U.S. patent application number 12/624875 was filed with the patent office on 2010-03-18 for bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
This patent application is currently assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG. Invention is credited to Anke BAUM, Frank HIMMELSBACH, Birgit JUNG, Elke LANGKOPF, Thomas METZ, Flavio SOLCA.
Application Number | 20100069414 12/624875 |
Document ID | / |
Family ID | 27213849 |
Filed Date | 2010-03-18 |
United States Patent
Application |
20100069414 |
Kind Code |
A1 |
HIMMELSBACH; Frank ; et
al. |
March 18, 2010 |
BICYCLIC HETEROCYCLES, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE
COMPOUNDS, THEIR USE AND PROCESSES FOR PREPARING THEM
Abstract
The present invention relates to bicyclic heterocycles of
general formula ##STR00001## wherein R.sub.a to R.sub.c, A to E and
X are defined as in claim 1, the tautomers, stereoisomers and salts
thereof, particularly the physiologically acceptable salts thereof
with inorganic or organic acids or bases which have valuable
pharmacological properties, in particular an inhibitory effect on
signal transduction mediated by tyrosine kinases, their use in the
treatment of diseases, especially tumoral diseases and diseases of
the lungs and airways, and the preparation thereof.
Inventors: |
HIMMELSBACH; Frank;
(Mittelbiberach, DE) ; LANGKOPF; Elke;
(Warthausen, DE) ; METZ; Thomas; (Glottertal,
DE) ; SOLCA; Flavio; (Vienna, AT) ; JUNG;
Birgit; (Laupheim, DE) ; BAUM; Anke; (Vienna,
AT) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY ROAD, P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
BOEHRINGER INGELHEIM PHARMA GMBH
& CO. KG
Ingelheim
DE
|
Family ID: |
27213849 |
Appl. No.: |
12/624875 |
Filed: |
November 24, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11734350 |
Apr 12, 2007 |
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12624875 |
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10016280 |
Dec 10, 2001 |
7220750 |
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11734350 |
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PCT/EP00/05547 |
Jun 16, 2000 |
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10016280 |
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60146644 |
Jul 30, 1999 |
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Current U.S.
Class: |
514/266.22 ;
514/266.4; 544/293 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 35/00 20180101; C07D 239/94 20130101; C07D 401/12 20130101;
C07D 215/54 20130101; C07D 215/42 20130101; A61P 1/00 20180101;
A61P 1/16 20180101; C07D 405/12 20130101 |
Class at
Publication: |
514/266.22 ;
544/293; 514/266.4 |
International
Class: |
A61K 31/517 20060101
A61K031/517; C07D 401/02 20060101 C07D401/02; C07D 239/72 20060101
C07D239/72; A61P 35/00 20060101 A61P035/00; A61P 11/00 20060101
A61P011/00; A61P 1/00 20060101 A61P001/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 21, 1999 |
DE |
19928281.1 |
May 11, 2000 |
DE |
10023085.7 |
Claims
1. Bicyclic heterocycles of general formula ##STR00005## wherein
R.sub.a denotes a hydrogen atom or a C.sub.1-4-alkyl group, R.sub.b
denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl
nucleus is substituted in each case by the groups R.sub.1 to
R.sub.3, whilst R.sub.1 and R.sub.2, which may be identical or
different, in each case denote a hydrogen, fluorine, chlorine,
bromine or iodine atom, a C.sub.1-4-alkyl, hydroxy,
C.sub.1-4-alkoxy, C.sub.3-6-cycloalkyl, C.sub.4-6-cycloalkoxy,
C.sub.2-5-alkenyl or C.sub.2-5-alkynyl group, an aryl, aryloxy,
arylmethyl or arylmethoxy group, a C.sub.3-5-alkenyloxy or
C.sub.3-5-alkynyloxy group, whilst the unsaturated moiety may not
be linked to the oxygen atom, a C.sub.1-4-alkylsulfenyl,
C.sub.1-4-alkylsulfinyl, C.sub.1-4-alkylsulfonyl,
C.sub.1-4-alkylsulfonyloxy, trifluoromethylsulfenyl,
trifluoromethylsulfinyl or trifluoromethylsulfonyl group, a methyl
or methoxy group substituted by 1 to 3 fluorine atoms, an ethyl or
ethoxy group substituted by 1 to 5 fluorine atoms, a cyano or nitro
group or an amino group optionally substituted by one or two
C.sub.1-4-alkyl groups, wherein the substituents may be identical
or different, or R.sub.1 together with R.sub.2, if they are bound
to adjacent carbon atoms, denote a --CH.dbd.CH--CH.dbd.CH,
--CH.dbd.CH--NH or --CH.dbd.N--NH group and R.sub.3 denotes a
hydrogen, fluorine, chlorine or bromine atom, a C.sub.1-4-alkyl,
trifluoromethyl or C.sub.1-4-alkoxy group, X denotes a methine
group substituted by a cyano group or a nitrogen atom, A denotes an
imino group optionally substituted by a C.sub.1-4-alkyl group, B
denotes a carbonyl or sulfonyl group, C denotes a 1,3-allenylene,
1,1- or 1,2-vinylene group which may be substituted in each case by
one or two methyl groups or by a trifluoromethyl group, an
ethynylene group or a 1,3-butadien-1,4-ylene group optionally
substituted by 1 to 4 methyl groups or by a trifluoromethyl group,
D denotes an alkylene, --CO-alkylene or --SO.sub.2-alkylene group
wherein the alkylene moiety in each case contains 1 to 8 carbon
atoms and additionally 1 to 4 hydrogen atoms in the alkylene moiety
may be replaced by fluorine atoms, whilst the linking of the
--CO-alkylene or --SO.sub.2-alkylene group to the adjacent group C
in each case must take place via the carbonyl or sulfonyl group, a
--CO---O-alkylene, --CO--NR.sub.4-alkylene or
--SO.sub.2--NR.sub.4-alkylene group wherein the alkylene moiety in
each case contains 1 to 8 carbon atoms, whilst the linking to the
adjacent group C in each case must take place via the carbonyl or
sulfonyl group, wherein R.sub.4 denotes a hydrogen atom or a
C.sub.1-4-alkyl group, or, if D is bound to a carbon atom of the
group E, it may also denote a bond or, if D is bound to a nitrogen
atom of the group E, it may also denote a carbonyl or sulfonyl
group, E denotes an amino, C.sub.1-4-alkylamino or
di-(C.sub.1-4-alkyl)-amino group wherein the alkyl moieties may be
identical or different, a C.sub.2-4-alkylamino group wherein the
alkyl moiety is substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the nitrogen atom of the amino
group by the group R.sub.5, whilst R.sub.5 denotes a hydroxy,
C.sub.1-4-alkoxy, amino, C.sub.1-4-alkylamino or
di-(C.sub.1-4-alkyl)-amino group, a 4- to 7-membered alkyleneimino
group optionally substituted by one or two methyl groups or a 6- to
7-membered alkyleneimino group optionally substituted by one or two
methyl groups wherein in each case a methylene group in position 4
is replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl,
imino or N--(C.sub.1-4-alkyl)-imino group, an
N--(C.sub.1-4-alkyl)-N--(C.sub.2-4-alkyl)-amino group wherein the
C.sub.2-4-alkyl moiety is substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the nitrogen atom of the amino
group by the group R.sub.5, whilst R.sub.5 is as hereinbefore
defined, a di-(C.sub.2-4-alkyl)-amino group wherein the two
C.sub.2-4-alkyl moieties are substituted in each case in .beta.-,
.gamma.-, or .delta.-position with regard to the nitrogen atom of
the amino group by the group R.sub.5, whilst the substituents may
be identical or different and R.sub.5 is as hereinbefore defined, a
C.sub.3-7-cycloalkylamino or
C.sub.3-7-cycloalkyl-C.sub.1-3-alkylamino group wherein in each
case the nitrogen atom may be substituted by a further
C.sub.1-4-alkyl group, an amino or C.sub.1-4-alkylamino group
wherein in each case the nitrogen atom is substituted by a
tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, 1-(tetrahydrofuran-3-yl)-piperidin-4-yl,
1-(tetrahydropyran-3-yl)-piperidin-4-yl,
1-(tetrahydropyran-4-yl)-piperidin-4-yl, 3-pyrrolidinyl,
3-piperidinyl, 4-piperidinyl, 3-hexahydro-azepinyl or
4-hexahydro-azepinyl group optionally substituted by 1 to 3
C.sub.1-4-alkyl groups, a 4- to 7-membered alkyleneimino group
optionally substituted by 1 to 4 C.sub.1-2-alkyl groups, which may
be substituted by the group R.sub.5 either at a cyclic carbon atom
or at one of the alkyl groups, whilst R.sub.5 is as hereinbefore
defined, a piperidino group substituted by a tetrahydrofuranyl,
tetrahydropyranyl or tetrahydrofuranylmethyl group, a 6- to
7-membered alkyleneimino group optionally substituted by 1 or 2
C.sub.1-2-alkyl groups wherein a methylene group in each case is
replaced in the 4 position by an oxygen or sulfur atom, by an imino
group substituted by the group R.sub.6, or by a sulfinyl or
sulfonyl group, whilst R.sub.6 denotes a hydrogen atom, a
C.sub.1-4-alkyl, 2-methoxy-ethyl, 3-methoxy-propyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-4-alkyl,
tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, formyl, C.sub.1-4-alkylcarbonyl,
C.sub.1-4-alkylsulfonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl or di-(C.sub.1-4-alkyl)-aminocarbonyl
group, an imidazolyl group optionally substituted by 1 to 3 methyl
groups, a C.sub.5-7-cycloalkyl group wherein a methylene group is
replaced by an oxygen or sulfur atom, by an imino group substituted
by the group R.sub.6, by a sulfinyl or sulfonyl group, whilst
R.sub.6 is as hereinbefore defined, or D together with E denotes a
hydrogen, fluorine or chlorine atom, a C.sub.1-4-alkyl group
optionally substituted by 1 to 5 fluorine atoms, a
C.sub.3-6-cycloalkyl group, an aryl, heteroaryl,
C.sub.1-4-alkylcarbonyl or arylcarbonyl group, a carboxy,
C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl or di-(C.sub.1-4-alkyl)-aminocarbonyl
group or a carbonyl which is substituted by a 4- to 7-membered
alkyleneimino group, whilst in the abovementioned 6- to 7-membered
alkyleneimino groups in each case a methylene group may be replaced
in the 4 position by an oxygen or sulfur atom, by an imino group
substituted by the group R.sub.6, by a sulfinyl or sulfonyl group,
whilst R.sub.6 is as hereinbefore defined, and R.sub.c denotes a
C.sub.4-7-cycloalkoxy or C.sub.3-7-cycloalkyl-C.sub.1-6-alkoxy
group wherein the cycloalkyl moiety in each case may be substituted
by a C.sub.1-3-alkyl, hydroxy, C.sub.1-4-alkoxy, amino,
C.sub.1-4-alkylamino, di-(C.sub.1-4-alkyl)-amino, pyrrolidino,
piperidino, morpholino, piperazino,
N--(C.sub.1-2-alkyl)-piperazino, hydroxy-C.sub.1-2-alkyl,
C.sub.1-4-alkoxy-C.sub.1-2-alkyl, amino-C.sub.1-2-alkyl,
C.sub.1-4-alkylamino-C.sub.1-2-alkyl,
di-(C.sub.1-4-alkyl)-amino-C.sub.1-2-alkyl,
pyrrolidino-C.sub.1-2-alkyl, piperidino-C.sub.1-2-alkyl,
morpholino-C.sub.1-2-alkyl, piperazino-C.sub.1-2-alkyl or
N--(C.sub.1-2-alkyl)-piperazino-C.sub.1-2-alkyl group, whilst the
abovementioned monosubstituted cycloalkyl moieties may additionally
be substituted by a C.sub.1-3-alkyl group, a
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group, an
C.sub.2-4-alkoxy group substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the oxygen atom by an
azetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino
group, a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C.sub.1-4-alkyloxy,
3-pyrrolidinyl-C.sub.1-4-alkyloxy, 3-piperidinyloxy,
4-piperidinyloxy, 2-piperidinyl-C.sub.1-4-alkyloxy,
3-piperidinyl-C.sub.1-4-alkyloxy, 4-piperidinyl-C.sub.1-4-alkyloxy,
3-hexahydro-azepinyloxy, 4-hexahydro-azepinyloxy,
2-hexahydro-azepinyl-C.sub.1-4-alkyloxy,
3-He-xahydro-azepinyl-C.sub.1-4-alkyloxy or
4-hexahydro-azepinyl-C.sub.1-4-alkyloxy group wherein in each case
the cyclic nitrogen atom is substituted by the group R.sub.6, where
R.sub.6 is as hereinbefore defined, whilst by the aryl moieties
mentioned in the definition of the abovementioned groups is meant a
phenyl group which in each case may be monosubstituted by R.sub.7,
mono-, di- or trisubstituted by R.sub.8 or monosubstituted by
R.sub.7 and additionally mono- or disubstituted by R.sub.8, wherein
the substituents may be identical or different and R.sub.7 denotes
a cyano, carboxy, C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl, di-(C.sub.1-4-alkyl)-aminocarbonyl,
C.sub.1-4-alkylsulfenyl, C.sub.1-4-alkylsulfinyl,
C.sub.1-4-alkylsulfonyl, hydroxy, C.sub.1-4-alkylsulfonyloxy,
trifluoromethyloxy, nitro, amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, C.sub.1-4-alkylcarbonylamino,
N--(C.sub.1-4-alkyl)-C.sub.1-4-alkylcarbonylamino,
C.sub.1-4-alkylsulfonylamino,
N--(C.sub.1-4-alkyl)-C.sub.1-4-alkylsulfonylamino, aminosulfonyl,
C.sub.1-4-alkylaminosulfonyl or di-(C.sub.1-4-alkyl)-aminosulfonyl
group or a carbonyl group which is substituted by a 5- to
7-membered alkyleneimino group, whilst in the abovementioned 6- to
7-membered alkyleneimino groups in each case a methylene group in
the 4 position may be replaced by an oxygen or sulfur atom, by a
sulfinyl, sulfonyl, imino or N--(C.sub.1-4-alkyl)-imino group, and
R.sub.8 denotes a fluorine, chlorine, bromine or iodine atom, a
C.sub.1-4-alkyl, trifluoromethyl or C.sub.1-4-alkoxy group or two
groups R.sub.8, if they are bound to adjacent carbon atoms,
together denote a C.sub.3-5-alkylene, methylenedioxy or
1,3-butadien-1,4-ylene group, and the heteroaryl groups mentioned
in the definition of the abovementioned groups include a 5-membered
heteroaromatic group which contains an imino group, an oxygen or
sulfur atom or an imino group, an oxygen or sulfur atom and one or
two nitrogen atoms, or a 6-membered heteroaromatic group which
contains one, two or three nitrogen atoms, whilst the
abovementioned 5-membered heteroaromatic groups may be substituted
in each case by 1 or 2 methyl or ethyl groups and the
abovementioned 6-membered heteroaromatic groups may be substituted
in each case by 1 or 2 methyl or ethyl groups or by a fluorine,
chlorine, bromine or iodine atom or by a trifluoromethyl, hydroxy,
methoxy or ethoxy group, the tautomers, stereoisomers and salts
thereof.
