
EXAMPLE 54
(S)-N-[1-(2-CHLORO-PHENYL)-3-(TETRAHYDRO-FURAN-2-YL)-4,5-DIHYDRO-1H-PYRAZO-
LO[3',4':3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1201] ##STR257##
[1202] Analogously to Example 10.08 g product are obtained from 0.1
g (0.3 mmol) intermediate compound 15 and 0.05 g (0.3 mmol)
2-chloro-phenylhydrazine-hydrochloride after purification by column
chromatography.
EXAMPLE 55
N-[1-(2-CHLORO-PHENYL)-3-TRIMETHYLSILANYLETHYNYL-4,5-DIHYDRO-1H-PYRAZOLO[3-
',4':3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1203] ##STR258##
[1204] Analogously to Example 10.02 g product are obtained from 0.1
g (0.3 mmol) intermediate compound 16 and 0.06 g (0.3 mmol)
2-chlorophenylhydrazine-hydrochloride after purification by column
chromatography.
EXAMPLE 56
N-[3-ETHYNYL-1-(2-TRIFLUOROMETHYL-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,-
4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE
[1205] ##STR259##
[1206] Analogously to Example 10.05 g product are obtained from 0.3
g (0.9 mmol) intermediate compound 16 and 0.16 g (0.9 mmol)
2-(trifluoromethyl)phenylhydrazine after purification by column
chromatography. Of this, 0.04 g are placed in 5 ml THF and combined
with 0.1 ml (0.1 mmol) tetrabutylammonium fluoride solution (1 M in
THF). The mixture is stirred for 0.5 hours at ambient temperature
and then water is added. The aqueous phase is extracted with ethyl
acetate, the organic phase is washed with water and 1 N
hydrochloric acid. The organic phase is dried and evaporated to
dryness. The residue is purified by chromatography. Yield: 0.012
g
EXAMPLE 57
N-(1-PHENYL-3-TRIFLUOROMETHYL-4,5-DIHYDRO-1H-PYRAZOLO[3',4':3,4]BENZO[1,2--
d]THIAZOL-7-YL)-ACETAMIDE
[1207] ##STR260##
[1208] Analogously to Example 10.04 g product are obtained from 0.3
g (1.0 mmol) intermediate compound 19 and 0.15 g (1.0 mmol)
phenylhydrazine-hydrochloride.
EXAMPLE 58
N-[4-(4-CHLORO-PHENYL)-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTAL-
EN-2-YL]-ACETAMIDE
[1209] ##STR261## 0.50 g (1.56 mmol) intermediate compound 22 are
suspended in 8 ml glacial acetic acid, combined with 0.34 g (1.88
mmol) 4-chlorophenylhydrazine-hydrochloride. The mixture is stirred
for 1.5 hours at 60.degree. C., then cooled to ambient temperature.
After the addition of 50 ml of water a precipitate is formed. This
is stirred for 0.1 hours at 5.degree. C., suction filtered and
recrystallised from methanol.
[1210] Yield: 0.19 g (m.p.: 296-305.degree. C.)
EXAMPLE 59
4-PHENYL-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTALEN-2-YL-AMINE
[1211] ##STR262##
[1212] 2.9 g (8.71 mmol)
N-(4-phenyl-4,7-dihydro-3-thia-1,4,5-triaza-cyclopenta[a]pentalen-2-yl)-a-
cetamide (prepared analogously to Example 58 from intermediate
compound 22) are suspended in 20 ml of water and 20 ml 32%
hydrochloric acid and refluxed for 2 hours with stirring. After
cooling to ambient temperature the mixture is extracted with
diethyl ether and the aqueous phase is made basic. The precipitate
formed is stirred for 0.25 hours at 5.degree. C., suction filtered
and dried. The crude product is suspended in 150 ml of
tetrahydrofuran and combined with 5 ml of conc. hydrochloric acid,
then stirred for 16 hours at 60.degree. C. After cooling to
5.degree. C. the precipitate is suction filtered and dried.
[1213] Yield: 1.8 g ##STR263##
EXAMPLE 60
4-o-TOLYL-3A,4,7,7A-TETRAHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTALEN-2-
-YLAMINE
[1214] Analogously to Example 5914 mg product are obtained from 140
mg (0.5 mmol)
N-(4-o-tolyl-4,7-dihydro-3-thia-1,4,5-triaza-cyclopenta[a]pentalen-2-yl)--
acetamide (prepared analogously to Example 58) in 1 ml of water and
1 ml hydrochloric acid after purification by column
chromatography.
EXAMPLE 61
4-DIMETHYLAMINO-N-(4-PHENYL-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]P-
ENTALEN-2-YL)-BUTANOIC ACID AMIDE
[1215] ##STR264##
[1216] 0.5 g (1.72 mmol) of the compound described under Example 59
are suspended in 25 ml dichloromethane, combined with 0.8 ml (6.02
mmol) triethylamine and refluxed. 0.8 g (4.30 mmol)
4-dimethylamine-butyric acid chloride-hydrochloride in 5 ml
dichloromethane are added dropwise within 0.1 hours and the
reaction mixture is refluxed for 16 hours. After cooling to ambient
temperature the precipitate is suction filtered and the filtrate is
washed with 5% sodium hydrogen carbonate solution and water. The
organic phase is dried and evaporated to dryness. The residue is
triturated with diethyl ether and suction filtered. Yield: 0.2 g
(m.p.: 218-222.degree. C.)
EXAMPLE 62
N-[4-(2-CHLORO-PHENYL)-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTAL-
EN-2-YL]-4-DIMETHYLAMINO-BUTANOIC ACID AMIDE
[1217] ##STR265##
[1218] Analogously to Example 59, 2.5 g of a compound are obtained
from 3.9 g (11.7 mmol)
4-(2-chloro-phenyl)-4,7-dihydro-3-thia-1,4,5-triaza-cyclopenta[a]pentalen-
-2-ylamine (prepared analogously to Example 58), of which 0.7 g
(1.7 mmol) are reacted as in Example 61 to form 0.2 g product
(m.p.: 167-170.degree. C.).
EXAMPLE 63
PIPERIDINE-1-CARBOXYLIC
ACID-(4-PHENYL-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTALEN-2-YL-
)-AMIDE
[1219] ##STR266##
[1220] A suspension of 2.3 g (8 mol) of the compound obtained under
Example 59 in 60 ml of pyridine is heated to 50.degree. C., then
combined with 1.6 ml (10 mmol) ethyl chlorothioformate. The
reaction mixture is stirred for 12 hours at 70.degree. C., then
stirred into 600 ml of water. The precipitate formed is suction
filtered and washed with water and ether. Yield: 2.3 g (M.p.:
142-145.degree. C.)
[1221] In a sealable pressurised glass tube 0.3 g (0.7 mmol) of the
compound described previously are suspended in 8 ml of ethanol,
combined with 1 ml (10.5 mmol) piperidine and refluxed for 16 hours
with stirring. After cooling to ambient temperature the reaction
mixture is concentrated by evaporation. The crude product is
filtered through silica gel. The residue is triturated with 20 ml
of water and 5 drops of acetonitrile, suction filtered and dried.
Yield: 0.07 g (m.p.: 120-125.degree. C.)
EXAMPLE 64
N-[8-(4-HYDROXY-PHENYL)-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL]-ACETAM-
IDE
[1222] ##STR267##
[1223] 2.7 g (11.3 mmol) intermediate compound 2 and 1.7 g (12.6
mmol) 4-hydroxybenzamidine are suspended in 6 ml of pyridine and
heated to 100.degree. C. for 2 hours. The reaction mixture is
combined with ether and the precipitate formed is stirred with
methanol. Yield: 2.1 g
EXAMPLE 65
4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLINE-2,8-DIAMINE
[1224] ##STR268##
[1225] 10 g (42 mmol) intermediate compound 2, 4 g (42 mmol)
guanidine-hydrochloride and 2.2 g (21 mmol) sodium carbonate are
suspended in 30 ml amyl alcohol and refluxed for 1 hour using the
water separator. The reaction mixture is evaporated down, the
residue is distilled off with xylene several times and then
purified by chromatography. The product is taken up in methanol and
precipitated with methanolic hydrochloric acid as the
hydrochloride. Yield: 1.2 g (M.p.: 293-300.degree. C.)
EXAMPLE 66
N-(8-ACETYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETAMIDE
[1226] ##STR269##
[1227] 0.5 g (1.7 mmol) of the compound described in Example 65 and
0.4 g (4.6 mmol) sodium acetate are suspended in 15 ml acetic
anhydride and stirred for 2 hours at 100.degree. C. The mixture is
cooled to 5.degree. C., the resulting solid is suction filtered and
washed with water. The crude product is stirred with methanol.
Yield: 0.4 g (M.p.: >310.degree. C.)