2. Bicyclic heterocycles of general formula I according to claim 1,
wherein R.sub.a denotes a hydrogen atom, R.sub.b denotes a phenyl,
benzyl or 1-phenylethyl group wherein the phenyl nucleus is
substituted in each case by the groups R.sub.1 to R.sub.3, whilst
R.sub.1 and R.sub.2, which may be identical or different, in each
case denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
a C.sub.1-4-alkyl, hydroxy, C.sub.1-4-alkoxy, C.sub.3-6-cycloalkyl,
C.sub.4-6-cycloalkoxy, C.sub.2-5-alkenyl or C.sub.2-5-alkynyl
group, an aryl, aryloxy, arylmethyl or arylmethoxy group, a methyl
or methoxy group substituted by 1 to 3 fluorine atoms, a cyano or
nitro group and R.sub.3 denotes a hydrogen, fluorine, chlorine or
bromine atom, a C.sub.1-4-alkyl, trifluoromethyl or
C.sub.1-4-alkoxy group, X denotes a methine group substituted by a
cyano group or a nitrogen atom, A denotes an imino group, B denotes
a carbonyl or sulfonyl group, C denotes a 1,3-allenylene, 1,1- or
1,2-vinylene group, an ethynylene or 1,3-butadien-1,4-ylene group,
D denotes an alkylene, --CO-alkylene or --SO.sub.2-alkylene group
wherein the alkylene moiety in each case contains 1 to 4 carbon
atoms and additionally 1 to 4 hydrogen atoms in the alkylene moiety
may be replaced by fluorine atoms, whilst the linking of the
--CO-alkylene or --SO.sub.2-alkylene group to the adjacent group C
in each case must take place via the carbonyl or sulfonyl group, a
--CO--O-alkylene, --CO--NR.sub.4-alkylene or
--SO.sub.2--NR.sub.4-alkylene group wherein the alkylene moiety in
each case contains 1 to 4 carbon atoms, whilst the linking to the
adjacent group C in each case must take place via the carbonyl or
sulfonyl group, wherein R.sub.4 denotes a hydrogen atom or a
C.sub.1-4-alkyl group, or, if D is bound to a carbon atom of the
group E, it may also denote a bond, or, if D is bound to a nitrogen
atom of the group E, it may also denote a carbonyl or sulfonyl
group, E denotes a di-(C.sub.1-4-alkyl)-amino group wherein the
alkyl moieties may be identical or different, an
N--(C.sub.1-4-alkyl)-N--(C.sub.2-4-alkyl)-amino group wherein the
C.sub.2-4-alkyl moiety is substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the nitrogen atom of the amino
group by the group R.sub.5, where R.sub.5 denotes a hydroxy,
C.sub.1-4-alkoxy or di-(C.sub.1-4-alkyl)-amino group, a 4- to
7-membered alkyleneimino group optionally substituted by one or two
methyl groups or a 6- to 7-membered alkyleneimino group optionally
substituted by one or two methyl groups wherein in each case a
methylene group in position 4 is replaced by an oxygen or sulfur
atom, or by a sulfinyl, sulfonyl or N--(C.sub.1-4-alkyl)-imino
group, a di-(C.sub.2-4-alkyl)-amino group wherein the two
C.sub.2-4-alkyl moieties in each case are substituted in .beta.-,
.gamma.-, or .delta.-position with regard to the nitrogen atom of
the amino group by the group R.sub.5, wherein the substituents may
be identical or different and R.sub.5 is as hereinbefore defined, a
C.sub.3-7-cycloalkylamino or
C.sub.3-7-cycloalkyl-C.sub.1-3-alkylamino group wherein in each
case the nitrogen atom is substituted by a further C.sub.1-4-alkyl
group, a C.sub.1-4-alkylamino group wherein the nitrogen atom is
substituted by a tetrahydrofuran-3-yl, tetrahydropyran-3-yl,
tetrahydropyran-4-yl, tetrahydrofuranylmethyl,
1-(tetrahydrofuran-3-yl)-piperidin-4-yl,
1-(tetrahydropyran-3-yl)-piperidin-4-yl,
1-(tetrahydropyran-4-yl)-piperidin-4-yl,
N--(C.sub.1-2-alkyl)-3-pyrrolidinyl,
N--(C.sub.1-2-alkyl)-3-piperidinyl,
N--(C.sub.1-2-alkyl)-4-piperidinyl,
N--(C.sub.1-2-alkyl)-3-hexahydro-azepinyl or
N--(C.sub.1-2-alkyl)-4-hexahydro-azepinyl group, an 4- to
7-membered alkyleneimino group optionally substituted by 1 to 4
methyl groups, which may be substituted either at a cyclic carbon
atom or at one of the methyl groups by the group R.sub.5, where
R.sub.5 is as hereinbefore defined, a piperidino group substituted
by a tetrahydrofuranyl, tetrahydropyranyl or
tetrahydrofuranylmethyl group, a 6- to 7-membered alkyleneimino
group optionally substituted by 1 or 2 methyl groups wherein in
each case a methylene group is replaced in the 4 position by an
oxygen or sulfur atom, by an imino group substituted by the group
R.sub.6, by a sulfinyl or sulfonyl group, whilst R.sub.6 denotes a
C.sub.1-4-alkyl, 2-methoxy-ethyl, 3-methoxy-propyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-4-alkyl,
tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, formyl, C.sub.1-4-alkylcarbonyl,
C.sub.1-4-alkylsulfonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl or di-(C.sub.1-4-alkyl)-aminocarbonyl
group, a C.sub.5-7-cycloalkyl group wherein a methylene group is
replaced by an oxygen or sulfur atom, by an imino group substituted
by the group R.sub.6, or by a sulfinyl or sulfonyl group, where
R.sub.6 is as hereinbefore defined, or D together with E denotes a
hydrogen, fluorine or chlorine atom, a C.sub.1-4-alkyl group
optionally substituted by 1 to 5 fluorine atoms, a
C.sub.3-6-cycloalkyl group, an aryl, C.sub.1-4-alkylcarbonyl or
arylcarbonyl group, a carboxy, C.sub.1-4-alkoxycarbonyl,
aminocarbonyl, C.sub.1-4-alkylaminocarbonyl or
di-(C.sub.1-4-alkyl)-aminocarbonyl group or a carbonyl group which
is substituted by a 4- to 7-membered alkyleneimino group, whilst in
the abovementioned 6- to 7-membered alkyleneimino groups in each
case a methylene group in the 4 position may be replaced by an
oxygen or sulfur atom, by an imino group substituted by the group
R.sub.6, or by a sulfinyl or sulfonyl group, where R.sub.6 is as
hereinbefore defined, and R.sub.c denotes a C.sub.4-7-cycloalkoxy
or C.sub.3-7-cycloalkyl-C.sub.1-6-alkoxy group wherein the
cycloalkyl moiety in each case may be substituted by a
C.sub.1-3-alkyl, hydroxy, C.sub.1-4-alkoxy,
di-(C.sub.1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino,
N--(C.sub.1-2-alkyl)-piperazino, hydroxy-C.sub.1-2-alkyl,
C.sub.1-4-alkoxy-C.sub.1-2-alkyl,
di-(C.sub.1-4-alkyl)-amino-C.sub.1-2-alkyl,
pyrrolidino-C.sub.1-2-alkyl, piperidino-C.sub.1-2-alkyl,
morpholino-C.sub.1-2-alkyl or
N--(C.sub.1-2-alkyl)-piperazino-C.sub.1-2-alkyl group, whilst the
abovementioned monosubstituted cycloalkyl moieties may additionally
be substituted by a C.sub.1-3-alkyl group, a
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group, an
C.sub.2-4-alkoxy group substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the oxygen atom by an
azetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino
group, a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C.sub.1-4-alkyloxy,
3-pyrrolidinyl-C.sub.1-4-alkyloxy, 3-piperidinyloxy,
4-piperidinyloxy, 2-piperidinyl-C.sub.1-4-alkyloxy,
3-piperidinyl-C.sub.1-4-alkyloxy, 4-piperidinyl-C.sub.1-4-alkyloxy,
3-hexahydro-azepinyloxy, 4-hexahydro-azepinyloxy,
2-hexahydro-azepinyl-C.sub.1-4-alkyloxy,
3-hexahydro-azepinyl-C.sub.1-4-alkyloxy or
4-hexahydro-azepinyl-C.sub.1-4-alkyloxy group wherein in each case
the cyclic nitrogen atom is substituted by the group R.sub.6, where
R.sub.6 is as hereinbefore defined, whilst by the aryl moieties
mentioned in the definition of the abovementioned groups is meant a
phenyl group which may in each case be monosubstituted by R.sub.7,
mono-, di- or trisubstituted by R.sub.8 or monosubstituted by
R.sub.7 and additionally mono- or disubstituted by R.sub.8, wherein
the substituents may be identical or different and R.sub.7 denotes
a cyano, carboxy, C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl, di-(C.sub.1-4-alkyl)-aminocarbonyl,
C.sub.1-4-alkylsulfenyl, C.sub.1-4-alkylsulfinyl,
C.sub.1-4-alkylsulfonyl, hydroxy, C.sub.1-4-alkylsulfonyloxy,
trifluoromethyloxy, nitro, amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, C.sub.1-4-alkylcarbonylamino,
N--(C.sub.1-4-alkyl)-C.sub.1-4-alkylcarbonylamino,
C.sub.1-4-alkylsulfonylamino,
N--(C.sub.1-4-alkyl)-C.sub.1-4-alkylsulfonylamino, aminosulfonyl,
C.sub.1-4-alkylaminosulfonyl or di-(C.sub.1-4-alkyl)-aminosulfonyl
group or a carbonyl group which is substituted by a 5- to
7-membered alkyleneimino group, whilst in the abovementioned 6- to
7-membered alkyleneimino groups in each case a methylene group may
be replaced in the 4 position by an oxygen or sulfur atom, by a
sulfinyl, sulfonyl, imino or N--(C.sub.1-4-alkyl)-imino group, and
R.sub.8 denotes a fluorine, chlorine, bromine or iodine atom, a
C.sub.1-4-alkyl, trifluoromethyl or C.sub.1-4-alkoxy group or two
groups R.sub.8, if they are bound to adjacent carbon atoms,
together denote a C.sub.3-5-alkylene, methylenedioxy or
1,3-butadien-1,4-ylene group, the tautomers, stereoisomers and
salts thereof.
3. Bicyclic heterocycles of general formula I according to claim 1,
wherein R.sub.a denotes a hydrogen atom, R.sub.b denotes a phenyl,
benzyl or 1-phenylethyl group wherein the phenyl nucleus is
substituted in each case by the groups R.sub.1 and R.sub.2, where
R.sub.1 and R.sub.2, which may be identical or different, in each
case denote a hydrogen, fluorine, chlorine or bromine atom, a
methyl, trifluoromethyl or methoxy group, X denotes a nitrogen
atom, A denotes an imino group, B denotes a carbonyl group, C
denotes a 1,2-vinylene group, an ethynylene or
1,3-butadien-1,4-ylene group, D denotes a C.sub.1-4-alkylene group,
or, if D is bound to a carbon atom of the group E, it may also
denote a bond, or, if D is bound to a nitrogen atom of the group E,
it may also denote a carbonyl group, E denotes a
di-(C.sub.1-4-alkyl)-amino group wherein the alkyl moieties may be
identical or different, an
N--(C.sub.1-4-alkyl)-N--(C.sub.2-4-alkyl)-amino group wherein the
C.sub.2-4-alkyl moiety is substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the nitrogen atom of the amino
group by the group R.sub.5, whilst R.sub.5 denotes a hydroxy,
C.sub.1-3-alkoxy or di-(C.sub.1-3-alkyl)-amino group, a
pyrrolidino, piperidino or morpholino group, a
di-(C.sub.2-4-alkyl)-amino group wherein the two C.sub.2-4-alkyl
moieties in each case are substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the nitrogen atom of the amino
group by the group R.sub.5, wherein the substituents may be
identical or different and R.sub.5 is as hereinbefore defined, an
C.sub.1-4-alkylamino group substituted at the nitrogen atom by a
tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, 1-(C.sub.1-2-alkyl)-pyrrolidin-3-yl,
1-(C.sub.1-2-alkyl)-piperidin-3-yl,
1-(C.sub.1-2-alkyl)-piperidin-4-yl,
1-(tetrahydrofuran-3-yl)-piperidin-4-yl,
1-(tetrahydropyran-3-yl)-piperidin-4-yl or
1-(tetrahydropyran-4-yl)-piperidin-4-yl group, a
C.sub.3-5-cycloalkylamino or
C.sub.3-5-cycloalkyl-C.sub.1-3-alkylamino group wherein in each
case the nitrogen atom is substituted by a further C.sub.1-3-alkyl
group, a 5- to 7-membered alkyleneimino group optionally
substituted by 1 or 2 methyl groups which may be substituted either
at a cyclic carbon atom or at one or the methyl groups by the group
R.sub.5, where R.sub.5 is as hereinbefore defined, or a piperidino
group substituted by a tetrahydrofuranyl, tetrahydropyranyl or
tetrahydrofuranylmethyl group, a piperidino group optionally
substituted by 1 or 2 methyl groups wherein the methylene group is
replaced in the 4 position by an oxygen or sulfur atom, by sulfinyl
or sulfonyl group or by an imino group substituted by the group
R.sub.6, whilst R.sub.6 denotes a C.sub.1-3-alkyl, 2-methoxy-ethyl,
3-methoxy-propyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, tetrahydrofuran-3-yl,
tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, C.sub.1-3-alkylcarbonyl,
C.sub.1-3-alkylsulfonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group, or D together with E denotes a hydrogen atom, a
C.sub.1-3-alkyl group, an aryl or C.sub.1-4-alkylcarbonyl group or
a C.sub.1-4-alkoxycarbonyl group, R.sub.c denotes a
C.sub.4-7-cycloalkoxy or C.sub.3-7-cycloalkyl-C.sub.1-4-alkoxy
group wherein the cycloalkyl moiety in each case may be substituted
by a C.sub.1-3-alkyl or C.sub.1-3-alkoxy group, a
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group, an
C.sub.2-4-alkoxy group substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the oxygen atom by an
azetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino
group, a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C.sub.1-3-alkyloxy,
3-pyrrolidinyl-C.sub.1-3-alkyloxy, 3-piperidinyloxy,
4-piperidinyloxy, 2-piperidinyl-C.sub.1-3-alkyloxy,
3-piperidinyl-C.sub.1-3-alkyloxy, 4-piperidinyl-C.sub.1-3-alkyloxy,
3-hexahydro-azepinyloxy, 4-hexahydro-azepinyloxy,
2-hexahydro-azepinyl-C.sub.1-3-alkyloxy,
3-hexahydro-azepinyl-C.sub.1-3-alkyloxy or
4-hexahydro-azepinyl-C.sub.1-3-alkyloxy group wherein in each case
the cyclic nitrogen atom is substituted by a methyl or ethyl group,
whilst by the aryl moieties mentioned in the definition of the
abovementioned groups is meant a phenyl group which may be mono-,
di- or trisubstituted by R.sub.8, wherein the substituents may be
identical or different and R.sub.8 denotes a fluorine, chlorine,
bromine or iodine atom, a C.sub.1-4-alkyl, trifluoromethyl or
C.sub.1-4-alkoxy group, the tautomers, stereoisomers and salts
thereof.
4. Bicyclic heterocycles of general formula I according to claim 1,
wherein R.sub.a denotes a hydrogen atom, R.sub.b denotes a phenyl,
benzyl or 1-phenylethyl group, whilst the phenyl nucleus is
substituted in each case by the radicals R.sub.1 and R.sub.2,
whilst R.sub.1 and R.sub.2, which may be identical or different,
each denotes a hydrogen, fluorine, chlorine or bromine atom, X
denotes a nitrogen atom, A denotes an imino group, B denotes a
carbonyl group, C denotes a 1,2-vinylene, ethinylene or
1,3-butadien-1,4-ylene group, D denotes an C.sub.1-3-alkylene
group, E denotes a Di-(C.sub.1-4-alkyl)-amino group, wherein the
alkyl moieties may be identical or different, a methylamino or
ethylamino group each substituted at the nitrogen atom by a
2-methoxyethyl, 1-methoxy-2-propyl, 2-methoxypropyl,
3-methoxypropyl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuran-2-ylmethyl, 1-methylpiperidin-4-yl,
1-ethyl-piperidin-4-yl, 1-(tetrahydrofuran-3-yl)-piperidin-4-yl,
cyclopropyl or cyclopropylmethyl group, a Bis(2-methoxyethyl)amino
group, a pyrrolidino, piperidino or morpholino group each
optionally substituted by one or two methyl groups, a piperazino
group substituted in 4-position by a methyl, ethyl, cyclopropyl,
cyclopropylmethyl, 2-methoxy-ethyl, tetrahydrofuran-3-yl,
tetrahydropyran-4-yl or tetrahydrofuran-2-ylmethyl group, a
thiomorpholino, S-oxidothiomorpholino or S,S-dioxidothiomorpholino
group, a 2-(methoxymethyl)pyrrolidino, 2-(ethoxymethyl)pyrrolidino,
4-hydroxypiperidino, 4-methoxypiperidino, 4-ethoxypiperidino,
4-(tetrahydrofuran-3-yl)piperidino or 4-morpholinopiperidino group
or D together with E denote a hydrogen atom, a methyl, phenyl,
methoxycarbonyl or ethoxycarbonyl group and R.sub.c denotes a
cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or
cyclohexylmethoxy group, a cyclobutyloxy, cyclopentyloxy or
cyclohexyloxy group, a tetrahydrofuran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuran-2-ylmethoxy group, a
straight chained C.sub.2-4-alkoxy group terminally substituted by
an azetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino
group, a 1-methyl-piperidin-4-yloxy or 1-ethyl-piperidin-4-yloxy
group, a (1-methyl-piperidin-4-yl)-C.sub.1-3-alkyloxy or
(1-ethyl-piperidin-4-yl)-C.sub.1-3-alkyloxy group, the tautomers,
stereoisomers and salts thereof.
5. Bicyclic heterocycles of general formula I according to claim 1,
wherein R.sub.a denotes a hydrogen atom, R.sub.b denotes a
1-phenylethyl group or a phenyl group wherein the phenyl nucleus is
substituted by the radicals R.sub.1 and R.sub.2, whilst R.sub.1 and
R.sub.2, which may be identical or different, each denote a
hydrogen, fluorine, chlorine or bromine atom, X denotes a nitrogen
atom, A denotes an imino group, B denotes a carbonyl group, C
denotes a 1,2-vinylene, ethinylene or 1,3-butadien-1,4-ylene group,
D denotes a methylene group, E denotes a dimethylamino,
diethylamino, Bis(2-methoxyethyl)amino,
N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino,
N-methyl-N-cyclopropylamino, N-methyl-N-cyclopropylmethyl-amino,
N-methyl-N-(1-methoxy-2-propyl)amino,
N-methyl-N-(2-methoxypropyl)amino,
N-methyl-N-(3-methoxypropyl)amino,
N-methyl-N-(tetrahydrofuran-3-yl)amino,
N-methyl-N-(tetrahydropyran-4-yl)amino,
N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino or
N-methyl-N-(1-methylpiperidin-4-yl)amino group, a pyrrolidino,
piperidino or morpholino group each optionally substituted by one
or two methyl groups, a piperazino group substituted in 4-position
by a methyl, ethyl, cyclopropylmethyl or 2-methoxyethyl group, a
S-oxidothiomorpholino group, a 2-(methoxymethyl)pyrrolidino,
4-hydroxypiperidino or 4-methoxypiperidino group or D together with
E denote a hydrogen atom, a methyl, phenyl or ethoxycarbonyl group,
and R.sub.c denotes a cyclopropylmethoxy, cyclobutyloxy or
cyclopentyloxy group, a tetrahydrofuran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuran-2-ylmethoxy group, a
straight chained C.sub.2-4-alkoxy group terminally substituted by
an azetidin-1-yl or 4-methylhomopiperazino group, a
1-methyl-piperidin-4-yloxy group or a
(1-methylpiperidin-4-yl)-C.sub.1-3-alkyloxy group, the tautomers,
stereoisomers and salts thereof.
6. The following compounds of general formula I according to claim
1: (a)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy-
]-6-[(vinylcarbonyl)amino]quinazoline, (b)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxyquinazoline and (c)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline as well as the salts
thereof.
7. Physiologically acceptable salts of the compounds according to
claim 1 with inorganic or organic acids or bases.
8. Pharmaceutical compositions containing a compound, or a
physiologically acceptable salt thereof, according to claim 1
optionally together with one or more inert carriers and/or
diluents.
9. Use of a compound according to claim 1 for preparing a
pharmaceutical composition which is suitable for treating benign or
malignant tumors, for preventing and treating diseases of the
airways and lungs and for treating diseases of the gastrointestinal
tract and the bile duct and gall bladder.
10. Process for preparing the compounds of general formula I
according to claim 1, characterized in that a) a compound of
general formula ##STR00006## wherein R.sub.a to R.sub.c, A and X
are defined as in claim 1, is reacted with a compound of general
formula Z.sub.1--B--C-D-E (III) wherein B to E are defined as in
claim 1 and Z.sub.1 denotes a leaving group, or b) in order to
prepare compounds of general formula I wherein the group E is
linked to the group D via a nitrogen atom, a compound of general
formula ##STR00007## wherein R.sub.a to R.sub.c, A to D and X are
defined as in claim 1 and Z.sub.2 denotes a leaving group, is
reacted with a compound of general formula H-E' (V) wherein E'
denotes one of the groups mentioned for E in claim 1 which is
linked to the group D via a nitrogen atom, and if desired a
compound of general formula I thus obtained which contains an
amino, alkylamino or imino group is converted by acylation or
sulfonylation into a corresponding acyl or sulfonyl compound of
general formula I and/or a compound of general formula I thus
obtained which contains an amino, alkylamino or imino group is
converted by alkylation or reductive alkylation into a
corresponding alkyl compound of general formula I and/or a compound
of general formula I thus obtained which contains a carboxy or
hydroxyphosphoryl group is converted by esterification into a
corresponding ester of general formula I and/or a compound of
general formula I thus obtained which contains a carboxy or ester
group is converted by reaction with a corresponding amine into a
corresponding amide of general formula I and/or if necessary any
protecting group used during the above reactions is cleaved again
and/or if desired a compound of general formula I thus obtained is
resolved into its stereoisomers and/or a compound of general
formula I thus obtained is converted into the salts thereof, more
particularly, for pharmaceutical use, into the physiologically
acceptable salts thereof.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/734,350, filed Apr. 12, 2007, which is a continuation of
U.S. application Ser. No. 10/016,280, filed Dec. 10, 2001, now U.S.
Pat. No. 7,220,750, which is a continuation of International
Application No. PCT/EP00/05547, filed Jun. 16, 2000, which claims
benefit of U.S. Provisional Application No. 60/146,644, filed Jul.
30, 1999, and German Application Nos. DE 19928281.1 and DE
10023085.7, filed Jun. 21, 1999 and May 11, 2000, respectively.
[0002] The present invention relates to bicyclic heterocycles of
general formula
##STR00002##
the tautomers, the stereoisomers and the salts thereof,
particularly the physiologically acceptable salts thereof with
inorganic or organic acids or bases which have valuable
pharmacological properties, particularly an inhibitory effect on
signal transduction mediated by tyrosine kinases, the use thereof
for treating diseases, particularly tumoral diseases, diseases of
the lungs and respiratory tract, and the preparation thereof.
[0003] In the above general formula I:
R.sub.a denotes a hydrogen atom or a C.sub.1-4-alkyl group, R.sub.b
denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl
nucleus is substituted in each case by the groups R.sub.1 to
R.sub.3, whilst [0004] R.sub.1 and R.sub.2, which may be identical
or different, in each case denote a hydrogen, fluorine, chlorine,
bromine or iodine atom, [0005] a C.sub.1-4-alkyl, hydroxy,
C.sub.1-4-alkoxy, C.sub.3-6-cycloalkyl, C.sub.4-6-cycloalkoxy,
C.sub.2-5-alkenyl or C.sub.2-5-alkynyl group, [0006] an aryl,
aryloxy, arylmethyl or arylmethoxy group, [0007] a
C.sub.3-5-alkenyloxy or C.sub.3-5-alkynyloxy group, whilst the
unsaturated moiety may not be linked to the oxygen atom, [0008] a
C.sub.1-4-alkylsulfenyl, C.sub.1-4-alkylsulfinyl,
C.sub.1-4-alkylsulfonyl, C.sub.1-4-alkylsulfonyloxy,
trifluoromethylsulfenyl, trifluoromethylsulfinyl or
trifluoromethylsulfonyl group, [0009] a methyl or methoxy group
substituted by 1 to 3 fluorine atoms, [0010] an ethyl or ethoxy
group substituted by 1 to 5 fluorine atoms, [0011] a cyano or nitro
group or an amino group optionally substituted by one or two
C.sub.1-4-alkyl groups, wherein the substituents may be identical
or different, or [0012] R.sub.1 together with R.sub.2, if they are
bound to adjacent carbon atoms, denote a --CH.dbd.CH--CH.dbd.CH,
--CH.dbd.CH--NH or --CH.dbd.N--NH group and [0013] R.sub.3 denotes
a hydrogen, fluorine, chlorine or bromine atom, [0014] a
C.sub.1-4-alkyl, trifluoromethyl or C.sub.1-4-alkoxy group, X
denotes a methine group substituted by a cyano group or a nitrogen
atom, A denotes an imino group optionally substituted by a
C.sub.1-4-alkyl group, B denotes a carbonyl or sulfonyl group, C
denotes a 1,3-allenylene, 1,1- or 1,2-vinylene group which may be
substituted in each case by one or two methyl groups or by a
trifluoromethyl group, an ethynylene group or a
1,3-butadien-1,4-ylene group optionally substituted by 1 to 4
methyl groups or by a trifluoromethyl group, D denotes an alkylene,
--CO-alkylene or --SO.sub.2-alkylene group wherein the alkylene
moiety in each case contains 1 to 8 carbon atoms and additionally 1
to 4 hydrogen atoms in the alkylene moiety may be replaced by
fluorine atoms, whilst the linking of the --CO-alkylene or
--SO.sub.2-alkylene group to the adjacent group C in each case must
take place via the carbonyl or sulfonyl group, a --CO--O-alkylene,
--CO--NR.sub.4-alkylene or --SO.sub.2--NR.sub.4-alkylene group
wherein the alkylene moiety in each case contains 1 to 8 carbon
atoms, whilst the linking to the adjacent group C in each case must
take place via the carbonyl or sulfonyl group, wherein [0015]
R.sub.4 denotes a hydrogen atom or a C.sub.1-4-alkyl group, or, if
D is bound to a carbon atom of the group E, it may also denote a
bond or, if D is bound to a nitrogen atom of the group E, it may
also denote a carbonyl or sulfonyl group, E denotes an amino,
C.sub.1-4-alkylamino or di-(C.sub.1-4-alkyl)-amino group wherein
the alkyl moieties may be identical or different, a
C.sub.2-4-alkylamino group wherein the alkyl moiety is substituted
in .beta.-, .gamma.-, or .delta.-position with regard to the
nitrogen atom of the amino group by the group R.sub.5, whilst
[0016] R.sub.5 denotes a hydroxy, C.sub.1-4-alkoxy, amino,
C.sub.1-4-alkylamino or di-(C.sub.1-4-alkyl)-amino group, [0017] a
4- to 7-membered alkyleneimino group optionally substituted by one
or two methyl groups or [0018] a 6- to 7-membered alkyleneimino
group optionally substituted by one or two methyl groups wherein in
each case a methylene group in position 4 is replaced by an oxygen
or sulfur atom, by a sulfinyl, sulfonyl, imino or
N--(C.sub.1-4-alkyl)-imino group, an