EXAMPLE 67
N-(6-OXO-8-PHENYL-4,5,6,7-TETRAHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETA-
MIDE
[1228] ##STR270##
[1229] In a pressurised glass tube 0.1 g (0.35 mmol) intermediate
compound 18 and 0.1 g (0.83 mmol) benzamidine are placed in 1 ml of
pyridine and heated to 160.degree. C. for 4 hours. The solvent is
concentrated by evaporation, the residue is stirred with hot
ethanol and suction filtered. Yield: 14 mg
EXAMPLE 68
N-(8-ETHYLSULPHANYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETAMIDE
[1230] ##STR271##
[1231] 10.0 g (42 mmol) intermediate compound 2 and 14.6 g (80
mmol) ethylisothiourea-hydrobromide are suspended in 20 ml of
pyridine and then stirred for 3 hours at 110.degree. C. After
cooling to ambient temperature the reaction mixture is triturated
with a little methanol, suction filtered and dried. Yield: 10.2
g
EXAMPLE 69
N-(8-ETHANESULPHONYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETAMIDE
[1232] ##STR272##
[1233] 10.6 g (34.6 mmol) of the compound prepared under Example 68
are dissolved in 100 ml dichloromethane, 17.0 g (75.9 mmol)
m-chloroperbenzoic acid are added and the mixture is then stirred
for 24 hours at ambient temperature. The reaction mixture is
diluted with dichloromethane and extracted with sodium carbonate
solution. The organic phase is washed with water, dried and
evaporated to dryness. Yield: 8.8 g
EXAMPLE 70
TERT-BUTYL
[1-(2-ACETYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-8-YL)-P-
IPERIDIN-3-YLMETHYL]-CARBAMATE
[1234] ##STR273##
[1235] 0.2 g (0.6 mmol) of the compound prepared under Example 69
and 0.25 g (1.2 mmol) tert-butyl piperidin-3-ylmethyl-carbamate are
placed in 2 ml N-methylpyrrolidine and refluxed for 24 hours with
stirring. Then the reaction mixture is combined with dilute
potassium carbonate solution and dichloromethane and extracted. The
organic phase is washed with water, dried and evaporated to
dryness. The residue is purified by chromatography. Yield: 0.03 g
(m.p.: 250-255.degree. C.)
EXAMPLE 71
8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YLAMINE
[1236] ##STR274##
[1237] 9.0 g (28 mmol)
N-(8-phenyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamide
(prepared analogously to Example 64) are refluxed for 2 hours in
130 ml semi-concentrated hydrochloric acid. After cooling the
reaction mixture is made basic, the precipitate formed is suction
filtered and dried. Yield: 7.3 g
EXAMPLE 72
N.sup.8,
N.sup.8-DIMETHYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLINE-2,8-DIAMI-
NE
[1238] ##STR275##
[1239] Analogously to Example 710.14 g product (M.p.:
292-295.degree. C.) may be obtained from 0.20 g (0.7 mmol)
N-(8-dimethylamino-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamide
(obtained analogously to Example 58).
EXAMPLE 73
N-(8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-PROPIONIC
ACID AMIDE
[1240] ##STR276##
[1241] 0.3 g (1.1 mmol) of the compound obtained in Example 71 are
suspended in 15 ml dichloromethane, combined with 0.4 ml (2.5 mmol)
triethylamine and gently refluxed. 0.2 ml (2.3 mmol) propionic acid
chloride are added and the mixture is refluxed for 5 hours with
stirring. After cooling to ambient temperature the reaction
solution is washed with sodium hydrogen carbonate and water, dried
and evaporated to dryness. The residue is stirred with diethyl
ether and suction filtered.
[1242] Yield: 0.2 g (m.p.: 274-275.degree. C.)
EXAMPLE 74
4-DIMETHYLAMINO-N-(8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-BU-
TYRIC ACID AMIDE
[1243] ##STR277##
[1244] Analogously to Example 73, 0.03 g product are obtained from
0.15 g (0.5 mmol) of the compound obtained in Example 71, 1 ml
triethylamine and 0.2 g (1.3 mmol) 4-dimethylamine-butyric acid
chloride-hydrochloride.
EXAMPLE 75
N-(8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-FORMAMIDE
[1245] ##STR278##
[1246] 0.2 g (0.71 mmol) of the compound described in Example 71
and 2.5 ml (22.7 mmol) phenyl formate are placed in a pressurised
glass tube and stirred for 16 hours at 80.degree. C. Then the
reaction mixture is concentrated by evaporation and the residue is
triturated with diethyl ether/ethanol. Yield: 0.17 g (m.p.:
304-306.degree. C.)
EXAMPLE 76
MORPHOLINE-4-CARBOXYLIC
ACID-(8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-AMIDE
[1247] ##STR279##
[1248] 2.5 g (8.9 mmol) of the compound obtained in Example 71 are
placed in 50 ml of pyridine and heated to 50.degree. C. 1.5 ml
(13.8 mmol) ethyl chlorothioformate are added and the mixture is
stirred for 20 hours at 50.degree. C. After cooling to ambient
temperature the reaction solution is added to water and extracted
with dichloromethane. The organic phase is dried and evaporated to
dryness. The residue is crystallised with diethyl ether. Yield: 1.0
g
[1249] 0.2 g (0.54 mmol) of the intermediate described above and
0.1 g (1.15 mmol) morpholine in 5 ml of ethanol are placed in a
pressurised glass tube and then stirred for 16 hours at 80.degree.
C. After cooling to ambient temperature the precipitate formed is
suction filtered and dried. Yield: 0.14 g (m.p.: 165-168.degree.
C.)
EXAMPLE 77
4-(2-ACETYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-8-YL)-N,N-DIMETHYL--
BENZAMIDE
[1250] ##STR280##
[1251] 1.0 g (3.8 mmol) of the intermediate compound 2 and 0.8 g
(3.1 mmol) carbamimidoyl-benzoic acid-methanesulphonate are placed
in 5 ml of pyridine and heated to 180.degree. C. for 5 hours. After
cooling to ambient temperature the reaction mixture is stirred with
ethanol and suction filtered. Yield: 0.6 g
[1252] 0.1 g (0.27 mmol) of the previously prepared compound and
0.1 g O-(1H-benzotriazol-1-yl)-N,N,
N',N'-tetramethyluronium-tetrafluoroborate (TBTU) are placed in 2
ml of dimethylformamide, combined with 0.2 ml diisopropylethylamine
and stirred for 0.5 hours at ambient temperature. 0.2 ml (4.0 mmol)
dimethylamine (2 M in THF) are added and the mixture is stirred for
a further 16 hours at ambient temperature. The resulting suspension
is dissolved with dimethylformamide, then purified by RP-HPLC.
Corresponding fractions are combined and freeze-dried.
[1253] Yield: 0.04 g (m.p.: >300.degree. C.)
EXAMPLE 78
N-[8-(2-OXO-PYRROLIDIN-1-YL)-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL]-A-
CETAMIDE
[1254] ##STR281##
[1255] 2.0 g (8.4 mmol) intermediate compound 2 and 2.4 g (16.8
mmol) 4-guanidine-butyric acid in 30 ml of pyridine are placed in a
pressurised glass tube and then heated to 190.degree. C. for 20
hours. The reaction mixture is concentrated by evaporation, the
residue is boiled with methanol and insoluble constituents are
filtered off. The crude product is precipitated from the mother
liquor in the form of the hydrochloride, suction filtered and
dried. The solid is purified by column chromatography. Yield: 0.02
g (m.p.: >160.degree. C.)
EXAMPLE 79
N-[8-(3-AMINOMETHYL-PIPERIDIN-1-YL)-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN--
2-YL]-ACETAMIDE
[1256] ##STR282##
[1257] 0.05 g (0.1 mmol) of the compound described under Example 70
are dissolved in 5 ml ethereal hydrochloric acid and stirred for 16
hours at ambient temperature.
[1258] The resulting solid is suction filtered, washed with diethyl
ether and dried. Yield: 0.035 g
EXAMPLE 80
N-{8-[3-(ISOPROPYLAMINO-METHYL)-PIPERIDIN-1-YL]-4,5-DIHYDRO-THIAZOLO[4,5-h-
]QUINAZOLIN-2-YL}-ACETAMIDE
[1259] ##STR283## 0.2 g (0.5 mmol) of the compound obtained in
Example 79, 0.05 ml (0.6 mmol) acetone and 0.02 g (0.5 mol) sodium
borohydride are dissolved in methanol and is stirred for 0.5 hours
at 40.degree. C. The same amounts of acetone and sodium borohydride
are added again and the mixture is stirred for a further 16 hours
at ambient temperature. Then the reaction mixture is concentrated
by evaporation, the residue is extracted with dichloromethane and
water. The organic phase is dried and evaporated to dryness. The
crude product is triturated with diethyl ether and suction
filtered. Yield: 0.040 g
EXAMPLE 81
N-{8-[ACETYL-(2-DIMETHYLAMINO-ETHYL)-AMINO]-4,5-DIHYDRO-THIAZOLO[4,5-h]QUI-
NAZOLIN-2-YLACETAMIDE
[1260] ##STR284##
[1261] 0.4 g (1.2 mmol) of the compound obtained under Example 69
and 0.4 ml (4.5 mmol) N.sup.1,N.sup.1-dimethylethane-1,2-diamine
are placed in 5 ml N-methylpyrrolidine and stirred for 48 hours at
90.degree. C. The reaction mixture is extracted with
dichloromethane and 10% potassium carbonate solution. The organic
phase is dried and evaporated to dryness. Yield: 0.08 g
[1262] 0.08 g (0.28 mmol) of the compound described previously are
dissolved in 5 ml (49 mmol) acetic anhydride and stirred for 1 hour
at 140.degree. C. The reaction mixture is concentrated by
evaporation, the residue is stirred with acetonitrile and suction
filtered. Yield: 0.07 g
EXAMPLE 82
TERT-BUTYL
(2-ACETYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-8-YL)-PROP-
-2-YNYL-CARBAMATE
[1263] ##STR285##
[1264] 0.34 g (2.2 mmol) tert-butyl prop-2-ynyl-carbamate are
placed in 3 ml of tetrahydrofuran and cooled to -30.degree. C. 2.3
ml (4.4 mmol) 2 M isopropylmethyl-magnesium chloride solution in
tetrahydrofuran are slowly added dropwise and the mixture is
stirred for 0.5 hours. Then a solution of 0.34 g (1.0 mmol) of the
compound described in Example 69 in 4 ml of tetrahydrofuran is
added at -10.degree. C. and the mixture is stirred for 4 hours,
while heating to ambient temperature. The reaction mixture is
extracted with water and dichloromethane, the organic phase is
dried and evaporated to dryness. The residue is triturated with
diethyl ether. Yield: 0.18 g
EXAMPLE 83
N-(8-PROP-2-YNYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETAMID-
E
[1265] ##STR286##
[1266] 0.05 g (0.13 mmol) of the compound obtained in Example 82
are dissolved in 5 ml ethereal hydrochloric acid and stirred for 16
hours at ambient temperature. The resulting solid is suction
filtered, triturated with diethyl ether/acetone 9:1 and suction
filtered again. Yield: 0.03 g
EXAMPLE 84
N-[1-(4-METHOXY-PHENYL)-1,4,5,6-TETRAHYDRO-9-THIA-1,2,7-TRIAZA-CYCLOPENTA[-
E]AZULEN-8-YL]-ACETAMIDE
[1267] ##STR287##
[1268] A solution of 0.25 g (1 mmol) intermediate compound 23 and
0.18 mg (1 mmol) 4-methoxyphenylhydrazine-hydrochloride in 5 ml
glacial acetic acid is heated to 60.degree. C. for 2 h. The mixture
is combined with water and extracted three times with ethyl
acetate. The combined organic phases are dried over magnesium
sulphate and evaporated down. The residue is purified first of all
by column chromatography (eluant: dichloromethane/methanol 95:5),
then by RP-HPLC.