N--(C.sub.1-4-alkyl)-N--(C.sub.2-4-alkyl)-amino group wherein the
C.sub.2-4-alkyl moiety is substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the nitrogen atom of the amino
group by the group R.sub.5, whilst R.sub.5 is as hereinbefore
defined, a di-(C.sub.2-4-alkyl)-amino group wherein the two
C.sub.2-4-alkyl moieties are substituted in each case in .beta.-,
.gamma.-, or .delta.-position with regard to the nitrogen atom of
the amino group by the group R.sub.5, whilst the substituents may
be identical or different and R.sub.5 is as hereinbefore defined, a
C.sub.3-7-cycloalkylamino or
C.sub.3-7-cycloalkyl-C.sub.1-3-alkylamino group wherein in each
case the nitrogen atom may be substituted by a further
C.sub.1-4-alkyl group, an amino or C.sub.1-4-alkylamino group
wherein in each case the nitrogen atom is substituted by a
tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, 1-(tetrahydrofuran-3-yl)piperidin-4-yl,
1-(tetrahydropyran-3-yl)piperidin-4-yl,
1-(tetrahydropyran-4-yl)piperidin-4-yl, 3-pyrrolidinyl,
3-piperidinyl, 4-piperidinyl, 3-hexahydro-azepinyl or
4-hexahydro-azepinyl group optionally substituted by 1 to 3
C.sub.1-4-alkyl groups, a 4- to 7-membered alkyleneimino group
optionally substituted by 1 to 4 C.sub.1-2-alkyl groups, which may
be substituted by the group R.sub.5 either at a cyclic carbon atom
or at one of the alkyl groups, whilst R.sub.5 is as hereinbefore
defined, a piperidino group substituted by a tetrahydrofuranyl,
tetrahydropyranyl or tetrahydrofuranylmethyl group, a 6- to
7-membered alkyleneimino group optionally substituted by 1 or 2
C.sub.1-2-alkyl groups wherein a methylene group in each case is
replaced in the 4 position by an oxygen or sulfur atom, by an imino
group substituted by the group R.sub.6, or by a sulfinyl or
sulfonyl group, whilst [0019] R.sub.6 denotes a hydrogen atom, a
C.sub.1-4-alkyl, 2-methoxyethyl, 3-methoxypropyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-4-alkyl,
tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, formyl, C.sub.1-4-alkylcarbonyl,
C.sub.1-4-alkylsulfonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl or di-(C.sub.1-4-alkyl)-aminocarbonyl
group, an imidazolyl group optionally substituted by 1 to 3 methyl
groups, a C.sub.5-7-cycloalkyl group wherein a methylene group is
replaced by an oxygen or sulfur atom, by an imino group substituted
by the group R.sub.6, by a sulfinyl or sulfonyl group, whilst
R.sub.6 is as hereinbefore defined, or D together with E denotes a
hydrogen, fluorine or chlorine atom, a C.sub.1-4-alkyl group
optionally substituted by 1 to 5 fluorine atoms, a
C.sub.3-6-cycloalkyl group, an aryl, heteroaryl,
C.sub.1-4-alkylcarbonyl or arylcarbonyl group, a carboxy,
C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl or di-(C.sub.1-4-alkyl)-aminocarbonyl
group or a carbonyl which is substituted by a 4- to 7-membered
alkyleneimino group, whilst in the abovementioned 6- to 7-membered
alkyleneimino groups in each case a methylene group may be replaced
in the 4 position by an oxygen or sulfur atom, by an imino group
substituted by the group R.sub.6, by a sulfinyl or sulfonyl group,
whilst R.sub.6 is as hereinbefore defined, and R.sub.c denotes a
C.sub.4-7-cycloalkoxy or C.sub.3-7-cycloalkyl-C.sub.1-6-alkoxy
group wherein the cycloalkyl moiety in each case may be substituted
by a C.sub.1-3-alkyl, hydroxy, C.sub.1-4-alkoxy, amino,
C.sub.1-4-alkylamino, di-(C.sub.1-4-alkyl)-amino, pyrrolidino,
piperidino, morpholino, piperazino,
N--(C.sub.1-2-alkyl)-piperazino, hydroxy-C.sub.1-2-alkyl,
C.sub.1-4-alkoxy-C.sub.1-2-alkyl, amino-C.sub.1-2-alkyl,
C.sub.1-4-alkylamino-C.sub.1-2-alkyl,
di-(C.sub.1-4-alkyl)-amino-C.sub.1-2-alkyl,
pyrrolidino-C.sub.1-2-alkyl, piperidino-C.sub.1-2-alkyl,
morpholino-C.sub.1-2-alkyl, piperazino-C.sub.1-2-alkyl or
N--(C.sub.1-2-alkyl)-piperazino-C.sub.1-2-alkyl group, whilst the
abovementioned monosubstituted cycloalkyl moieties may additionally
be substituted by a C.sub.1-3-alkyl group, a
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group, an
C.sub.2-4-alkoxy group substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the oxygen atom by an
azetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino
group, a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C.sub.1-4-alkyloxy,
3-pyrrolidinyl-C.sub.1-4-alkyloxy, 3-piperidinyloxy,
4-piperidinyloxy, 2-piperidinyl-C.sub.1-4-alkyloxy,
3-piperidinyl-C.sub.1-4-alkyloxy, 4-piperidinyl-C.sub.1-4-alkyloxy,
3-hexahydro-azepinyloxy, 4-hexahydro-azepinyloxy,
2-hexahydro-azepinyl-C.sub.1-4-alkyloxy,
3-He-xahydro-azepinyl-C.sub.1-4-alkyloxy or
4-hexahydro-azepinyl-C.sub.1-4-alkyloxy group wherein in each case
the cyclic nitrogen atom is substituted by the group R.sub.6, where
R.sub.6 is as hereinbefore defined, particularly those compounds of
general formula I wherein R.sub.a, R.sub.b, A to C and X are as
hereinbefore defined, E denotes an amino, C.sub.1-4-alkylamino or
di-(C.sub.1-4-alkyl)-amino group wherein the alkyl moieties may be
identical or different, a C.sub.2-4-alkylamino group wherein the
alkyl moiety is substituted from position 2 by the group R.sub.5,
whilst [0020] R.sub.5 denotes a hydroxy, C.sub.1-4-alkoxy, amino,
C.sub.1-4-alkylamino or di-(C.sub.1-4-alkyl)-amino group, [0021] a
4- to 7-membered alkyleneimino group optionally substituted by one
or two methyl groups or [0022] a 6- to 7-membered alkyleneimino
group optionally substituted by one or two methyl groups wherein in
each case a methylene group in position 4 is replaced by an oxygen
or sulfur atom, by a sulfinyl, sulfonyl, imino or
N--(C.sub.1-4-alkyl)-imino group, an
N--(C.sub.1-4-alkyl)-N--(C.sub.2-4-alkyl)-amino group wherein the
C.sub.2-4-alkyl moiety is substituted from position 2 onwards by
the group R.sub.5, where R.sub.5 is as hereinbefore defined, a
di-(C.sub.2-4-alkyl)-amino group wherein the two C.sub.2-4-alkyl
moieties are substituted in each case from position 2 onwards by
the group R.sub.5, whilst the substituents may be identical or
different and R.sub.5 is as hereinbefore defined, a
C.sub.3-7-cycloalkylamino or
C.sub.3-7-cycloalkyl-C.sub.1-3-alkylamino group wherein in each
case the nitrogen atom may be substituted by a further
C.sub.1-4-alkyl group, an amino or C.sub.1-4-alkylamino group
wherein in each case the nitrogen atom is substituted by a
3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexahydro-azepinyl
or 4-hexahydro-azepinyl group optionally substituted by 1 to 3
C.sub.1-4-alkyl groups, a 4- to 7-membered alkyleneimino group
optionally substituted by 1 to 4 C.sub.1-2-alkyl groups, which may
be substituted by the group R.sub.5 either at a cyclic carbon atom
or at one of the alkyl groups, whilst R.sub.5 is as hereinbefore
defined, or a 6- to 7-membered alkyleneimino group optionally
substituted by 1 or 2 C.sub.1-2-alkyl groups wherein a methylene
group in each case is replaced in the 4 position by an oxygen or
sulfur atom, by an imino group substituted by the group R.sub.6, or
by a sulfinyl or sulfonyl group, whilst [0023] R.sub.6 denotes a
hydrogen atom, a C.sub.1-4-alkyl, C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-4-alkyl, formyl,
C.sub.1-4-alkylcarbonyl, C.sub.1-4-alkylsulfonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl or di-(C.sub.1-4-alkyl)-aminocarbonyl
group, an imidazolyl group optionally substituted by 1 to 3 methyl
groups, a C.sub.5-7-cycloalkyl group wherein a methylene group is
replaced by an oxygen or sulfur atom, by an imino group substituted
by the group R.sub.6, by a sulfinyl or sulfonyl group, whilst
R.sub.6 is as hereinbefore defined, or D together with E denotes a
hydrogen, fluorine or chlorine atom, a C.sub.1-4-alkyl group
optionally substituted by 1 to 5 fluorine atoms, a
C.sub.3-6-cycloalkyl group, an aryl, heteroaryl,
C.sub.1-4-alkylcarbonyl or arylcarbonyl group, a carboxy,
C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl or di-(C.sub.1-4-alkyl)-aminocarbonyl
group or a carbonyl which is substituted by a 4- to 7-membered
alkyleneimino group, whilst in the abovementioned 6- to 7-membered
alkyleneimino groups a methylene group may in each case be replaced
in the 4 position by an oxygen or sulfur atom, by an imino group
substituted by the group R.sub.6, by a sulfinyl or sulfonyl group,
whilst R.sub.6 is as hereinbefore defined, and R.sub.c denotes a
C.sub.4-7-cycloalkoxy or C.sub.3-7-cycloalkyl-C.sub.1-6-alkoxy
group wherein the cycloalkyl moiety in each case may be substituted
by a C.sub.1-3-alkyl, hydroxy, C.sub.1-4-alkoxy, amino,
C.sub.1-4-alkylamino, di-(C.sub.1-4-alkyl)-amino, pyrrolidino,
piperidino, morpholino, piperazino,
N--(C.sub.1-2-alkyl)-piperazino, hydroxy-C.sub.1-2-alkyl,
C.sub.1-4-alkoxy-C.sub.1-2-alkyl, amino-C.sub.1-2-alkyl,
C.sub.1-4-alkylamino-C.sub.1-2-alkyl,
di-(C.sub.1-4-alkyl)-amino-C.sub.1-2-alkyl,
pyrrolidino-C.sub.1-2-alkyl, piperidino-C.sub.1-2-alkyl,
morpholino-C.sub.1-2-alkyl, piperazino-C.sub.1-2-alkyl or
N--(C.sub.1-2-alkyl)-piperazino-C.sub.1-2-alkyl group, whilst the
abovementioned monosubstituted cycloalkyl moieties may additionally
be substituted by a C.sub.1-3-alkyl group, or a 3-pyrrolidinyloxy,
2-pyrrolidinyl-C.sub.1-4-alkyloxy,
3-pyrrolidinyl-C.sub.1-4-alkyloxy, 3-piperidinyloxy,
4-piperidinyloxy, 2-piperidinyl-C.sub.1-4-alkyloxy,
3-piperidinyl-C.sub.1-4-alkyloxy, 4-piperidinyl-C.sub.1-4-alkyloxy,
3-hexahydro-azepinyloxy, 4-hexahydro-azepinyloxy,
2-hexahydro-azepinyl-C.sub.1-4-alkyloxy,
3-hexahydro-azepinyl-C.sub.1-4-alkyloxy or
4-hexahydro-azepinyl-C.sub.1-4-alkyloxy group wherein in each case
the cyclic nitrogen atom is substituted by the group R.sub.6, where
R.sub.6 is as hereinbefore defined.
[0024] By the aryl moieties mentioned in the definition of the
abovementioned groups is meant a phenyl group which in each case
may be monosubstituted by R.sub.7, mono-, di- or trisubstituted by
R.sub.8 or monosubstituted by R.sub.7 and additionally mono- or
disubstituted by R.sub.8, wherein the substituents may be identical
or different and [0025] R.sub.7 denotes a cyano, carboxy,
C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl, di-(C.sub.1-4-alkyl)-aminocarbonyl,
C.sub.1-4-alkylsulfenyl, C.sub.1-4-alkylsulfinyl,
C.sub.1-4-alkylsulfonyl, hydroxy, C.sub.1-4-alkylsulfonyloxy,
trifluoromethyloxy, nitro, amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, C.sub.1-4-alkylcarbonylamino,
N--(C.sub.1-4-alkyl)-C.sub.1-4-alkylcarbonylamino,
C.sub.1-4-alkylsulfonylamino,
N--(C.sub.1-4-alkyl)-C.sub.1-4-alkylsulfonylamino, aminosulfonyl,
C.sub.1-4-alkylaminosulfonyl or di-(C.sub.1-4-alkyl)-aminosulfonyl
group or a carbonyl group which is substituted by a 5- to
7-membered alkyleneimino group, whilst in the abovementioned 6- to
7-membered alkyleneimino groups in each case a methylene group in
the 4 position may be replaced by an oxygen or sulfur atom, by a
sulfinyl, sulfonyl, imino or N--(C.sub.1-4-alkyl)-imino group, and
[0026] R.sub.8 denotes a fluorine, chlorine, bromine or iodine
atom, a C.sub.1-4-alkyl, trifluoromethyl or C.sub.1-4-alkoxy group
or [0027] two groups R.sub.8, if they are bound to adjacent carbon
atoms, together denote a C.sub.3-5-alkylene, methylenedioxy or
1,3-butadien-1,4-ylene group.
[0028] The heteroaryl groups mentioned in the definition of the
abovementioned groups also include a 5-membered heteroaromatic
group which contains an imino group, an oxygen or sulfur atom or an
imino group, an oxygen or sulfur atom and one or two nitrogen
atoms, or
a 6-membered heteroaromatic group which contains one, two or three
nitrogen atoms, whilst the abovementioned 5-membered heteroaromatic
groups may be substituted in each case by 1 or 2 methyl or ethyl
groups and the abovementioned 6-membered heteroaromatic groups may
be substituted in each case by 1 or 2 methyl or ethyl groups or by
a fluorine, chlorine, bromine or iodine atom or by a
trifluoromethyl, hydroxy, methoxy or ethoxy group.