[1269] Yield: 0.07 g
EXAMPLE 85
N-(8-NITRO-4,5-DIHYDRO-3H-1.lamda..sup.4-NAPHTHO[2,1-d]THIAZOL-2-YL)-ACETA-
MIDE
[1270] ##STR288##
[1271] 0.8 g (10.0 mmol) sodium acetate and 1.9 g (9.40 mmol)
7-nitro-3,4-dihydro-1H-naphthalen-2-one (prepared according to D.
E. Nichols et al., J. Med. Chem. 1989, 32, 2128-2134) are dissolved
in 40 ml acetic acid and cooled to 15.degree. C. 0.5 g (3.19 mmol)
bromine are added and the mixture is stirred for 0.1 hours, until
the bromine has finished reacting completely. Then 0.8 g (10.5
mmol) thiourea are added. The reaction mixture is heated to
60.degree. C. for 0.25 hours, then suction filtered and washed. The
crystals are recrystallised from ethanol. Yield: 0.75 g (M.p.:
247-248.degree. C.)
[1272] 0.75 g (3.0 mmol) of the compound described previously are
placed in 5 ml (49 mmol) acetic anhydride and refluxed for 0.1
hours. After cooling to ambient temperature the precipitate formed
is suction filtered, washed with ethyl acetate and diethyl ether
and dried. Yield: 0.8 g (M.p.: >315.degree. C.)
EXAMPLE 86
N-(8-ACETYLAMINO-4,5-DIHYDRO-3H-1.lamda..sup.4-NAPHTHO[2,1-d]THIAZOL-2-YL)-
-ACETAMIDE
[1273] ##STR289##
[1274] 0.5 g (1.7 mmol) of the compound described in Example 85 are
suspended in 10 ml acetic acid and combined with 2 g iron powder.
The reaction mixture is heated to 70.degree. C. and stirred for 0.1
hours. Then it is suction filtered and the mother liquor is
concentrated by evaporation. The residue is combined with water,
the precipitate is suction filtered, washed and dried. Yield: 0.4
g
[1275] 0.1 g (0.4 mmol) of the compound described previously, 0.1 g
(1,0 mmol) acetic anhydride and 0.1 ml triethylamine are placed in
5 ml dichloromethane and stirred for 1 hour at ambient temperature.
Then the reaction mixture is washed with 2 N hydrochloric acid and
2 N sodium hydroxide solution. The organic phase is dried and
evaporated to dryness. The residue is crystallised from ethyl
acetate. Yield: 0.07 g (m.p.: 181-183.degree. C.)
EXAMPLE 87
N-(2-ACETYLAMINO-4,5-DIHYDRO-NAPHTHO[2,1-d]THIAZOL-8-YL)-ISOBUTYRIC
ACID AMIDE
[1276] ##STR290##
[1277] Analogously to Example 860.075 g product (M.p.:
272-274.degree. C.) may be obtained from 0.1 g (0.4 mmol) of the
intermediate described therein, 0.045 g (0.4 mmol) isobutyric acid
chloride and 0.1 ml triethylamine in 5 ml dichloromethane.
EXAMPLE 88
N-(8-ISOPROPYLAMINO-4,5-DIHYDRO-3H-1.lamda..sup.4-NAPHTHO[2,1-d]THIAZOL-2--
YL)-ACETAMIDE
[1278] ##STR291##
[1279] 0.15 g (0.58 mmol) of the intermediate described in Example
86, 1.0 g (17.2 mmol) acetone and 0.4 g sodium
triacetoxyborohydride are placed in 10 ml dichloromethane and
stirred for 4 hours at ambient temperature. The reaction mixture is
combined with 50 ml of water and 2 g potassium carbonate, the
organic phase is separated off, dried and evaporated to dryness.
The residue is purified by chromatography, then crystallised from
diethyl ether. Yield: 0.11 g (m.p.: 183-184.degree. C.)
EXAMPLE 89
N-[5-(2-CHLORO-PHENYL)-8H-3-THIA-1,4,6-TRIAZA-CYCLOPENTA[A]INDEN-2-YL]-ACE-
TAMIDE
[1280] ##STR292##
[1281] 350 mg (1.56 mmol) intermediate compound 22 and 298 mg (1.56
mmol) 2-chlorobenzamidine are suspended in 1.5 mL pyridine and
heated to 160.degree. C. for 1 hour. The reaction mixture is
evaporated down and purified by RP-HPLC. Yield: 14 mg (m.p.:
257.degree. C.)
EXAMPLE 90
N-(5-MORPHOLIN-4-YL-8H-3-THIA-1,4,6-TRIAZA-CYCLOPENTA[A]INDEN-2-YL)-ACETAM-
IDE
[1282] ##STR293##
[1283] 350 mg (1.56 mmol) intermediate compound 22 and 260 mg (1.57
mmol) morpholinecarboxamidine are suspended in 1.5 mL pyridine and
heated to 160.degree. C. for 1 hour. The reaction mixture is
evaporated down and purified by RP-HPLC. Yield: 11 mg (m.p.:
>300.degree. C.)
EXAMPLE 91
N-(5-PHENYL-8H-3-THIA-1,4,6-TRIAZA-CYCLOPENTA[A]INDEN-2-YL)-ACETAMIDE
[1284] ##STR294##
[1285] 350 mg (1.56 mmol) intermediate compound 22 and 190 mg (1.58
mmol) benzamidine are suspended in 1.5 mL pyridine and heated to
160.degree. C. for 1 hour. The reaction mixture is evaporated down
and purified by RP-HPLC. Yield: 16 mg (m.p.: >300.degree.
C.)
[1286] Some compounds which may be prepared by one of the methods
of synthesis described above are hereinafter listed by way of
example. All the melting points (m.sub.p) are given in .degree. C.
In order to determine the inhibitory activity of the compounds on
PI3K.gamma., an in-vitro kinase assay is set up which is based on
the transfer of the terminal .gamma.-phosphate of ATP to
phosphatidylinositol-4,5-bisphosphate (PIP.sub.2). The enzyme
activity used is the G.beta..sub.1.gamma..sub.2-His stimulated
PI3K.gamma.. The expression and purification of
G.beta..sub.1.gamma..sub.2-His and p101-GST/p110.gamma. from
Sf9-cells (Spodoptera frugiperda 9) has already been described
(Maier et al., J. Biol. Chem. 1999 (274) 29311-29317).
[1287] The kinase assay is carried out in white 384-well
flat-bottomed dishes. Each well contained 5 .mu.l of the compound
to be tested which had been dissolved in assay buffer (40 mM Hepes,
pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mM .beta.-glycerophosphate, 1 mM
DTT, 7 mM MgCl.sub.2 and 0.1% BSA; 6% DMSO). 15 .mu.l of lipid
vesicles containing 10 ng of PI3K.gamma. and 31.5 ng of
G.beta..sub.1.gamma..sub.2-His were added in each case. The lipid
vesicles in turn were generated by suspending PIP.sub.2 (0.35
.mu.g/well), phosphatidyl ethanolamine (3.75 .mu.g/well),
phosphatidyl serine (3.5 .mu.g/well), sphingomyelin (0.35
.mu.g/well) and phosphatidyl choline (1.6 .mu.g/well) in lipid
buffer (assay buffer without DMSO) by ultrasound treatment. After
the addition of the lipid vesicles the reaction is started by the
addition of 10 .mu.l reaction buffer (40 mM Hepes, pH 7.5, 100 mM
NaCl, 1 mM EGTA, 1 mM .beta.-glycerophosphate, 1 mM DTT, 7 mM
MgCl.sub.2 and 0.1% BSA; 1 .mu.M ATP and 0.2 .mu.Ci
[.gamma.-.sup.33P]-ATP). The reaction mixture is incubated in this
way for 1 h and then stopped by the addition of a suspension of
0.12 mg LEADseeker beads (Amersham Biosciences) in stop buffer (40
mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 12 mM EDTA, 1 mM
.beta.-glycerophosphate, 1 mM DTT). After 1 minute's centrifugation
at 500.times.g the plates were read and analysed using a LEADseeker
apparatus. All the compounds shown have an IC.sub.50 value of less
than 800 nM in the test.