[0029] Preferred compounds of the above general formula I are those
wherein
R.sub.a denotes a hydrogen atom, R.sub.b denotes a phenyl, benzyl
or 1-phenylethyl group wherein the phenyl nucleus is substituted in
each case by the groups R.sub.1 to R.sub.3, whilst [0030] R.sub.1
and R.sub.2, which may be identical or different, in each case
denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
[0031] a C.sub.1-4-alkyl, hydroxy, C.sub.1-4-alkoxy,
C.sub.3-6-cycloalkyl, C.sub.4-6-cycloalkoxy, C.sub.2-5-alkenyl or
C.sub.2-5-alkynyl group, [0032] an aryl, aryloxy, arylmethyl or
arylmethoxy group, [0033] a methyl or methoxy group substituted by
1 to 3 fluorine atoms, [0034] a cyano or nitro group and [0035]
R.sub.3 denotes a hydrogen, fluorine, chlorine or bromine atom,
[0036] a C.sub.1-4-alkyl, trifluoromethyl or C.sub.1-4-alkoxy
group, X denotes a methine group substituted by a cyano group or a
nitrogen atom, A denotes an imino group, B denotes a carbonyl or
sulfonyl group, C denotes a 1,3-allenylene, 1,1- or 1,2-vinylene
group, an ethynylene or 1,3-butadien-1,4-ylene group, D denotes an
alkylene, --CO-alkylene or --SO.sub.2-alkylene group wherein the
alkylene moiety in each case contains 1 to 4 carbon atoms and
additionally 1 to 4 hydrogen atoms in the alkylene moiety may be
replaced by fluorine atoms, whilst the linking of the --CO-alkylene
or --SO.sub.2-alkylene group to the adjacent group C in each case
must take place via the carbonyl or sulfonyl group, a
--CO--O-alkylene, --CO--NR.sub.4-alkylene or
--SO.sub.2--NR.sub.4-alkylene group wherein the alkylene moiety in
each case contains 1 to 4 carbon atoms, whilst the linking to the
adjacent group C in each case must take place via the carbonyl or
sulfonyl group, wherein [0037] R.sub.4 denotes a hydrogen atom or a
C.sub.1-4-alkyl group, or, if D is bound to a carbon atom of the
group E, it may also denote a bond, or, if D is bound to a nitrogen
atom of the group E, it may also denote a carbonyl or sulfonyl
group, E denotes a di-(C.sub.1-4-alkyl)-amino group wherein the
alkyl moieties may be identical or different, an
N--(C.sub.1-4-alkyl)-N--(C.sub.2-4-alkyl)-amino group wherein the
C.sub.2-4-alkyl moiety is substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the nitrogen atom of the amino
group by the group R.sub.5, where [0038] R.sub.5 denotes a hydroxy,
C.sub.1-4-alkoxy or di-(C.sub.1-4-alkyl)-amino group, [0039] a 4-
to 7-membered alkyleneimino group optionally substituted by one or
two methyl groups or [0040] a 6- to 7-membered alkyleneimino group
optionally substituted by one or two methyl groups wherein in each
case a methylene group in position 4 is replaced by an oxygen or
sulfur atom, or by a sulfinyl, sulfonyl or
N--(C.sub.1-4-alkyl)-imino group, a di-(C.sub.2-4-alkyl)-amino
group wherein the two C.sub.2-4-alkyl moieties in each case are
substituted in .beta.-, .gamma.-, or .delta.-position with regard
to the nitrogen atom of the amino group by the group R.sub.5,
wherein the substituents may be identical or different and R.sub.5
is as hereinbefore defined, a C.sub.3-7-cycloalkylamino or
C.sub.3-7-cycloalkyl-C.sub.1-3-alkylamino group wherein in each
case the nitrogen atom is substituted by a further C.sub.1-4-alkyl
group, a C.sub.1-4-alkylamino group wherein the nitrogen atom is
substituted by a tetrahydrofuran-3-yl, tetrahydropyran-3-yl,
tetrahydropyran-4-yl, tetrahydrofuranylmethyl,
1-(tetrahydrofuran-3-yl)piperidin-4-yl,
1-(tetrahydropyran-3-yl)piperidin-4-yl,
1-(tetrahydropyran-4-yl)piperidin-4-yl,
N--(C.sub.1-2-alkyl)-3-pyrrolidinyl,
N--(C.sub.1-2-alkyl)-3-piperidinyl,
N--(C.sub.1-2-alkyl)-4-piperidinyl,
N--(C.sub.1-2-alkyl)-3-hexahydro-azepinyl or
N--(C.sub.1-2-alkyl)-4-hexahydro-azepinyl group, an 4- to
7-membered alkyleneimino group optionally substituted by 1 to 4
methyl groups, which may be substituted either at a cyclic carbon
atom or at one of the methyl groups by the group R.sub.5, where
R.sub.5 is as hereinbefore defined, a piperidino group substituted
by a tetrahydrofuranyl, tetrahydropyranyl or
tetrahydrofuranylmethyl group, a 6- to 7-membered alkyleneimino
group optionally substituted by 1 or 2 methyl groups wherein in
each case a methylene group is replaced in the 4 position by an
oxygen or sulfur atom, by an imino group substituted by the group
R.sub.6, by a sulfinyl or sulfonyl group, whilst [0041] R.sub.6
denotes a C.sub.1-4-alkyl, 2-methoxyethyl, 3-methoxypropyl,
C.sub.3-7-cycloalkyl, C.sub.3-7-cycloalkyl-C.sub.1-4-alkyl,
tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, formyl, C.sub.1-4-alkylcarbonyl,
C.sub.1-4-alkylsulfonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl or di-(C.sub.1-4-alkyl)-aminocarbonyl
group, a C.sub.5-7-cycloalkyl group wherein a methylene group is
replaced by an oxygen or sulfur atom, by an imino group substituted
by the group R.sub.6, or by a sulfinyl or sulfonyl group, where
R.sub.6 is as hereinbefore defined, or D together with E denotes a
hydrogen, fluorine or chlorine atom, a C.sub.1-4-alkyl group
optionally substituted by 1 to 5 fluorine atoms, a
C.sub.3-6-cycloalkyl group, an aryl, C.sub.1-4-alkylcarbonyl or
arylcarbonyl group, a carboxy, C.sub.1-4-alkoxycarbonyl,
aminocarbonyl, C.sub.1-4-alkylaminocarbonyl or
di-(C.sub.1-4-alkyl)-aminocarbonyl group or a carbonyl group which
is substituted by a 4- to 7-membered alkyleneimino group, whilst in
the abovementioned 6- to 7-membered alkyleneimino groups in each
case a methylene group in the 4 position may be replaced by an
oxygen or sulfur atom, by an imino group substituted by the group
R.sub.6, or by a sulfinyl or sulfonyl group, where R.sub.6 is as
hereinbefore defined, and R.sub.c denotes a C.sub.4-7-cycloalkoxy
or C.sub.3-7-cycloalkyl-C.sub.1-6-alkoxy group wherein the
cycloalkyl moiety in each case may be substituted by a
C.sub.1-3-alkyl, hydroxy, C.sub.1-4-alkoxy,
di-(C.sub.1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino,
N--(C.sub.1-2-alkyl)-piperazino, hydroxy-C.sub.1-2-alkyl,
C.sub.1-4-alkoxy-C.sub.1-2-alkyl,
di-(C.sub.1-4-alkyl)-amino-C.sub.1-2-alkyl,
pyrrolidino-C.sub.1-2-alkyl, piperidino-C.sub.1-2-alkyl,
morpholino-C.sub.1-2-alkyl or
N--(C.sub.1-2-alkyl)-piperazino-C.sub.1-2-alkyl group, whilst the
abovementioned monosubstituted cycloalkyl moieties may additionally
be substituted by a C.sub.1-3-alkyl group, a
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group, an
C.sub.2-4-alkoxy group substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the oxygen atom by an
azetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino
group, a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C.sub.1-4-alkyloxy,
3-pyrrolidinyl-C.sub.1-4-alkyloxy, 3-piperidinyloxy,
4-piperidinyloxy, 2-piperidinyl-C.sub.1-4-alkyloxy,
3-piperidinyl-C.sub.1-4-alkyloxy, 4-piperidinyl-C.sub.1-4-alkyloxy,
3-hexahydro-azepinyloxy, 4-hexahydro-azepinyloxy,
2-hexahydro-azepinyl-C.sub.1-4-alkyloxy,
3-hexahydro-azepinyl-C.sub.1-4-alkyloxy or
4-hexahydro-azepinyl-C.sub.1-4-alkyloxy group wherein in each case
the cyclic nitrogen atom is substituted by the group R.sub.6, where
R.sub.6 is as hereinbefore defined, whilst by the aryl moieties
mentioned in the definition of the abovementioned groups is meant a
phenyl group which may in each case be monosubstituted by R.sub.7,
mono-, di- or trisubstituted by R.sub.8 or monosubstituted by
R.sub.7 and additionally mono- or disubstituted by R.sub.8, wherein
the substituents may be identical or different and [0042] R.sub.7
denotes a cyano, carboxy, C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylaminocarbonyl, di-(C.sub.1-4-alkyl)-aminocarbonyl,
C.sub.1-4-alkylsulfenyl, C.sub.1-4-alkylsulfinyl,
C.sub.1-4-alkylsulfonyl, hydroxy, C.sub.1-4-alkylsulfonyloxy,
trifluoromethyloxy, nitro, amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, C.sub.1-4-alkylcarbonylamino,
N--(C.sub.1-4-alkyl)-C.sub.1-4-alkylcarbonylamino,
C.sub.1-4-alkylsulfonylamino,
N--(C.sub.1-4-alkyl)-C.sub.1-4-alkylsulfonylamino, aminosulfonyl,
C.sub.1-4-alkylaminosulfonyl or di-(C.sub.1-4-alkyl)-aminosulfonyl
group or a carbonyl group which is substituted by a 5- to
7-membered alkyleneimino group, whilst in the abovementioned 6- to
7-membered alkyleneimino groups in each case a methylene group may
be replaced in the 4 position by an oxygen or sulfur atom, by a
sulfinyl, sulfonyl, imino or N--(C.sub.1-4-alkyl)-imino group, and
[0043] R.sub.8 denotes a fluorine, chlorine, bromine or iodine
atom, a C.sub.1-4-alkyl, trifluoromethyl or C.sub.1-4-alkoxy group
or [0044] two groups R.sub.8, if they are bound to adjacent carbon
atoms, together denote a C.sub.3-5-alkylene, methylenedioxy or
1,3-butadien-1,4-ylene group, the tautomers, stereoisomers and
salts thereof.
[0045] Particularly preferred compounds of the above general
formula I are those wherein
R.sub.a denotes a hydrogen atom, R.sub.b denotes a phenyl, benzyl
or 1-phenylethyl group wherein the phenyl nucleus is substituted in
each case by the groups R.sub.1 and R.sub.2, where [0046] R.sub.1
and R.sub.2, which may be identical or different, in each case
denote a hydrogen, fluorine, chlorine or bromine atom, [0047] a
methyl, trifluoromethyl or methoxy group, X denotes a nitrogen
atom, A denotes an imino group, B denotes a carbonyl group, C
denotes a 1,2-vinylene group, an ethynylene or
1,3-butadien-1,4-ylene group, D denotes a C.sub.1-4-alkylene group,
or, if D is bound to a carbon atom of the group E, it may also
denote a bond, or, if D is bound to a nitrogen atom of the group E,
it may also denote a carbonyl group, E denotes a
di-(C.sub.1-4-alkyl)-amino group wherein the alkyl moieties may be
identical or different, an
N--(C.sub.1-4-alkyl)-N--(C.sub.2-4-alkyl)-amino group wherein the
C.sub.2-4-alkyl moiety is substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the nitrogen atom of the amino
group by the group R.sub.5, whilst [0048] R.sub.5 denotes a
hydroxy, C.sub.1-3-alkoxy or di-(C.sub.1-3-alkyl)-amino group,
[0049] a pyrrolidino, piperidino or morpholino group, a
di-(C.sub.2-4-alkyl)-amino group wherein the two C.sub.2-4-alkyl
moieties in each case are substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the nitrogen atom of the amino
group by the group R.sub.5, wherein the substituents may be
identical or different and R.sub.5 is as hereinbefore defined, an
C.sub.1-4-alkylamino group substituted at the nitrogen atom by a
tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, 1-(C.sub.1-2-alkyl)-pyrrolidin-3-yl,
1-(C.sub.1-2-alkyl)-piperidin-3-yl,
1-(C.sub.1-2-alkyl)-piperidin-4-yl,
1-(tetrahydrofuran-3-yl)piperidin-4-yl,
1-(tetrahydropyran-3-yl)piperidin-4-yl or
1-(tetrahydropyran-4-yl)piperidin-4-yl group, a
C.sub.3-5-cycloalkylamino or
C.sub.3-5-cycloalkyl-C.sub.1-3-alkylamino group wherein in each
case the nitrogen atom is substituted by a further C.sub.1-3-alkyl
group, a 5- to 7-membered alkyleneimino group optionally
substituted by 1 or 2 methyl groups which may be substituted either
at a cyclic carbon atom or at one or the methyl groups by the group
R.sub.5, where R.sub.5 is as hereinbefore defined, or a piperidino
group substituted by a tetrahydrofuranyl, tetrahydropyranyl or
tetrahydrofuranylmethyl group, a piperidino group optionally
substituted by 1 or 2 methyl groups wherein the methylene group is
replaced in the 4 position by an oxygen or sulfur atom, by sulfinyl
or sulfonyl group or by an imino group substituted by the group
R.sub.6, whilst [0050] R.sub.6 denotes a C.sub.1-3-alkyl,
2-methoxyethyl, 3-methoxypropyl, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-alkyl, tetrahydrofuran-3-yl,
tetrahydropyran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuranylmethyl, C.sub.1-3-alkylcarbonyl,
C.sub.1-3-alkylsulfonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group, or D together with E denotes a hydrogen atom, a
C.sub.1-3-alkyl group, an aryl or C.sub.1-4-alkylcarbonyl group or
a C.sub.1-4-alkoxycarbonyl group, R.sub.c denotes a
C.sub.4-7-cycloalkoxy or C.sub.3-7-cycloalkyl-C.sub.1-4-alkoxy
group wherein the cycloalkyl moiety in each case may be substituted
by a C.sub.1-3-alkyl or C.sub.1-3-alkoxy group, a
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group, an
C.sub.2-4-alkoxy group substituted in .beta.-, .gamma.-, or
.delta.-position with regard to the oxygen atom by an
azetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino
group, a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C.sub.1-3-alkyloxy,
3-pyrrolidinyl-C.sub.1-3-alkyloxy, 3-piperidinyloxy,
4-piperidinyloxy, 2-piperidinyl-C.sub.1-3-alkyloxy,
3-piperidinyl-C.sub.1-3-alkyloxy, 4-piperidinyl-C.sub.1-3-alkyloxy,
3-hexahydro-azepinyloxy, 4-hexahydro-azepinyloxy,
2-hexahydro-azepinyl-C.sub.1-3-alkyloxy,
3-hexahydro-azepinyl-C.sub.1-3-alkyloxy or
4-hexahydro-azepinyl-C.sub.1-3-alkyloxy group wherein in each case
the cyclic nitrogen atom is substituted by a methyl or ethyl group,
whilst by the aryl moieties mentioned in the definition of the
abovementioned groups is meant a phenyl group which may be mono-,
di- or trisubstituted by R.sub.8, wherein the substituents may be
identical or different and [0051] R.sub.8 denotes a fluorine,
chlorine, bromine or iodine atom, a C.sub.1-4-alkyl,
trifluoromethyl or C.sub.1-4-alkoxy group, the tautomers,
stereoisomers and salts thereof.
[0052] Most particularly preferred compounds of the above general
formula I are those wherein
R.sub.a denotes a hydrogen atom, R.sub.b denotes a phenyl, benzyl
or 1-phenylethyl group, whilst the phenyl nucleus is substituted in
each case by the radicals R.sub.1 and R.sub.2, whilst [0053]
R.sub.1 and R.sub.2, which may be identical or different, each
denotes a hydrogen, fluorine, chlorine or bromine atom, X denotes a
nitrogen atom, A denotes an imino group, B denotes a carbonyl
group, C denotes a 1,2-vinylene, ethinylene or
1,3-butadien-1,4-ylene group, D denotes an C.sub.1-3-alkylene
group, E denotes a Di-(C.sub.1-4-alkyl)-amino group, wherein the
alkyl moieties may be identical or different, a methylamino or
ethylamino group each substituted at the nitrogen atom by a
2-methoxyethyl, 1-methoxy-2-propyl, 2-methoxypropyl,
3-methoxypropyl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl,
tetrahydrofuran-2-ylmethyl, 1-methylpiperidin-4-yl,
1-ethylpiperidin-4-yl, 1-(tetrahydrofuran-3-yl)piperidin-4-yl,
cyclopropyl or cyclopropylmethyl group, a Bis-(2-methoxyethyl)amino
group, a pyrrolidino, piperidino or morpholino group each
optionally substituted by one or two methyl groups, a piperazino
group substituted in 4-position by a methyl, ethyl, cyclopropyl,
cyclopropylmethyl, 2-methoxyethyl, tetrahydrofuran-3-yl,
tetrahydropyran-4-yl or tetrahydrofuran-2-ylmethyl group, a
thiomorpholino, S-oxidothiomorpholino or S,S-dioxidothiomorpholino
group, a 2-(methoxymethyl)pyrrolidino, 2-(ethoxymethyl)pyrrolidino,
4-hydroxypiperidino, 4-methoxypiperidino, 4-ethoxypiperidino,
4-(tetrahydrofuran-3-yl)piperidino or 4-morpholino-piperidino group
or D together with E denote a hydrogen atom, a methyl, phenyl,
methoxycarbonyl or ethoxycarbonyl group and R.sub.c denotes a
cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or
cyclohexylmethoxy group, a cyclobutyloxy, cyclopentyloxy or
cyclohexyloxy group, a tetrahydrofuran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuran-2-ylmethoxy group, a
straight chained C.sub.2-4-alkoxy group terminally substituted by
an azetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino
group, a 1-methylpiperidin-4-yloxy or 1-ethylpiperidin-4-yloxy
group, a (1-methylpiperidin-4-yl)-C.sub.1-3-alkyloxy or
(1-ethylpiperidin-4-yl)-C.sub.1-3-alkyloxy group, especially those
compounds wherein R.sub.a denotes a hydrogen atom, R.sub.b denotes
a 1-phenylethyl group or a phenyl group wherein the phenyl nucleus
is substituted by the radicals R.sub.1 and R.sub.2, whilst [0054]
R.sub.1 and R.sub.2, which may be identical or different, each
denote a hydrogen, fluorine, chlorine or bromine atom, X denotes a
nitrogen atom, A denotes an imino group, B denotes a carbonyl
group, C denotes a 1,2-vinylene, ethinylene or
1,3-butadien-1,4-ylene group, D denotes a methylene group, E
denotes a dimethylamino, diethylamino, bis(2-methoxyethyl)amino,
N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino,
N-methyl-N-cyclopropyl-amino, N-methyl-N-cyclopropylmethyl-amino,
N-methyl-N-(1-methoxy-2-propyl)amino,
N-methyl-N-(2-methoxypropyl)amino,
N-methyl-N-(3-methoxypropyl)amino-,
N-methyl-N-(tetrahydrofuran-3-yl)amino,
N-methyl-N-(tetrahydropyran-4-yl)amino,
N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino or
N-methyl-N-(1-methylpiperidin-4-yl)amino group, a pyrrolidino,
piperidino or morpholino group each optionally substituted by one
or two methyl groups, a piperazino group substituted in 4-position
by a methyl, ethyl, cyclopropylmethyl or 2-methoxyethyl group, a
S-oxidothiomorpholino group, a 2-(methoxymethyl)pyrrolidino,
4-hydroxypiperidino or 4-methoxypiperidino group or D together with
E denote a hydrogen atom, a methyl, phenyl or ethoxycarbonyl group,
and R.sub.c denotes a cyclopropylmethoxy, cyclobutyloxy or
cyclopentyloxy group, a tetrahydrofuran-3-yloxy,
tetrahydropyran-4-yloxy or tetrahydrofuran-2-ylmethoxy group, a
straight chained C.sub.2-4-alkoxy group terminally substituted by
an azetidin-1-yl or 4-methyl-homopiperazino group, a
1-methylpiperidin-4-yloxy group or a
(1-methylpiperidin-4-yl)-C.sub.1-3-alkyloxy group, the tautomers,
stereoisomers and salts thereof.
[0055] The following particularly valuable compounds of general
formula I may be mentioned by way of example: [0056] (a)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy-
]-6-[(vinylcarbonyl)amino]quinazoline, [0057] (b)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxyquinazoline and [0058] (c)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline as well as the salts
thereof.
[0059] The compounds of general formula I may be prepared, for
example, by the following processes:
a) reacting a compound of general formula
##STR00003##
wherein R.sub.a to R.sub.c, A and X are as hereinbefore defined,
with a compound of general formula
Z.sub.1--B--C-D-E (III)
wherein B to E are as hereinbefore defined and Z.sub.1 denotes a
leaving group such as a halogen atom, e.g., a chlorine or bromine
atom, or a hydroxy group.
[0060] The reaction is optionally carried out in a solvent or
mixture of solvents such as methylene chloride, dimethylformamide,
benzene, toluene, chlorobenzene, tetrahydrofuran,
benzene/-tetrahydrofuran or dioxane optionally in the presence of
an inorganic or organic base and optionally in the presence of a
dehydrating agent, expediently at temperatures between -50.degree.
C. and 150.degree. C., preferably at temperatures between
-20.degree. C. and 80.degree. C.
[0061] With a compound of general formula III wherein Z.sub.1
denotes a leaving group, the reaction is optionally carried out in
a solvent or mixture of solvents such as methylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in
the presence of a tertiary organic base such as triethylamine,
pyridine or 2-dimethylaminopyridine, in the presence of
N-ethyl-diisopropylamine (Hunig base), whilst these organic bases
may simultaneously also act as solvent, or in the presence of an
inorganic base such as sodium carbonate, potassium carbonate or
sodium hydroxide solution expediently at temperatures between
-50.degree. C. and 150.degree. C., preferably at temperatures
between -20.degree. C. and 80.degree. C.
[0062] With a compound of general formula III wherein Z.sub.1
denotes a hydroxy group, the reaction is preferably carried out in
the presence of a dehydrating agent, e.g., in the presence of
isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane,
phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane,
N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or
1-hydroxybenzotriazole and optionally also in the presence of
4-dimethylamino-pyridine, N,N'-carbonyldiimidazole or
triphenylphosphine/carbon tetrachloride, expediently in a solvent
such as methylene chloride, tetrahydrofuran, dioxane, toluene,
chlorobenzene, dimethylsulfoxide, ethylene glycol monomethylether,
ethylene glycol, diethylether or sulfolane and optionally in the
presence of a reaction accelerator such as 4-dimethylaminopyridine
at temperatures between -50.degree. C. and 150.degree. C., but
preferably at temperatures between -20.degree. C. and 80.degree.
C.
b) In order to prepare compounds of general formula I wherein the
group E is linked to the group D via a nitrogen atom: reacting a
compound of general formula
##STR00004##
wherein R.sub.a to R.sub.c, A to D and X are as hereinbefore
defined and Z.sub.2 denotes a leaving group such as a halogen atom,
a substituted hydroxy or sulfonyloxy group such as a chlorine or
bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group,
with a compound of general formula
H-E' (V)
wherein E' denotes one of the groups mentioned for E hereinbefore,
which is linked to the group D via a nitrogen atom.
[0063] The reaction is expediently carried out in a solvent such as
isopropanol, butanol, tetrahydrofuran, dioxane, toluene,
chlorobenzene, dimethylformamide, dimethylsulfoxide, methylene
chloride, ethylene glycol monomethylether, ethylene glycol
diethylether or sulfolane, optionally in the presence of an
inorganic or tertiary organic base, e.g., sodium carbonate or
potassium hydroxide, a tertiary organic base, e.g., triethylamine,
or in the presence of N-ethyl-diisopropylamine (Hunig base), whilst
these organic bases may simultaneously also serve as solvent, and
optionally in the presence of a reaction accelerator such as an
alkali metal halide at temperatures between -20.degree. C. and
150.degree. C., but preferably at temperatures between -10.degree.
C. and 100.degree. C. The reaction may, however, also be carried
out without a solvent or in an excess of the compound of general
formula V used.
[0064] If according to the invention a compound of general formula
I is obtained which contains an amino, alkylamino or imino group,
this may be converted by acylation or sulfonylation into a
corresponding acyl or sulfonyl compound of general formula I or
if a compound of general formula I is obtained which contains an
amino, alkylamino or imino group, this may be converted by
alkylation or reductive alkylation into a corresponding alkyl
compound of general formula I or if a compound of general formula I
is obtained which contains a carboxy or hydroxyphosphoryl group,
this may be converted by esterification into a corresponding ester
of general formula I or if a compound of general formula I is
obtained which contains a carboxy or ester group, this may be
converted by reaction with an amine into a corresponding amide of
general formula I.
[0065] The subsequent esterification is optionally carried out in a
solvent or mixture of solvents such as methylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane or most
advantageously in a corresponding alcohol, optionally in the
presence of an acid such as hydrochloric acid or in the presence of
a dehydrating agent, e.g., in the presence of isobutyl
chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric
acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus
trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or
1-hydroxybenzotriazole and optionally additionally in the presence
of 4-dimethylamino-pyridine, N,N'-carbonyldiimidazole or
triphenylphosphine/carbon tetrachloride, conveniently at
temperatures between 0.degree. C. and 150.degree. C., preferably at
temperatures between 0.degree. C. and 80.degree. C.
[0066] The subsequent ester formation may also be carried out by
reacting a compound which contains a carboxy or hydroxyphosphoryl
group with a corresponding alkyl halide.
[0067] The subsequent acylation or sulfonylation is conveniently
carried out in a solvent or mixture of solvents such as methylene
chloride, dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane with a
corresponding acyl or sulfonyl derivative optionally in the
presence of a tertiary organic base or in the presence of an
inorganic base or in the presence of a dehydrating agent, e.g., in
the presence of isobutyl chloroformate, thionyl chloride,
trimethylchlorosilane, sulfuric acid, methanesulfonic acid,
p-toluenesulfonic acid, phosphorus trichloride, phosphorus
pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or
1-hydroxybenzotriazole and optionally also in the presence of
4-dimethylamino-pyridine, N,N'-carbonyldiimidazole or
triphenylphosphine/carbon tetrachloride, expediently at
temperatures between 0.degree. C. and 150.degree. C., preferably at
temperatures between 0.degree. C. and 80.degree. C.
[0068] The subsequent alkylation is optionally carried out in a
solvent or mixture of solvents such as methylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane with an
alkylating agent such as a corresponding halide or sulfonic acid
ester, e.g., with methyl iodide, ethyl bromide, dimethyl sulfate or
benzyl chloride, optionally in the presence of a tertiary organic
base or in the presence of an inorganic base, expediently at
temperatures between 0.degree. C. and 150.degree. C., preferably at
temperatures between 0.degree. C. and 100.degree. C.
[0069] The subsequent reductive alkylation is carried out with a
corresponding carbonyl compound such as formaldehyde, acetaldehyde,
propionaldehyde, acetone or butyraldehyde in the presence of a
complex metal hydride such as sodium borohydride, lithium
borohydride, sodium triacetoxyborohydride or sodium
cyanoborohydride, expediently at a pH of 6-7 and at ambient
temperature or in the presence of a hydration catalyst, e.g., with
hydrogen in the presence of palladium/charcoal, at a hydrogen
pressure of 1 to 5 bar. The methylation can also be carried out in
the presence of formic acid as reduction agent at elevated
temperatures, e.g., at temperatures between 60.degree. C. and
120.degree. C.
[0070] The subsequent amide formation is carried out by reacting a
corresponding reactive carboxylic acid derivative with a
corresponding amine, optionally in a solvent or mixture of solvents
such as methylene chloride, dimethylformamide, benzene, toluene,
chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane,
whilst the amine used may simultaneously serve as solvent,
optionally in the presence of a tertiary organic base or in the
presence of an inorganic base or with a corresponding carboxylic
acid in the presence of a dehydrating agent, e.g., in the presence
of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane,
phosphorus trichloride, phosphorus pentoxide,
N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or
1-hydroxybenzotriazole and optionally also in the presence of
4-dimethylaminopyridine, N,N'-carbonyldiimidazole or
triphenylphosphine/carbon tetrachloride, expediently at
temperatures between 0.degree. C. and 150.degree. C., preferably at
temperatures between 0 and 80.degree. C.
[0071] In the reactions described hereinbefore, any reactive groups
present such as hydroxy, carboxy, phosphono, O-alkyl-phosphono,
amino, alkylamino or imino groups may be protected during the
reaction by conventional protecting groups which are cleaved again
after the reaction.
[0072] For example, a protecting group for a hydroxy group may be a
trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl,
benzyl or tetrahydropyranyl group,
protecting groups for a carboxy group may be a trimethylsilyl,
methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group,
protecting groups for a phosphono group may be an alkyl group such
as the methyl, ethyl, isopropyl or n-butyl group, the phenyl or
benzyl group, and protecting groups for an amino, alkylamino or
imino group may be a formyl, acetyl, trifluoroacetyl,
ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,
methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for
the amino group, a phthalyl group.
[0073] Any protecting group used is optionally subsequently cleaved
for example by hydrolysis in an aqueous solvent, e.g., in water,
isopropanol/water, acetic acid/water, tetrahydrofuran/water or
dioxane/water, in the presence of an acid such as trifluoroacetic
acid, hydrochloric acid or sulfuric acid or in the presence of an
alkali metal base such as sodium hydroxide or potassium hydroxide
or aprotically, e.g., in the presence of iodotrimethylsilane, at
temperatures between 0.degree. C. and 120.degree. C., preferably at
temperatures between 10.degree. C. and 100.degree. C.
[0074] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group
is cleaved, for example hydrogenolytically, e.g., with hydrogen in
the presence of a catalyst such as palladium/charcoal in a suitable
solvent such as methanol, ethanol, ethyl acetate or glacial acetic
acid, optionally with the addition of an acid such as hydrochloric
acid at temperatures between 0.degree. C. and 100.degree. C., but
preferably at temperatures between 20.degree. C. and 60.degree. C.,
and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5
bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in
trifluoroacetic acid in the presence of anisole.
[0075] A tert-butyl or tert-butyloxycarbonyl group is preferably
cleaved by treating with an acid such as trifluoroacetic acid or
hydrochloric acid or by treating with iodotrimethylsilane
optionally using a solvent such as methylene chloride, dioxane,
methanol or diethyl ether.
[0076] A trifluoroacetyl group is preferably cleaved by treating
with an acid such as hydrochloric acid, optionally in the presence
of a solvent such as acetic acid at temperatures between 50.degree.