EXAMPLES A
[1288] TABLE-US-00001 ##STR295## R.sup.a R.sup.b R.sup.c m.sub.p 1.
##STR296## H ##STR297## 2. ##STR298## H ##STR299## 3. ##STR300##
--CH.sub.3 ##STR301## >280 4. ##STR302## ##STR303## ##STR304##
258-260 5. ##STR305## ##STR306## ##STR307## 282-283 6. ##STR308##
##STR309## ##STR310## 286-288 7. ##STR311## ##STR312## ##STR313##
280-282 8. ##STR314## ##STR315## ##STR316## >300 9. ##STR317##
##STR318## ##STR319## 261-263 10. ##STR320## ##STR321## ##STR322##
295-298 11. ##STR323## ##STR324## ##STR325## >300 12. ##STR326##
##STR327## ##STR328## >300 13. ##STR329## ##STR330## ##STR331##
297-299 14. ##STR332## ##STR333## ##STR334## >300 15. ##STR335##
##STR336## ##STR337## >300 16. ##STR338## ##STR339## ##STR340##
>300 17. ##STR341## ##STR342## ##STR343## 259-261 18. ##STR344##
##STR345## ##STR346## >300 19. ##STR347## H ##STR348## 20.
##STR349## H ##STR350## 214-216 21. ##STR351## H ##STR352## 227-229
22. ##STR353## H ##STR354## 244-246 23. ##STR355## H ##STR356##
211-213 24. ##STR357## H ##STR358## 242-244 25. ##STR359## H
##STR360## 270-273 26. ##STR361## H ##STR362## 251-253 27.
##STR363## H ##STR364## 28. ##STR365## ##STR366## ##STR367##
277-290 Decomp. 29. ##STR368## ##STR369## ##STR370## 113-120
Decomp. 30. ##STR371## H ##STR372## 31. ##STR373## H ##STR374## 32.
##STR375## H ##STR376## 236-237,5 33. ##STR377## H ##STR378##
298-304 Decomp. 34. ##STR379## H ##STR380## 303,5-306 35.
##STR381## H ##STR382## 36. ##STR383## H ##STR384## 37. ##STR385##
H ##STR386## >300 38. ##STR387## H ##STR388## 39. ##STR389## H
##STR390## 154-157 40. ##STR391## ##STR392## ##STR393## 295-300 41.
##STR394## H ##STR395## 256-259 42. ##STR396## H ##STR397## 228-230
43. ##STR398## H ##STR399## 270-273 44. ##STR400## H ##STR401##
202-204 45. ##STR402## H ##STR403## 202-204 46. ##STR404## H
##STR405## >300.degree. 47. ##STR406## ##STR407## ##STR408##
295-305 48. ##STR409## H ##STR410## 264-266 49. ##STR411## H
##STR412## 294-296 50. ##STR413## H ##STR414## >300 51.
##STR415## H ##STR416## 52. ##STR417## ##STR418## ##STR419##
296->Decomp. 53. ##STR420## H ##STR421## 233-235 54. ##STR422##
H ##STR423## 234-235 55. ##STR424## H ##STR425## 56. ##STR426## H
##STR427## 249-251 57. ##STR428## H ##STR429## 248-249 58.
##STR430## H ##STR431## 135-137 59. ##STR432## H ##STR433## 239 60.
##STR434## H ##STR435## 61. ##STR436## H ##STR437## 62. ##STR438##
H ##STR439## 63. ##STR440## H ##STR441## 64. ##STR442## H
##STR443## 65. ##STR444## H ##STR445## 66. ##STR446## H ##STR447##
67. ##STR448## H ##STR449## 68. ##STR450## H ##STR451## 69.
##STR452## ##STR453## ##STR454## 70. ##STR455## ##STR456##
##STR457## 71. ##STR458## H ##STR459## 72. ##STR460## H ##STR461##
255-256 73. ##STR462## ##STR463## ##STR464## 74. ##STR465## H
##STR466## 75. ##STR467## H ##STR468## 76. ##STR469## ##STR470##
##STR471## 77. ##STR472## H ##STR473## 78. ##STR474## H ##STR475##
79. ##STR476## H ##STR477## 80. ##STR478## H ##STR479## 81.
##STR480## ##STR481## ##STR482## 82. ##STR483## H ##STR484## 83.
##STR485## ##STR486## ##STR487## 84. ##STR488## H ##STR489## 85.
##STR490## --CH.sub.3 ##STR491## 86. ##STR492## H ##STR493## 87.
##STR494## H ##STR495## 88. ##STR496## H ##STR497## 89. ##STR498##
H ##STR499## 230 90. ##STR500## ##STR501## ##STR502## ##STR503## H
##STR504## 227,4 91. ##STR505## H ##STR506## 92. ##STR507## H
##STR508## 93. ##STR509## ##STR510## ##STR511## 94. ##STR512## H
##STR513## 95. ##STR514## H ##STR515## >300 96. ##STR516## H
##STR517## 97. ##STR518## ##STR519## ##STR520## 98. ##STR521## H
##STR522## 99. ##STR523## H ##STR524## 100. ##STR525## ##STR526##
##STR527## 101. ##STR528## H ##STR529## 102. ##STR530## H
##STR531## 103. ##STR532## H ##STR533## 104. ##STR534## H
##STR535## 105. ##STR536## H ##STR537## 106. ##STR538## H
##STR539## 107. ##STR540## H ##STR541## 108. ##STR542## H
##STR543## 109. ##STR544## H ##STR545## 110. ##STR546## H
##STR547## 111. ##STR548## H ##STR549## 112. ##STR550## H
##STR551## 113. ##STR552## H ##STR553## 114. ##STR554## --CH.sub.3
##STR555## 115. ##STR556## H ##STR557## 116. ##STR558## H
##STR559## 117. ##STR560## ##STR561## ##STR562## 118. ##STR563## H
##STR564## 119. ##STR565## ##STR566## ##STR567## 120. ##STR568## H
##STR569##
121. ##STR570## H ##STR571## 122. ##STR572## H ##STR573## 280-281
123. ##STR574## H ##STR575## 245 124. ##STR576## H ##STR577##
317-319 125. ##STR578## H ##STR579## 300-310 126. ##STR580## H
##STR581## 226-227 127. ##STR582## H ##STR583## 240-250 128.
##STR584## H ##STR585## 304-310 129. ##STR586## H ##STR587## 130.
##STR588## H ##STR589## 131. ##STR590## H ##STR591## 132.
##STR592## H ##STR593## 133. ##STR594## H ##STR595##
[1289] TABLE-US-00002 R.sup.a R.sup.b R.sup.c m.sub.p 134.
##STR596## H ##STR597## 135. ##STR598## H ##STR599## 136.
##STR600## H ##STR601## 137. ##STR602## H ##STR603## 138.
##STR604## H ##STR605## 139. ##STR606## H ##STR607## 140.
##STR608## H ##STR609## 141. ##STR610## H ##STR611## 142.
##STR612## H ##STR613## 143. ##STR614## H ##STR615## 144.
##STR616## H ##STR617## 145. ##STR618## H ##STR619## 146.
##STR620## H ##STR621## 147. ##STR622## H ##STR623## 148.
##STR624## H ##STR625## 149. ##STR626## H ##STR627## 150.
##STR628## H ##STR629## 151. ##STR630## H ##STR631## 152.
##STR632## H ##STR633## 153. ##STR634## H ##STR635## 154.
##STR636## H ##STR637## 155. ##STR638## H ##STR639## 156.
##STR640## H ##STR641## 157. ##STR642## H ##STR643## 158.
##STR644## H ##STR645## 159. ##STR646## ##STR647## ##STR648## 303,1
160. ##STR649## ##STR650## ##STR651## 281,3 161. ##STR652##
##STR653## ##STR654## 248,3 162. ##STR655## ##STR656## ##STR657##
163. ##STR658## ##STR659## ##STR660## 164. ##STR661## H ##STR662##
>300 165. ##STR663## H ##STR664## >280 166. ##STR665##
##STR666## ##STR667## >300 167. ##STR668## ##STR669## ##STR670##
>300 168. ##STR671## H ##STR672## 248-251 169. ##STR673## H
##STR674## 242-245 170. ##STR675## ##STR676## ##STR677## >300
171. ##STR678## H ##STR679## 298->300 172. ##STR680## H
##STR681## >300 173. ##STR682## H ##STR683## 209-211 174.
##STR684## ##STR685## ##STR686## 175. ##STR687## ##STR688##
##STR689## 176. ##STR690## ##STR691## ##STR692## 177. ##STR693##
##STR694## ##STR695## 178. ##STR696## ##STR697## ##STR698## 179.
##STR699## ##STR700## ##STR701## 180. ##STR702## ##STR703##
##STR704## 181. ##STR705## ##STR706## ##STR707## 182. ##STR708##
##STR709## ##STR710## 183. ##STR711## ##STR712## ##STR713## 184.
##STR714## ##STR715## ##STR716## 185. ##STR717## ##STR718##
##STR719## 186. ##STR720## ##STR721## ##STR722## 187. ##STR723##
##STR724## ##STR725## 188. ##STR726## ##STR727## ##STR728## 189.
##STR729## ##STR730## ##STR731## 190. ##STR732## ##STR733##
##STR734## 191. ##STR735## ##STR736## ##STR737## 192. ##STR738##
##STR739## ##STR740## 193. ##STR741## ##STR742## ##STR743## 194.
##STR744## ##STR745## ##STR746## 195. ##STR747## ##STR748##
##STR749## 196. ##STR750## ##STR751## ##STR752## 197. ##STR753##
##STR754## ##STR755## 198. ##STR756## ##STR757## ##STR758## 199.
##STR759## H ##STR760## 200. ##STR761## H ##STR762## 201.
##STR763## H ##STR764## 202. ##STR765## H ##STR766## 203.
##STR767## H ##STR768## 204. ##STR769## H ##STR770## 205.
##STR771## H ##STR772## 206. ##STR773## H ##STR774## 207.
##STR775## H ##STR776## 208. ##STR777## H ##STR778## 209.
##STR779## H ##STR780## 210. ##STR781## H ##STR782## 211.
##STR783## H ##STR784## 212. ##STR785## H ##STR786## 213.
##STR787## H ##STR788## 214. ##STR789## H ##STR790## 215.
##STR791## H ##STR792## 216. ##STR793## H ##STR794## 217.
##STR795## H ##STR796## 218. ##STR797## H ##STR798## 219.
##STR799## H ##STR800## 220. ##STR801## H ##STR802## 221.
##STR803## H ##STR804## 222. ##STR805## H ##STR806## 223.
##STR807## H ##STR808## 224. ##STR809## H ##STR810## 225.
##STR811## H ##STR812## 226. ##STR813## H ##STR814## 227.
##STR815## H ##STR816## 228. ##STR817## H ##STR818## 229.
##STR819## H ##STR820## 230. ##STR821## H ##STR822## 231.
##STR823## H ##STR824## 232. ##STR825## H ##STR826## 233.
##STR827## H ##STR828## 234. ##STR829## H ##STR830## 235.
##STR831## H ##STR832## 236. ##STR833## H ##STR834## 237.
##STR835## H ##STR836## 238. ##STR837## H ##STR838## 239.
##STR839## H ##STR840## 240. ##STR841## H ##STR842## 241.
##STR843## H ##STR844## 242. ##STR845## H ##STR846## 243.
##STR847## H ##STR848## 244. ##STR849## H ##STR850## 245.
##STR851## H ##STR852## 246. ##STR853## H ##STR854## 247.
##STR855## H ##STR856## 248. ##STR857## H ##STR858## 249.
##STR859## H ##STR860## 250. ##STR861## H ##STR862## 251.
##STR863## H ##STR864## 252. ##STR865## H ##STR866## 253.
##STR867## H ##STR868## 254. ##STR869## H ##STR870## 255.
##STR871## H ##STR872##
[1290] TABLE-US-00003 R.sup.a R.sup.b R.sup.c m.sub.p 256.
##STR873## H ##STR874## 257. ##STR875## H ##STR876## 258.
##STR877## H ##STR878## 259. ##STR879## H ##STR880## 260.
##STR881## H ##STR882## 261. ##STR883## H ##STR884## 262.
##STR885## H ##STR886## 263. ##STR887## H ##STR888## 264.
##STR889## H ##STR890## 265. ##STR891## H ##STR892## 266.
##STR893## H ##STR894## 267. ##STR895## H ##STR896## 268.
##STR897## H ##STR898## 269. ##STR899## H ##STR900## 270.
##STR901## H ##STR902## 271. ##STR903## H ##STR904## 272.
##STR905## H ##STR906## 273. ##STR907## H ##STR908## 274.
##STR909## H ##STR910## 275. ##STR911## H ##STR912## 276.
##STR913## H ##STR914## 277. ##STR915## H ##STR916## 278.
##STR917## H ##STR918## 279. ##STR919## H ##STR920## 280.
##STR921## ##STR922## ##STR923## 281. ##STR924## ##STR925##
##STR926## 282. ##STR927## ##STR928## ##STR929## 283. ##STR930## H
##STR931## 284. ##STR932## H ##STR933## 285. ##STR934## H
##STR935## 286. ##STR936## H ##STR937## 287. ##STR938## H
##STR939## 288. ##STR940## H ##STR941## 289. ##STR942## H
##STR943## 290. ##STR944## H ##STR945## 291. ##STR946## H
##STR947## 292. ##STR948## H ##STR949## 293. ##STR950## H
##STR951## 294. ##STR952## H ##STR953## 295. ##STR954## H
##STR955## 296. ##STR956## H ##STR957## 297. ##STR958## H
##STR959## 298. ##STR960## H ##STR961## 299. ##STR962## H
##STR963## 300. ##STR964## H ##STR965## 301. ##STR966## H
##STR967## 302. ##STR968## H ##STR969## 303. ##STR970## H
##STR971## 304. ##STR972## H ##STR973## 305. ##STR974## H
##STR975## 306. ##STR976## H ##STR977## 307. ##STR978## H
##STR979## 308. ##STR980## H ##STR981## 309. ##STR982## H
##STR983## 310. ##STR984## H ##STR985## 311. ##STR986## H
##STR987## 312. ##STR988## H ##STR989## 313. ##STR990## H
##STR991## 314. ##STR992## H ##STR993## 315. ##STR994## H
##STR995## 316. ##STR996## H ##STR997## 317. ##STR998## H
##STR999## 318. ##STR1000## H ##STR1001## 319. ##STR1002## H
##STR1003## 320. ##STR1004## H ##STR1005## 321. ##STR1006## H
##STR1007## 322. ##STR1008## H ##STR1009## 323. ##STR1010## H
##STR1011## 324. ##STR1012## H ##STR1013## 325. ##STR1014## H
##STR1015## 326. ##STR1016## H ##STR1017## 327. ##STR1018## H
##STR1019## 328. ##STR1020## H ##STR1021## 329. ##STR1022## H
##STR1023## 330. ##STR1024## H ##STR1025## 331. ##STR1026## H
##STR1027## 332. ##STR1028## H ##STR1029## 333. ##STR1030## H
##STR1031## 334. ##STR1032## H ##STR1033## 335. ##STR1034## H
##STR1035## 336. ##STR1036## H ##STR1037## 337. ##STR1038## H
##STR1039## 338. ##STR1040## H ##STR1041## 339. ##STR1042## H
##STR1043## 340. ##STR1044## H ##STR1045## 341. ##STR1046##
##STR1047## ##STR1048## 342. ##STR1049## H ##STR1050## 343.
##STR1051## H ##STR1052##
EXAMPLES B
[1291] TABLE-US-00004 ##STR1053## R.sup.a R.sup.b R.sup.c m.sub.p
344. ##STR1054## H ##STR1055## >300 345. ##STR1056## H
##STR1057## 298-305 346. ##STR1058## H ##STR1059## 255-260 347.
##STR1060## H ##STR1061## 245-252 348. ##STR1062## H ##STR1063##
288-295 349. ##STR1064## H ##STR1065## 350. ##STR1066## H
##STR1067## >300 351. ##STR1068## H ##STR1069## 296-300 352.
##STR1070## H ##STR1071## 292-300 353. ##STR1072## H ##STR1073##
>280 354. ##STR1074## H ##STR1075## 238-243 355. ##STR1076## H
##STR1077## >300 356. ##STR1078## H ##STR1079## 205-210 357.
##STR1080## H ##STR1081## 200-204 358. ##STR1082## H ##STR1083##
108-115 359. ##STR1084## H ##STR1085## >300 360. ##STR1086## H
##STR1087## 175-180 361. ##STR1088## H ##STR1089## 172-175 362.
##STR1090## H ##STR1091## 220-222 363. ##STR1092## H ##STR1093##
>250 364. ##STR1094## H ##STR1095## 239-242 365. ##STR1096## H
##STR1097## 216-219 366. ##STR1098## H ##STR1099## >300 367.
##STR1100## H ##STR1101## 199-201 368. ##STR1102## H ##STR1103##
>300 369. ##STR1104## H ##STR1105## 246-247
EXAMPLES C
[1292] TABLE-US-00005 ##STR1106## R.sup.a R.sup.b R.sup.c m.sub.p
370. ##STR1107## H ##STR1108## >275 371. ##STR1109## H
##STR1110## 267-268 372. ##STR1111## H ##STR1112## 373. ##STR1113##
H ##STR1114## >295 374. ##STR1115## H ##STR1116## >300 375.
##STR1117## H ##STR1118## >300 376. ##STR1119## H ##STR1120##
208-209 377. ##STR1121## H ##STR1122## 132-133 378. ##STR1123## H
##STR1124## >300 379. ##STR1125## H ##STR1126## 147.4-150 380.
##STR1127## H ##STR1128## 147-149.3 381. ##STR1129## H ##STR1130##
263.4-264.5 382. ##STR1131## H ##STR1132## 237.9-239.4 383.
##STR1133## H ##STR1134## 272-273 384. ##STR1135## H ##STR1136##
242-243 385. ##STR1137## H ##STR1138## >300 386. ##STR1139## H
##STR1140## 196-199 387. ##STR1141## H ##STR1142## 221-222 388.
##STR1143## H ##STR1144## >300 389. ##STR1145## H ##STR1146##
231-232 390. ##STR1147## H ##STR1148## >300 391. ##STR1149## H
##STR1150## 234-234.5 392. ##STR1151## H ##STR1152## 273-274 393.
##STR1153## H ##STR1154## 194-196 394. ##STR1155## H ##STR1156##
287.7-289 395. ##STR1157## OH ##STR1158##
EXAMPLES D
[1293] TABLE-US-00006 ##STR1159## R.sup.a R.sup.b R.sup.c m.sub.p
396. ##STR1160## ##STR1161## ##STR1162## 289-290 397. ##STR1163##
##STR1164## ##STR1165## >300 398. ##STR1166## ##STR1167##
##STR1168## 399. ##STR1169## ##STR1170## ##STR1171## 400.