C. and 120.degree. C. or by treating with sodium hydroxide solution
optionally in the presence of a solvent such as tetrahydrofuran at
temperatures between 0.degree. C. and 50.degree. C.
[0077] A phthalyl group is preferably cleaved in the presence of
hydrazine or a primary amine such as methylamine, ethylamine or
n-butylamine in a solvent such as methanol, ethanol, isopropanol,
toluene/water or dioxane at temperatures between 20.degree. C. and
50.degree. C.
[0078] A single alkyl group may be cleaved from an
O,O'-dialkylphosphono group with sodium iodide, for example, in a
solvent such as acetone, methyl ethyl ketone, acetonitrile or
dimethylformamide at temperatures between 40.degree. C. and
150.degree. C., but preferably at temperatures between 60.degree.
C. and 100.degree. C.
[0079] Both alkyl groups may be cleaved from an
O,O'-dialkylphosphono group with iodotrimethylsilane,
bromotrimethylsilane or chlorotrimethylsilane/sodium iodide, for
example, in a solvent such as methyl chloride, chloroform or
acetonitrile at temperatures between 0.degree. C. and the boiling
temperature of the reaction mixture, but preferably at temperatures
between 20.degree. C. and 60.degree. C.
[0080] Moreover, the compounds of general formula I obtained may be
resolved into their enantiomers and/or diastereomers, as mentioned
hereinbefore. Thus, for example, cis/trans mixtures may be resolved
into their cis and trans isomers, and compounds with at least one
optically active carbon atom may be separated into their
enantiomers.
[0081] Thus, for example, the cis/trans mixtures may be resolved by
chromatography into the cis and trans isomers thereof, the
compounds of general formula I obtained which occur as racemates
may be separated by methods known per se (cf. N. L. Allinger and E.
L. Eliel in "Topics in Stereochemistry", Vol. 6, Wiley
Interscience, 1971) into their optical antipodes and compounds of
general formula I with at least 2 asymmetric carbon atoms may be
resolved into their diastereomers on the basis of their
physical-chemical differences using methods known per se, e.g., by
chromatography and/or fractional crystallization, and, if these
compounds are obtained in racemic form, they may subsequently be
resolved into the enantiomers as mentioned above.
[0082] The enantiomers are preferably separated by column
separation on chiral phases or by recrystallization from an
optically active solvent or by reacting with an optically active
substance which forms salts or derivatives such as e.g., esters or
amides with the racemic compound, particularly acids and the
activated derivatives or alcohols thereof, and separating the
diastereomeric mixture of salts or derivatives thus obtained, e.g.,
on the basis of their differences in solubility, whilst the free
antipodes may be released from the pure diastereomeric salts or
derivatives by the action of suitable agents. Optically active
acids in common use are e.g., the D- and L-forms of tartaric acid
or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid,
mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid
or quinic acid. An optically active alcohol may be for example (+)
or (-)-menthol and an optically active acyl group in amides, for
example, may be a (+)- or (-)-menthyloxycarbonyl.
[0083] Furthermore, the compounds of formula I may be converted
into the salts thereof, particularly for pharmaceutical use into
the physiologically acceptable salts with inorganic or organic
acids. Acids which may be used for this purpose include for example
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid or maleic acid.
[0084] Moreover, if the new compounds of formula I thus obtained
contain a carboxy, hydroxyphosphoryl, sulfo or 5-tetrazolyl group,
they may subsequently, if desired, be converted into the salts
thereof with inorganic or organic bases, particularly for
pharmaceutical use into the physiologically acceptable salts
thereof. Suitable bases for this purpose include for example sodium
hydroxide, potassium hydroxide, arginine, cyclohexylamine,
ethanolamine, diethanolamine and triethanolamine.
[0085] The compounds of general formulae II to V used as starting
materials are known from the literature in some cases or may be
obtained by methods known from the literature (cf. Examples I to
VII).
[0086] For example, a starting compound of general formula I is
obtained by reacting a 7-fluoro-6-nitro compound correspondingly
substituted in the 4 position with a corresponding alkoxide and
subsequently reducing the nitro compound thus obtained or
a starting compound of general formula IV is obtained by reacting a
7-fluoro-6-nitro compound correspondingly substituted in the 4
position with a corresponding alkoxide, subsequently reducing the
nitro compound thus obtained and then acylating with a
corresponding compound.
[0087] As already mentioned hereinbefore, the compounds of general
formula I according to the invention and the physiologically
acceptable salts thereof have valuable pharmacological properties,
particularly an inhibiting effect on signal transduction mediated
by the Epidermal Growth Factor receptor (EGF-R), whilst this may be
achieved for example by inhibiting ligand bonding, receptor
dimerization or tyrosine kinase itself. It is also possible to
block the transmission of signals to components located further
down.
[0088] The biological properties of the new compounds were
investigated as follows:
[0089] The inhibition of the EGF-R-mediated signal transmission can
be demonstrated e.g., with cells which express human EGF-R and
whose survival and proliferation depend on stimulation by EGF or
TGF-alpha. A cell line of murine origin dependent on
interleukin-3-(IL-3) which was genetically modified to express
functional human EGF-R was used here. The proliferation of these
cells known as F/L-HERc can therefore be stimulated either by
murine IL-3 or by EGF (cf. T. von Ruden et al., EMBO J. 7,
2749-2756 (1988) and J. H Pierce et al., Science 239, 628-631
(1988)).
[0090] The starting material used for the F/L-HERc cells was the
cell line FDC-P.sub.1, the production of which has been described
by T. M. Dexter et al., J. Exp. Med. 152, 1036-1047 (1980).
Alternatively, however, other growth-factor-dependent cells may
also be used (cf., for example, J. H. Pierce et al., Science 239,
628-631 (1988); H. Shibuya et al., Cell 70, 57-67 (1992); and W. S.
Alexander et al., EMBO J. 10, 3683-3691 (1991)). For expressing the
human EGF-R cDNA (cf. Ullrich, A. et al. in Nature 309, 418-425
(1984)) recombinant retroviruses were used as described by T. von
Ruden et al., EMBO J. 7, 2749-2756 (1988), except that the
retroviral vector LXSN (cf. A. D. Miller et al., BioTechniques 7,
980-990 (1989)) was used for the expression of the EGF-R cDNA and
the line GP+E86 (cf. D. Markowitz et al., J. Virol. 62, 1120-1124
(1988)) was used as the packaging cell.
[0091] The test was performed as follows:
[0092] F/L-HERc cells were cultivated in RPMI/1640 medium
(BioWhittaker), supplemented with 10% fetal calf serum (FCS,
Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard
antibiotics and 20 ng/ml of human EGF (Promega), at 37.degree. C.
and 5% CO.sub.2. In order to investigate the inhibitory activity of
the compounds according to the invention, 1.5.times.10.sup.4 cells
per well were cultivated in triplicate in 96-well dishes in the
above medium (200 .mu.l), the cell proliferation being stimulated
with either EGF (20 ng/ml) or murine IL-3. The IL-3 used was
obtained from culture supernatants of the cell line X63/0 mIL-3
(cf. H. Karasuyama et al., Eur. J. Immunol. 18, 97-104 (1988)). The
compounds according to the invention were dissolved in 100%
dimethylsulfoxide (DMSO) and added to the cultures in various
dilutions, the maximum DMSO concentration being 1%. The cultures
were incubated for 48 hours at 37.degree. C.
[0093] In order to determine the inhibitory activity of the
compounds according to the invention the relative cell number was
measured in O.D. units using the Cell Titer 96.TM. Aqueous
Non-Radioactive Cell Proliferation Assay (Promega). The relative
cell number was calculated as a percentage of the control (F/LHERc
cells without inhibitor) and the concentration of active substance
which inhibits the proliferation of the cells by 50% (IC.sub.50)
was derived therefrom. The following results were obtained:
TABLE-US-00001 Compound Inhibition of EGF-Dependent (Example No.)
Proliferation IC.sub.50 [nM] 1 <0.35 2(3) 0.35 1(7) <0.5 3 5
3(1) 0.2
[0094] The compounds of general formula I according to the
invention thus inhibit signal transduction by tyrosine kinases, as
demonstrated by the example of the human EGF receptor, and are
therefore useful for treating pathophysiological processes caused
by hyperfunction of tyrosine kinases. These are e.g., benign or
malignant tumors, particularly tumors of epithelial and
neuroepithelial origin, metastasization and the abnormal
proliferation of vascular endothelial cells (neoangiogenesis).
[0095] The compounds according to the invention are also useful for
preventing and treating diseases of the airways and lungs which are
accompanied by increased or altered production of mucus caused by
stimulation by tyrosine kinases, e.g., in inflammatory diseases of
the airways such as chronic bronchitis, chronic obstructive
bronchitis, asthma, bronchiectasis, allergic or non-allergic
rhinitis or sinusitis, cystic fibrosis, .alpha..sub.1-antitrypsin
deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and
hyperreactive airways.
[0096] The compounds are also suitable for treating diseases of the
gastrointestinal tract and bile duct and gall bladder which are
associated with disrupted activity of the tyrosine kinases, such as
may be found e.g., in chronic inflammatory changes such as
cholecystitis, Crohns' disease, ulcerative colitis, and ulcers in
the gastrointestinal tract or such as may occur in diseases of the
gastrointestinal tract which are associated with increased
secretions, such as Menetrier's disease, secreting adenomas and
protein loss syndrome.
[0097] In addition, the compounds of general formula I and the
physiologically acceptable salts thereof may be used to treat other
diseases caused by abnormal function of tyrosine kinases, such as
e.g., epidermal hyperproliferation (psoriasis), inflammatory
processes, diseases of the immune system, hyperproliferation of
hematopoietic cells, etc.
[0098] By reason of their biological properties the compounds
according to the invention may be used on their own or in
conjunction with other pharmacologically active compounds, for
example in tumour therapy, in monotherapy or in conjunction with
other anti-tumour therapeutic agents, for example in combination
with topoisomerase inhibitors (e.g., etoposide), mitosis inhibitors
(e.g., vinblastine), compounds which interact with nucleic acids
(e.g., cis-platin, cyclophosphamide, adriamycin), hormone
antagonists (e.g., tamoxifen), inhibitors of metabolic processes
(e.g., 5-FU etc.), cytokines (e.g., interferons), antibodies, etc.
For treating respiratory tract diseases, these compounds may be
used on their own or in conjunction with other therapeutic agents
for the airways, such as substances with a secretolytic,
broncholytic and/or antiinflammatory activity. For treating
diseases in the region of the gastrointestinal tract, these
compounds may also be administered on their own or in conjunction
with substances having an effect on motility or secretion. These
combinations may be administered either simultaneously or
sequentially.
[0099] These compounds may be administered either on their own or
in conjunction with other active substances by intravenous,
subcutaneous, intramuscular, intraperitoneal or intranasal route,
by inhalation or transdermally or orally, whilst aerosol
formulations are particularly suitable for inhalation.
[0100] For pharmaceutical use the compounds according to the
invention are generally used for warm-blooded vertebrates,
particularly humans, in doses of 0.01-100 mg/kg of body weight,
preferably 0.1-15 mg/kg. For administration they are formulated
with one or more conventional inert carriers and/or diluents, e.g.,
with corn starch, lactose, glucose, microcrystalline cellulose,
magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric
acid, water, water/ethanol, water/glycerol, water/sorbitol,
water/polyethylene glycol, propylene glycol, stearyl alcohol,
carboxymethylcellulose or fatty substances such as hard fat or
suitable mixtures thereof in conventional galenic preparations such
as plain or coated tablets, capsules, powders, suspensions,
solutions, sprays or suppositories.
[0101] The following Examples are intended to illustrate the
present invention without restricting it:
PREPARATION OF THE STARTING COMPOUNDS
Example I
6-Amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]qu-
inazoline
[0102] 1.00 g of
4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-nitroq-
uinazoline is dissolved in 16 ml of water, 35 ml of ethanol and 1.3
ml of glacial acetic acid and heated to boiling. Then 540 mg of
iron powder are added with stirring. The reaction mixture is
refluxed for about another 35 minutes. For working up the cooled
reaction mixture is diluted with 15 ml of ethanol, made alkaline
with 15 N sodium hydroxide solution, combined with 20 g of
Extrelute and stirred for about 20 minutes. The precipitate formed
is suction filtered and washed with 200 ml of warm ethanol. The
filtrate is concentrated by evaporation, mixed with about 30 ml of
water and extracted 3.times. with 70 ml of methylene
chloride/methanol (9:1) each time. The combined extracts are dried
over sodium sulfate and concentrated by evaporation, leaving a
beige solid. Yield: 716 mg (76% of theory); melting point:
191.degree. C.-198.degree. C.; mass spectrum (ESI.sup.+): m/z=470,
472 [M+H].sup.+.
[0103] The following compounds are obtained analogously to Example
I:
(1)
6-Amino-4-[(3-bromophenyl)amino]-7-[2-(1-methylpiperidin-4-yl)ethoxy]q-
uinazoline
[0104] Melting point: 197.degree. C.; mass spectrum (ESI.sup.+):
m/z=456, 458 [M+H].sup.+.
(2)
6-Amino-4-[(3-bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]qu-
inazoline
[0105] Melting point: 207.degree. C.-208.degree. C.; mass spectrum
(ESI.sup.+): m/z=442, 444 [M+H].sup.+.
(3)
6-Amino-4-[(3-bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)oxy]quinaz-
oline
[0106] Melting point: 170.degree. C.; mass spectrum (ESI.sup.+):
m/z=428, 430 [M+H].sup.+.
(4)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxyquinazo-
line
[0107] Melting point: 209.degree. C.; R.sub.f value: 0.68 (silica
gel, ethyl acetate).
(5)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclobutyloxyquinazoline
[0108] R.sub.f value: 0.32 (silica gel, cyclohexane/ethyl
acetate=3:4); mass spectrum (ESI.sup.+): m/z=359, 361
[M+H].sup.+.
(6)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopentyloxyquinazoline
[0109] R.sub.f value: 0.33 (silica gel, cyclohexane/ethyl
acetate=1:1); mass spectrum (ESI.sup.+): m/z=373, 375
[M+H].sup.+.
(7)
6-Amino-4-[(R)-(1-phenylethyl)amino]-7-cyclobutyloxyquinazoline
[0110] R.sub.f value: 0.28 (silica gel, ethyl acetate); mass
spectrum (ESI.sup.+): m/z=335 [M+H].sup.+.
(8)
6-Amino-4-[(R)-(1-phenylethyl)amino]-7-cyclopropylmethoxyquinazoline
[0111] R.sub.f value: 0.54 (silica gel, ethyl acetate); mass
spectrum (ESI.sup.+): m/z=335 [M+H].sup.+.