##STR1172## ##STR1173## ##STR1174## >300 401. ##STR1175##
##STR1176## ##STR1177## >300 402. ##STR1178## ##STR1179##
##STR1180##
EXAMPLES E
[1294] TABLE-US-00007 ##STR1181## R.sup.a R.sup.b R.sup.c m.sub.p
403. --CH.sub.3 H ##STR1182## 404. ##STR1183## H ##STR1184## 405.
##STR1185## H ##STR1186## 406. ##STR1187## H ##STR1188## 407.
##STR1189## H ##STR1190## 408. ##STR1191## H ##STR1192## 409.
##STR1193## H ##STR1194## 246-247 410. ##STR1195## H ##STR1196##
411. ##STR1197## H ##STR1198## 412. ##STR1199## H ##STR1200## 413.
##STR1201## H ##STR1202## 191 414. ##STR1203## H ##STR1204## 415.
##STR1205## H ##STR1206## 416. ##STR1207## H ##STR1208##
EXAMPLES F
[1295] TABLE-US-00008 ##STR1209## R.sup.a R.sup.b R.sup.c m.sub.p
417. ##STR1210## H ##STR1211## 418. ##STR1212## H ##STR1213## 419.
##STR1214## H ##STR1215## 420. ##STR1216## H ##STR1217## 421.
##STR1218## H ##STR1219## 422. ##STR1220## H ##STR1221## 423.
##STR1222## H ##STR1223## 235-238 424. ##STR1224## H ##STR1225##
281-282 425. --CF.sub.3 H ##STR1226## 366-370 4267. ##STR1227## H
##STR1228## 248.4-250.6 427. ##STR1229## H ##STR1230## 198-199 428.
--CH.sub.3 H ##STR1231## 224-225 429. ##STR1232## H ##STR1233##
94-103 430. ##STR1234## H ##STR1235## 220.5-221.5 431. ##STR1236##
H ##STR1237## 432. ##STR1238## H ##STR1239## 367.9-368.5 433.
##STR1240## H ##STR1241## 369.4-370.4 434. ##STR1242## H
##STR1243## 294.2-296.7 435. ##STR1244## H ##STR1245## 274-276 436.
##STR1246## H ##STR1247## 299-301 437. ##STR1248## H ##STR1249##
267-269 438. ##STR1250## H ##STR1251## 439. ##STR1252## H
##STR1253## 440. ##STR1254## H ##STR1255## 441. ##STR1256## OH
##STR1257## 442. ##STR1258## H ##STR1259## 443. ##STR1260## H
##STR1261## 444. ##STR1262## H ##STR1263##
EXAMPLES G
[1296] TABLE-US-00009 ##STR1264## R.sup.a R.sup.b R.sup.c m.sub.p
445. ##STR1265## H ##STR1266## 446. ##STR1267## H ##STR1268## 447.
##STR1269## H ##STR1270## 448. ##STR1271## H ##STR1272## 449.
##STR1273## H ##STR1274## 450. ##STR1275## H ##STR1276## 451.
##STR1277## H ##STR1278## 208-209 452. ##STR1279## H ##STR1280##
453. ##STR1281## H ##STR1282## 454. ##STR1283## H ##STR1284##
EXAMPLES H
[1297] TABLE-US-00010 m.sub.p 455. ##STR1285## 181-183 Decomp. 456.
##STR1286## 272-274 Decomp. 457. ##STR1287## >315 458.
##STR1288## 183-184
Ranges of Indications
[1298] It has been found that the compounds of formula 1 are
characterised by a variety of possible applications in the
therapeutic field. Particular mention should be made of those
applications for which the compounds of formula 1 according to the
invention are preferably used by virtue of their pharmaceutical
activity as PI3-kinasemodulators.
[1299] Generally speaking, these are diseases in whose pathology
PI3-kinases are implicated, particularly inflammatory and allergic
diseases. Particular mention is should be made of inflammatory and
allergic respiratory complaints, inflammatory diseases of the
gastrointestinal tract, inflammatory diseases of the motor
apparatus, inflammatory and allergic skin diseases, inflammatory
eye diseases, diseases of the nasal mucosa, inflammatory or
allergic ailments which involve autoimmune reactions or
inflammation of the kidneys. The treatment may be symptomatic,
adaptive, curative or preventative.
[1300] Respiratory complaints deserving special mention would be
chronic and/or obstructive respiratory complaints. The compounds of
formula 1 according to the invention may, by virtue of their
pharmacological properties, bring about a reduction in
[1301] Tissue damage
[1302] Inflammation of the airways
[1303] bronchial hyperreactivity
[1304] the process of reconstruction of the lung as a result of
inflammation
[1305] worsening of the disease (progression).
[1306] The compounds according to the invention are particularly
preferred for preparing a medicament for the treatment of chronic
bronchitis, acute bronchitis, bronchitis caused by bacterial or
viral infection or fungi or helminths, allergic bronchitis, toxic
bronchitis, chronic obstructive bronchitis (COPD), asthma
(intrinsic or allergic), paediatric asthma, bronchiectasis,
allergic alveolitis, allergic or non-allergic rhinitis, chronic
sinusitis, cystic fibrosis or mucoviscidosis, alpha-1-antitrypsin
deficiency, cough, pulmonary emphysema, interstitial lung diseases
such as e.g. pulmonary fibrosis, asbestosis and silicosis and
alveolitis; hyperreactive airways, nasal polyps, pulmonary oedema
such as e.g. toxic pulmonary oedema and ARDS/IRDS, pneumonitis of
different origins, e.g. radiation-induced or by caused by
aspiration or infectious pneumonitis, collagenoses such as lupus
eryth, systemic sclerodermy, sarcoidosis or Boeck's disease.
[1307] The compounds of formula 1 are also suitable for the
treatment of diseases of the skin, such as e.g. psoriasis, contact
dermatitis, atopic dermatitis, alopecia greata (circular hair
loss), erythema exsudativum multiforme (Stevens-Johnson Syndrome),
dermatitis herpetiformis, sclerodermy, vitiligo, nettle rash
(urticaria), lupus erythematodes, follicular and surface pyodermy,
endogenous and exogenous acne, acne rosacea and other inflammatory
or allergic or proliferative skin diseases.
[1308] Moreover, the compounds of formula 1 are suitable for
therapeutic use in cases of inflammatory or allergic complaints
which involve autoimmune reactions, such as e.g. inflammatory bowel
diseases, e.g. Crohn's disease or ulcerative colitis; diseases of
the arthritis type, such as e.g. rheumatoid or psoriatic arthritis,
osteoarthritis, rheumatoid spondylitis and other arthritic
conditions or multiple sclerosis.
[1309] The following general inflammatory or allergic diseases may
also be mentioned, which can be treated with medicaments containing
compounds of formula 1: [1310] inflammation of the eye, such as
e.g. conjunctivitis of various kinds, e.g. caused by infections
with fungi or bacteria, allergic conjunctivitis, irritable
conjunctivitis, drug-induced conjunctivitis, keratitis, uveitis
[1311] diseases of the nasal mucosa, such as e.g. allergic
rhinitis/sinusitis or nasal polyps [1312] inflammatory or allergic
conditions, such as e.g. systemic lupus erythematodes, chronic
hepatitis, kidney inflammations such as glomerulonephritis,
interstitial nephritis or idiopathic nephrotic syndrome.
[1313] Other diseases which may be treated with a drug containing
compounds of formula 1 on the basis of their pharmacological
activity include toxic or septic shock syndrome, atherosclerosis,
middle ear infections (otitis media), hypertrophy of the heart,
cardiac insufficiency, stroke, ischaemic reperfusion injury or
neurodegenerative diseases such as Parkinson's disease or
Alzheimer's.
Combinations
[1314] The compounds of formula 1 may be used on their own or in
conjunction with other active substances of formula 1 according to
the invention. If desired the compounds of general formula 1 may
also be used in conjunction with other pharmacologically active
substances.
[1315] Preferably active substances are used which are selected,
for example, from among the betamimetics, anticholinergics,
corticosteroids, PDE4-inhibitors, LTD4-antagonists,
EGFR-inhibitors, dopamine-agonists, H1-antihistamines,
PAF-antagonists and PI3-kinase inhibitors or double or triple
combinations thereof, such as for example combinations of [1316]
Betamimetics with corticosteroids, PDE4-inhibitors, EGFR-inhibitors
or LTD4-antagonists, [1317] Anticholinergics with betamimetics,
corticosteroids, PDE4-inhibitors, EGFR-inhibitors or
LTD4-antagonists, [1318] corticosteroids with PDE4-inhibitors,
EGFR-inhibitors or LTD4-antagonists [1319] PDE4-inhibitors with
EGFR-inhibitors or LTD4-antagonists [1320] EGFR-inhibitors with
LTD4-antagonists. The invention also encompasses combinations of
three active substances, each selected from one of the
above-mentioned categories of compounds.
[1321] Suitable betamimetics used are preferably compounds selected
from among albuterol, arformoterol, bambuterol, bitolterol,
broxaterol, carbuterol, clenbuterol, fenoterol, formoterol,
hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol,
mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol,
procaterol, reproterol, rimiterol, ritodrine, salmefamol,
salmeterol, sulphsoterenol, sulphonterol, terbutaline, tiaramide,
tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and [1322]
3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzyl-sulphonamide [1323]
5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one [1324]
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethy-
l]-2(3H)-benzothiazolone [1325]
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol [1326]
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-m-
ethyl-2-butylamino]ethanol [1327]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol [1328]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol [1329]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol [1330]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol [1331]
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-
e [1332]
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)-
ethanol [1333]
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}4H-benzo[1,4]oxazin-3-one [1334]
6-hydroxy-8-{1-hydroxy-2-[2-(ethyl
4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}4H-benzo[1,4]oxazin-3-o-
ne [1335] 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic
acid)-1,1-dimethyl-ethylamino]-ethyl}4H-benzo[1,4]oxazin-3-one
[1336]
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one [1337]
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}4H-benzo[1,4]oxazin-3-one [1338]
6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-ethylamino]--
ethyl}4H-benzo[1,4]oxazin-3-one [1339]
8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one [1340]
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one [1341]
4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y-
l)-ethylamino]-2-methyl-propyl)phenoxy)-butyric acid [1342]
8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one [1343]
1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)etha-
nol optionally in the form of the racemates, enantiomers,
diastereomers and optionally in the form of the pharmacologically
acceptable acid addition salts, solvates or hydrates thereof.
According to the invention the acid addition salts of the
betamimetics are preferably selected from among the hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
[1344] The anticholinergics used are preferably compounds selected
from among the tiotropium salts, preferably the bromide salt,
oxitropium salts, preferably the bromide salt, flutropium salts,
preferably the bromide salt, ipratropium salts, preferably the
bromide salt, glycopyrronium salts, preferably the bromide salt,
trospium salts, preferably the chloride salt, tolterodine. In the
above-mentioned salts the cations are the pharmacologically active
ingredients. As anions the above-mentioned salts may preferably
contain chloride, bromide, iodide, sulphate, phosphate,
methanesulphonate, nitrate, maleate, acetate, citrate, fumarate,
tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,
while chloride, bromide, iodide, sulphate, methanesulphonate or
p-toluenesulphonate are preferred as counter-ions. Of all the salts
the chloride, bromide, iodide and methanesulphonate are
particularly preferred. Other named compounds are: [1345] tropenol
2,2-diphenylpropionate-methobromide [1346] scopine
2,2-diphenylpropionate-methobromide [1347] scopine
2-fluoro-2,2-diphenylacetate-methobromide [1348] tropenol
2-fluoro-2,2-diphenylacetate-methobromide [1349] tropenol
3,3',4,4'-tetrafluorobenzilate-methobromide [1350] scopine
3,3',4,4'-tetrafluorobenzilate-methobromide [1351] tropenol
4,4'-difluorobenzylate-methobromide [1352] scopine
4,4'-difluorobenzylate-methobromide [1353] tropenol
3,3'-difluorobenzylate-methobromide [1354] scopine
3,3'-difluorobenzylate-methobromide [1355] tropenol
9-hydroxy-fluorene-9-carboxylate-methobromide [1356] tropenol
9-fluoro-fluorene-9-carboxylate-methobromide [1357] scopine
9-hydroxy-fluorene-9-carboxylate-methobromide [1358] scopine
9-fluoro-fluorene-9-carboxylate-methobromide [1359] tropenol
9-methyl-fluorene-9-carboxylate-methobromide [1360] scopine
9-methyl-fluorene-9-carboxylate-methobromide [1361]
cyclopropyltropine benzylate-methobromide [1362] cyclopropyltropine
2,2-diphenylpropionat-methobromide [1363] cyclopropyltropine
9-hydroxy-xanthene-9-carboxylate-methobromide [1364] cyclotropine
9-methyl-fluorene-9-carboxylate-methobromide [1365] cyclotropine
9-methyl-xanthene-9-carboxylate-methobromide [1366] cyclotropine
9-hydroxy-fluorene-9-carboxylate-methobromide [1367] methyl
cyclopropyltropine 4,4'-difluorobenzylate-methobromide [1368]
tropenol 9-hydroxy-xanthene-9-carboxylate-methobromide [1369]
scopine 9-hydroxy-xanthene-9-carboxylate-methobromide [1370]
tropenol 9-methyl-xanthene-9-carboxylate-methobromide [1371]
scopine 9-methyl-xanthene-9-carboxylate methobromide [1372]
tropenol 9-ethyl-xanthene-9-carboxylate-methobromide [1373]
tropenol 9-difluormethyl-xanthene-9-carboxylate-methobromide [1374]
scopine 9-hydroxymethyl-xanthene-9-carboxylate-methobromide
[1375] Corticosteroids used here are preferably compounds selected
from among prednisolone, prednisone, butixocortpropionate,
flunisolide, beclomethasone, triamcinolone, budesonide,
fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone,
betamethasone, deflazacort, RPR-106541, NS-126, ST-26 and [1376]
(S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate [1377]
(S)-(2-oxo-tetrahydro-furan-3S-yl)
6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-
e-17-carbothionate, [1378] etiprednol-dichloroacetate optionally in
the form of the racemates, enantiomers or diastereomers thereof and
optionally in the form of the salts and derivatives, solvates
and/or hydrates thereof. Any reference to steroids includes a
reference to any salts or derivatives, hydrates or solvates thereof
which may exist. Examples of possible salts and derivatives of the
steroids may be: alkali metal salts, such as for example sodium or
potassium salts, sulfobenzoates, phosphates, isonicotinates,
acetates, propionates, dihydrogenphosphates, palmitates, pivalates
or furoates thereof.
[1379] PDE4 inhibitors which may be used are preferably compounds
selected from among enprofyllin, theophyllin, roflumilast, ariflo
(cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin,
atizoram, D4418, Bay-198004, BY343, CP-325,366, D-4396
(Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418,
PD-168787, T440, T-2585, V-11294A, Cl-1018, CDC-801, CDC-3052,
D-22888, YM-58997, Z-15370 and [1380]
N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethox-
ybenzamide [1381]
(-)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbe-
nzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide [1382]
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrol-
idone [1383]
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-5-methyl-isothioure-
ido]benzyl)-2-pyrrolidone [1384]
cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic
acid] [1385]
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cy-
clohexan-1-one [1386]
cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1--
ol] [1387]
(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]ac-
etate [1388]
(S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]ac-
etate [1389]
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4--
triazolo[4,3-a]pyridine [1390]
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-
-triazolo[4,3-a]pyridine optionally in the form of the racemates,
enantiomers, diastereomers and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. Preferably, according to the invention, the acid
addition salts of the PDE4 inhibitors are selected from among the
hydrochloride, hydrobromide, hydroiodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
[1391] LTD4-antagonists which may be used are preferably compounds
selected from among montelukast, pranlukast, zafirlukast, MCC-847
(ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707,
L-733321 and [1392]
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy--
2-propyl)phenyl)thio)methylcyclopropane-acetic acid, [1393] 1-(((1
(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3--
(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic
acid [1394]
[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl}acetic
acid optionally in the form of the racemates, enantiomers,
diastereomers and optionally in the form of the pharmacologically
acceptable acid addition salts, solvates or hydrates thereof.
Preferably, according to the invention, the acid addition salts of
the LTD4-antagonists are selected from among the hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,
hydrosuccinate, hydrobenzoate und hydro-p-toluenesulphonate. By
salts or derivatives which the LTD4-antagonists may be capable of
forming are meant, for example: alkali metal salts, such as for
example sodium or potassium salts, alkaline earth metal salts,
sulphobenzoates, phosphates, isonicotinates, acetates, propionates,
dihydrogenphosphates, palmitates, pivalates or furoates.
[1395] EGFR-inhibitors which may be used are preferably compounds
selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
[1396]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-
-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [1397]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [1398]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [1399]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]--
amino}-7-cyclopentyloxy-quinazoline [1400]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline
[1401]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoli-
ne [1402]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morp-
holin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy
quinazoline [1403]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morp-
holin-4-yl)-ethoxy]-7-methoxy-quinazoline [1404]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline
[1405]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentyloxy-quinazoline [1406]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-o-
xo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [1407]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-
-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline [1408]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]--
1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline [1409]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline
[1410]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline [1411]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline [1412]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline [1413]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-
-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline [1414]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[1415]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[1416]
4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline
[1417]
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propylox-
y]-6-[(vinylcarbonyl)amino]-quinazoline [1418]
4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrim-
idine [1419]
3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-ox-
o-2-buten-1-yl]amino}-7-ethoxy-quinoline [1420]
4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulpho-
nyl-ethyl)amino]methyl}-furan-2-yl)quinazoline [1421]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-
-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline [1422]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline [1423]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino-
]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline
[1424]
4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline [1425]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline [1426]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[1427]
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[1428]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperi-
din-1-yl]-ethoxy}-7-methoxy-quinazoline [1429]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidi-
n-4-yloxy]-7-methoxy-quinazoline [1430]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)--
7-methoxy-quinazoline [1431]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cycl-
ohexan-1-yloxy)-7-methoxy-quinazoline [1432]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-
-quinazoline [1433]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline [1434]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline [1435]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperi-
din-4-yloxy}-7-methoxy-quinazoline [1436]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quina-
zoline [1437]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin--
4-yloxy]-7-methoxy-quinazoline [1438]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy--
quinazoline [1439]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hyd-
roxy-quinazoline [1440]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
oxy-ethoxy)-quinazoline [1441]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [1442]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [1443]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonyl-
amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [1444]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acet-
ylamino-ethoxy)-quinazoline [1445]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
anesulphonylamino-ethoxy)-quinazoline [1446]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline [1447]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4--
yloxy)-7-methoxy-quinazoline [1448]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)ca-
rbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline
[1449]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [1450]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4N-[(morpholin-4-yl)sulphonyl]-
-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [1451]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclo-
hexan-1-yloxy)-7-methoxy-quinazoline [1452]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-ethoxy-quinazoline [1453]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-(2-methoxy-ethoxy)-quinazoline [1454]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-y-
loxy]-7-(2-methoxy-ethoxy)-quinazoline [1455]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline [1456]
4-[(3-ethynyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-ylox-
y]-7-methoxy-quinazoline [1457]
4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazo-
line [1458]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [1459]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl-
)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline
[1460]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)car-
bonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [1461]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]--
piperidin-4-yloxy}-7-methoxy-quinazoline [1462]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline [1463]
4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline [1464]
4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline [1465]
4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-me-
thoxy-quinazoline [1466]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-(2-m-
ethoxy-ethoxy)-quinazoline [1467]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-
-yloxy)-7-methoxy-quinazoline [1468]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline [1469]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-meth-
yl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [1470]
4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline
[1471]
4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-y-
loxy]-7-methoxy-quinazoline [1472]
4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y-
loxy}-7-methoxy-quinazoline [1473]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-y-
l)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline [1474]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbon-
yl]-piperidin-4-yloxy}-7-methoxy-quinazoline [1475]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.-
1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline
[1476]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amin-
o)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline [1477]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-metho-
xy-quinazoline [1478]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline [1479]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbony-
l]-piperidin-4-yloxy}-7-methoxy-quinazoline [1480]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline [1481]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cy-
clohexan-1-yloxy]-7-methoxy-quinazoline [1482]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-y-
loxy)-7-methoxy-quinazoline [1483]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-meth-
yl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline [1484]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-
-yloxy)-7-methoxy-quinazoline [1485]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4{N-[(morpholin-4-yl)carbony-
l]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [1486]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[1487]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-methoxy-quinazoline [1488]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-metho-
xy-quinazoline optionally in the form of the racemates,
enantiomers, diastereomers and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. Preferably, according to the invention, the acid
addition salts of the EGFR-inhibitors are selected from among the
hydrochloride, hydrobromide, hydroiodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
[1489] Dopamine agonists which may be used are preferably compounds
selected from among bromocriptin, cabergolin,
alpha-dihydroergocryptin, lisuride, pergolide, pramipexol,
roxindol, ropinirol, talipexol, terguride and viozan, optionally in
the form of the racemates, enantiomers, diastereomers and
optionally in the form of the pharmacologically acceptable acid
addition salts, solvates or hydrates thereof.
[1490] Preferably, according to the invention, the acid addition
salts of the Dopamine agonists are selected from among the
hydrochloride, hydrobromide, hydroiodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
[1491] H1-Antihistamines which may be used are preferably compounds
selected from among epinastin, cetirizin, azelastin, fexofenadin,
levocabastin, loratadin, mizolastin, ketotifen, emedastin,
dimetinden, clemastin, bamipin, cexchlorpheniramine, pheniramine,
doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine,
promethazine, ebastin, desloratidine and meclozine, optionally in
the form of the racemates, enantiomers, diastereomers and
optionally in the form of the pharmacologically acceptable acid
addition salts, solvates or hydrates thereof. Preferably, according
to the invention, the acid addition salts of the H1-Antihistamines
are selected from among the hydrochloride, hydrobromide,
hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
[1492] PAF-Antagonists which may be used are preferably compounds
selected from among [1493]
4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thien-
o-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine [1494]
6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-
-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
optionally in the form of the racemates, enantiomers, diastereomers
and optionally in the form of the pharmacologically acceptable acid
addition salts, solvates or hydrates thereof. Preferably, according
to the invention, the acid addition salts of the PAF-Antagonists
are selected from among the hydrochloride, hydrobromide,
hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
Formulations
[1495] The compounds according to the invention may be administered
by oral, transdermal, inhalative, parenteral or sublingual route.
The compounds according to the invention are present as active
ingredients in conventional preparations, for example in
compositions consisting essentially of an inert pharmaceutical
carrier and an effective dose of the active substance, such as for
example tablets, coated tablets, capsules, lozenges, powders,
solutions, suspensions, emulsions, syrups, suppositories,
transdermal systems etc. An effective dose of the compounds
according to the invention is between 0.1 and 5000, preferably
between 1 and 500, more preferably between 5-300 mg/dose for oral
administration, and between 0.001 and 50, preferably between 0.1
and 10 mg/dose for intravenous subcutaneous or intramuscular
administration. For inhalation, according to the invention,
solutions containing 0.01 to 1.0, preferably 0.1 to 0.5% active
substance are suitable. For administration by inhalation the use of
powders, ethanolic or aqueous solutions is preferred. It is also
possible to use the compounds according to the invention as a
solution for infusion, preferably in a physiological saline or
nutrient saline solution.
[1496] The compounds according to the invention may be used on
their own or in conjunction with other active substances according
to the invention, optionally also in conjunction with other
pharmacologically active substances. Suitable formulations include,
for example, tablets, capsules, suppositories, solutions, syrups,
emulsions or dispersible powders. Corresponding tablets may be
obtained for example by mixing the active substance(s) with known
excipients, for example inert diluents, such as calcium carbonate,
calcium phosphate or lactose, disintegrants such as maize starch or
alginic acid, binders such as starch or gelatine, lubricants such
as magnesium stearate or talc and/or agents for delaying release,
such as carboxymethyl cellulose, cellulose acetate phthalate, or
polyvinyl acetate. The tablets may also comprise several
layers.
[1497] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example collidone or shellac, gum arabic,
talc, titanium dioxide or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number of
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
[1498] Syrups containing the active substances or combinations
thereof according to the invention may additionally contain a
sweetener such as saccharine, cyclamate, glycerol or sugar and a
flavour enhancer, e.g. a flavouring such as vanillin or orange
extract. They may also contain suspension adjuvants or thickeners
such as sodium carboxymethyl cellulose, wetting agents such as, for
example, condensation products of fatty alcohols with ethylene
oxide, or preservatives such as p-hydroxybenzoates.
[1499] Solutions for injection are prepared in the usual way, e.g.
with the addition of preservatives such as p-hydroxybenzoates, or
stabilisers such as alkali metal salts of ethylenediamine
tetraacetic acid, and transferred into injection vials or
ampoules.
[1500] Capsules containing one or more active substances or
combinations of active substances may for example be prepared by
mixing the active substances with inert carriers such as lactose or
sorbitol and packing them into gelatine capsules.
[1501] Suitable suppositories may be made for example by mixing
with carriers provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.
[1502] A therapeutically effective daily dose is between 1 and 2000
mg, preferably 10-500 mg per adult.
[1503] The Examples which follow illustrate the present invention
without restricting its scope:
[1504] Examples of Pharmaceutical Formulations TABLE-US-00011 A)
Tablets per tablet active substance 100 mg lactose 140 mg maize
starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg
500 mg
[1505] The finely ground active substance, lactose and some of the
corn starch are mixed together. The mixture is screened, then
moistened with a solution of polyvinylpyrrolidone in water,
kneaded, granulated while wet and dried. The granulate, the rest of
the corn starch and the magnesium stearate are screened and mixed
together. The mixture is compressed to form tablets of a suitable
shape and size. TABLE-US-00012 B) Tablets per tablet active
substance 80 mg corn starch 190 mg lactose 55 mg microcrystalline
cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl
starch 23 mg magnesium stearate 2 mg 400 mg
[1506] The finely ground active substance, some of the corn starch,
lactose, microcrystalline cellulose and polyvinylpyrrolidone are
mixed together, the mixture is screened and worked with the
remaining corn starch and water to form a granulate which is dried
and screened. The sodium-carboxymethyl starch and the magnesium
stearate are added and mixed in and the mixture is compressed to
form tablets of a suitable size. TABLE-US-00013 C) Coated tablets
per coated tablet Active substance 5 mg Corn starch 41.5 mg Lactose
30 mg Polyvinylpyrrolidone 3 mg Magnesium stearate 0.5 mg 80 mg
[1507] The active substance, corn starch, lactose and
polyvinylpyrrolidone are thoroughly mixed and moistened with water.
The moist mass is pushed through a screen with a 1 mm mesh size,
dried at about 45.degree. C. and the granules are then passed
through the same screen. After the magnesium stearate has been
mixed in, convex tablet cores with a diameter of 6 mm are
compressed in a tablet-making machine. The tablet cores thus
produced are coated in a known manner with a covering consisting
essentially of sugar and talc. The finished coated tablets are
polished with wax TABLE-US-00014 D) Capsules per capsule Active
substance 50 mg Corn starch 268.5 mg Magnesium stearate 1.5 mg 320
mg
[1508] The substance and corn starch are mixed and moistened with
water. The moist mass is screened and dried. The dry granules are
screened and mixed with magnesium stearate. The finished mixture is
packed into size 1 hard gelatine capsules. TABLE-US-00015 E)
Ampoule solution active substance 50 mg sodium chloride 50 mg water
for inj. 5 ml
[1509] The active substance is dissolved in water at its own pH or
optionally at pH 5.5 to 6.5 and sodium chloride is added to make it
isotonic. The solution obtained is filtered free from pyrogens and
the filtrate is transferred under aseptic conditions into ampoules
which are then sterilised and sealed by fusion. The ampoules
contain 5 mg, 25 mg and 50 mg of active substance. TABLE-US-00016
F) Suppositories Active substance 50 mg Solid fat 1650 mg 1700
mg
[1510] The hard fat is melted. At 40.degree. C. the ground active
substance is homogeneously dispersed. It is cooled to 38.degree. C.
and poured into slightly chilled suppository moulds. TABLE-US-00017
G) Oral suspension active substance 50 mg hydroxyethylcellulose 50
mg sorbic acid 5 mg sorbitol (70%) 600 mg glycerol 200 mg
flavouring 15 mg water ad 5 ml
[1511] Distilled water is heated to 70.degree. C.
Hydroxyethyl-cellulose is dissolved therein with stirring. After
the addition of sorbitol solution and glycerol the mixture is
cooled to ambient temperature. At ambient temperature, sorbic acid,
flavouring and substance are added. To eliminate air from the
suspension it is evacuated with stirring.
* * * * *