(9)
6-Amino-4-[(R)-(1-phenylethyl)amino]-7-cyclopentyloxyquinazoline
[0112] R.sub.f value: 0.20 (silica gel, ethyl acetate); mass
spectrum (ESI.sup.+): m/z=349 [M+H].sup.+.
(10)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(1-methylpiperidin-4--
yl)propyloxy]quinazoline
[0113] R.sub.f value: 0.12 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=444, 446 [M+H].sup.+.
(11)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydrofuran-2-yl)m-
ethoxy]quinazoline
[0114] Melting point: 162.degree. C.-164.degree. C.; R.sub.f value:
0.55 (silica gel, ethyl acetate/methanol=9:1); mass spectrum
(ESI.sup.-): m/z=387, 389 [M-H].sup.-.
(12)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3--
yl)oxy]quinazoline
[0115] R.sub.f value: 0.27 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.-): m/z=373, 375
[M-H].sup.-.
(13)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydropyran-4-yl)o-
xy]quinazoline
[0116] R.sub.f value: 0.41 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.-): m/z=387, 389
[M-H].sup.-.
(14)
6-Amino-4-[(R)-(1-phenylethyl)amino]-7-[2-(azetidin-1-yl)-ethoxy]quin-
azoline
[0117] R.sub.f value: 0.37 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=364 [M+H].sup.+.
(15)
6-Amino-4-[(R)-(1-phenylethyl)amino]-7-[2-(4-methyl-perhydro-1,4-diaz-
epin-1-yl)-ethoxy]quinazoline
[0118] R.sub.f value: 0.10 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:1);
mass spectrum (ESI.sup.+): m/z=421 [M+H].sup.+.
(16)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-methyl-perhydro-1,-
4-diazepin-1-yl)propyloxy]quinazoline
[0119] R.sub.f value: 0.09 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=459, 461 [M+H].sup.+.
(17)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(azetidin-1-yl)propyl-
oxy]quinazoline
[0120] R.sub.f value: 0.11 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=402, 404 [M+H].sup.+.
Example II
4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-nitroqu-
inazoline
[0121] To a solution of 1.45 g of
3-(1-methylpiperidin-4-yl)propan-1-ol in 40 ml of tetrahydrofuran
are added 360 mg of sodium hydride. The white suspension formed is
stirred for 15 minutes at 65.degree. C., cooled and mixed with 1.45
g of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline,
whereupon the mixture suddenly turns dark red. The reaction mixture
is stirred first for 10 minutes at ambient temperature, then for 45
minutes at 65.degree. C. As the reaction is not yet complete, a
further 150 mg of sodium hydride are added and the mixture is
stirred for a further 45 minutes at 65.degree. C. The solvent is
distilled off using a rotary evaporator and the brown residue is
stirred with 50 ml of ice water. The aqueous phase is extracted
with methylene chloride. The combined extracts are washed with
water, dried over sodium sulfate and concentrated by evaporation.
The crude product is purified by chromatography over a silica gel
column with methylene chloride/methanol/concentrated ammonia
solution (90:10:0.05). Yield: 1.30 g of (65% of theory); R.sub.f
value: 0.28 (silica gel, methylene chloride/methanol/concentrated
aqueous ammonia solution=90:10:0.1); mass spectrum (ESI.sup.+):
m/z=500, 502 [M+H].sup.+.
[0122] The following compounds are prepared analogously to Example
II:
(1)
4-[(3-Bromophenyl)amino]-7-[2-(1-methylpiperidin-4-yl)ethoxy]-6-nitroq-
uinazoline
[0123] Melting point: 152.degree. C.; mass spectrum (ESI.sup.+):
m/z=486, 488 [M+H].sup.+.
(2)
4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]-6-nitroqu-
inazoline
[0124] Melting point: 205.degree. C.-207.degree. C.; mass spectrum
(ESI.sup.+): m/z=472, 474 [M+H].sup.+.
(3)
4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)oxy]-6-nitroquinaz-
oline
[0125] Melting point: 219.degree. C.; mass spectrum (ESI.sup.+):
m/z=458, 460 [M+H].sup.+.
(4)
4-[(3-Chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-6-nitroquinazo-
line
[0126] Carried out in dimethylformamide with potassium
tert-butoxide as base. Melting point: 211.degree. C.-213.degree.
C.; mass spectrum (ESI.sup.+): m/z=389, 391 [M+H].sup.+.
(5)
4-[(3-Chloro-4-fluorophenyl)amino]-7-cyclobutyloxy-6-nitroquinazoline
[0127] Carried out in dimethylformamide with potassium
tert-butoxide as base. Melting point: 235.degree. C.; R.sub.f
value: 0.65 (silica gel, cyclohexane/ethyl acetate=3:4).
(6)
4-[(3-Chloro-4-fluorophenyl)amino]-7-cyclopentyloxy-6-nitroquinazoline
[0128] Carried out in dimethylformamide with potassium
tert-butoxide as base. Melting point: 230.degree. C.; mass spectrum
(ESI.sup.+): m/z=403, 405 [M+H].sup.+.
(7)
4-[(R)-(1-Phenylethyl)amino]-7-cyclobutyloxy-6-nitroquinazoline
[0129] Carried out in dimethylformamide with potassium
tert-butoxide as base. Melting point: 108.degree. C.-110.degree.
C.; R.sub.f value: 0.54 (silica gel, ethyl acetate).
(8)
4-[(R)-(1-Phenylethyl)amino]-7-cyclopropylmethoxy-6-nitroquinazoline
[0130] Carried out in dimethylformamide with potassium
tert-butoxide as base. Melting point: 155.degree. C.; R.sub.f
value: 0.24 (silica gel, cyclohexane/ethyl acetate=1:1).
(9)
4-[(R)-(1-Phenylethyl)amino]-7-cyclopentyloxy-6-nitroquinazoline
[0131] Carried out in dimethylformamide with potassium
tert-butoxide as base. R.sub.f value: 0.24 (silica gel, petroleum
ether/ethyl acetate=1:1); mass spectrum (ESI.sup.+): m/z=379
[M+H].sup.+.
(10)
4-[(3-Chloro-4-fluorophenyl)amino]-6-nitro-7-[3-(1-methylpiperidin-4--
yl)propyloxy]quinazoline
[0132] R.sub.f value: 0.30 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=474, 476 [M+H].sup.+.
(11)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[(tetrahydrofuran-2-yl)methoxy]--
6-nitroquinazoline
[0133] Carried out in dimethylformamide with potassium
tert-butoxide as base. R.sub.f value: 0.47 (silica gel, ethyl
acetate); mass spectrum (ESI.sup.-): m/z=417, 419 [M-H].sup.-.
(12)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]--
6-nitroquinazoline
[0134] Carried out in dimethylformamide with potassium
tert-butoxide as base. R.sub.f value: 0.45 (silica gel, ethyl
acetate); mass spectrum (ESI.sup.-): m/z=403, 405 [M-H].sup.-.
(13)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[(tetrahydropyran-4-yl)oxy]-6-ni-
troquinazoline
[0135] Carried out in dimethylformamide with potassium
tert-butoxide as base. R.sub.f value: 0.41 (silica gel, ethyl
acetate); mass spectrum (ESI.sup.-): m/z=417, 419 [M-H].sup.-.
(14)
4-[(R)-(1-Phenylethyl)amino]-7-[2-(tetrahydropyran-2-yloxy)ethoxy]-6--
nitroquinazoline
[0136] R.sub.f value: 0.12 (silica gel, cyclohexane/ethyl
acetate=1:1); mass spectrum (ESI.sup.+): m/z=439 [M+H].sup.+.
(15)
4-[(3-Chloro-4-fluorophenyl)amino]-7-{3-[(tert-butyldimethylsilyl)oxy-
]propyloxy}-6-nitroquinazoline
[0137] (carried out in dimethylformamide with potassium
tert-butoxide as base) R.sub.f value: 0.87 silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=507, 509 [M+H].sup.+.
Example III
4-[(R)-(1-Phenylethyl)amino]-6-nitro-7-fluoroquinazoline
[0138] A solution of 74 ml of (R)-1-phenylethylamine in 100 ml of
dioxane is dropped into 108.8 g of
4-chloro-6-nitro-7-fluoro-quinazoline in 800 ml of methylene
chloride with cooling. The reaction mixture is washed with water
after stirring overnight at room temperature, the organic phase is
separated, dried and evaporated. The obtained residue is purified
by chromatography over a silica gel column (petroleum ether/ethyl
acetate=1:1). Yield: 52.9 g (35% of theory); melting point:
203.degree. C.; mass spectrum (ESI.sup.+): m/z=313 [M+H].sup.+.
Example IV
4-[(R)-(1-Phenylethyl)amino]-7-[2-(azetidin-1-yl)ethoxy]-6-nitroquinazolin-
e
[0139] 221 mg of dried potassium carbonate and 50 mg of sodium
iodide were given to 600 mg of
4-[(R)-(1-phenylethyl)amino]-7-[2-methanesulfonyloxyethoxy]-6-nitroquinaz-
oline and 0.34 ml of azetidine in 5.0 ml of acetonitrile. The
reaction mixture was heated up to 70.degree. C. with stirring.
Subsequently 3 ml of acetonitrile were added after one hour and the
mixture was stirred for further about 40 hours at 70.degree. C. The
solvent was removed in vacuo and the obtained residue was mixed
with ice water. The precipitate was suction filtered and dried. The
aqueous phase was extracted with methylene chloride and evaporated.
The combined precipitates were dissolved in ethyl acetate and
stirred together with a little of silica gel and 120 mg of charcoal
for further purification. The obtained suspension was filtered and
evaporated yielding a yellow resin. Yield: 518 mg (95% of theory);
R.sub.f value: 0.40 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=394 [M+H].sup.+.
[0140] The following compounds were obtained analogously to Example
IV:
(1)
4-[(R)-(1-Phenylethyl)amino]-7-[2-(4-methyl-perhydro-1,4-diazepin-1-yl-
)-ethoxy]-6-nitroquinazoline
[0141] R.sub.f value: 0.30 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=451 [M+H].sup.+.
(2)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(4-methyl-perhydro-1,4-diazepi-
n-1-yl)propyloxy]-6-nitroquinazoline
[0142] R.sub.f value: 0.34 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=80:20:0.1);
mass spectrum (ESI.sup.+): m/z=489, 491 [M+H].sup.+.
(3)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(azetidin-1-yl)propyloxy]-6-ni-
troquinazoline
[0143] R.sub.f value: 0.23 silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=432, 434 [M+H].sup.+.
Example V
4-[(R)-(1-Phenylethyl)amino]-7-[2-(methanesulfonyloxy)ethoxy]-6-nitroquina-
zoline
[0144] A solution of 1.79 ml methanesulfonic acid chloride in 10 ml
of methylene chloride was dropped into a mixture of 8.08 g of
4-[(R)-(1-phenylethyl)amino]-7-(2-hydroxyethoxy)-6-nitroquinazoline
and 4.53 ml of ethyl-diisopropylamine in 90 ml of methylene
chloride with ice cooling. The reaction mixture was stirred about
one hour at room temperature whereby further 0.4 ml of
methanesulfonic acid chloride and 0.5 ml of ethyldiisopropylamine
were added to complete the reaction. Subsequently the reaction
mixture was mixed with ice water and stirred after addition of
saturated aqueous sodium carbonate solution. The organic phase was
separated, washed with water, dried over magnesium sulfate and
evaporated. The obtained dark resinous residue was crystallized by
stirring with little tent-butyl methyl ether, suction filtered and
dried in an exsiccator. Yield: 9.72 g (99% of theory); melting
point: 128.degree. C.-134.degree. C.; mass spectrum (ESI.sup.-):
m/z=431 [M-H].sup.-.
[0145] The following compound was obtained analogously to Example
V:
(1)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(methanesulfonyloxy)propyloxy]-
-6-nitroquinazoline
[0146] R.sub.f value: 0.75 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=471, 473 [M+H].sup.+.
Example VI
4-[(R)-(1-Phenylethyl)amino]-7-(2-hydroxyethoxy)-6-nitroquinazoline
[0147] 120 ml of methanol and 2 ml of concentrated hydrochloric
acid were given to 8.05 g of
4-[(R)-(1-Phenylethyl)amino]-7-[2-(tetrahydropyran-2-yloxy)ethoxy]-6-nitr-
oquinazoline. After stirring for 1.5 hours at 50.degree. C. the
reaction mixture was neutralized with concentrated aqueous sodium
carbonate solution and evaporated. The solid residue was dissolved
in ethyl acetate and the obtained solution was washed with water,
with concentrated aqueous sodium chloride solution, dried over
magnesium sulfate solution and evaporated. The obtained yellow
residue was stirred with 20 ml of tent-butyl methyl ether, suction
filtered and dried in an exsiccator. Yield: 4.53 g (91% of theory);
melting point: 192.degree. C.-194.degree. C.; mass spectrum
(ESI.sup.-): m/z=353 [M-H].sup.-.
Example VII
4-[(3-Chloro-4-fluorophenyl)amino]-7-(3-hydroxypropyloxy)-6-nitroquinazoli-
ne
[0148] Prepared from
4-[(3-Chloro-4-fluorophenyl)amino]-7-{3-[(tert-butyldimethylsilyl)oxy]pro-
pyloxy}-6-nitroquinazoline by splitting off the protective silyl
group with tetrabutyl ammonium fluoride in tetrahydrofuran. Yield:
94% of theory; R.sub.f value: 0.61 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.-): m/z=391, 393 [M-H].sup.-.
Preparation of the End Products
Example 1
4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(vinyl-
carbonyl)amino]quinazoline
[0149] To a solution of 300 mg of
6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]q-
uinazoline in 7 ml of dichloromethane are added 0.28 ml of
triethylamine. The reaction mixture is cooled to about -10.degree.
C. in an ice/sodium chloride cooling bath. Then a solution of 59
.mu.l of acrylic acid chloride in 1 ml of tetrahydrofuran is added
dropwise within 10 minutes. The cooling bath is removed and the
mixture is stirred for a further 15 minutes at ambient temperature.
For working up, the reaction mixture is poured on to 20 ml of ice
water and mixed with 2-3 ml of 2 N sodium hydroxide solution,
whereupon a light-colored precipitate is formed. The precipitate is
suction filtered, washed with cold water and dissolved in
dichloromethane. The solution is dried over sodium sulfate and
concentrated by evaporation. The resin-like crude product is
purified by chromatography over a silica gel column with methylene
chloride/methanol/concentrated ammonia solution (90:10:0.5). Yield:
118 mg (35% of theory); R.sub.f value: 0.35 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=524, 526 [M+H].sup.+.
[0150] The following compounds are obtained analogously to Example
1:
(1)
4-[(3-Bromophenyl)amino]-7-[2-(1-methylpiperidin-4-yl)ethoxy]-6-[(viny-
lcarbonyl)amino]quinazoline
[0151] Melting point: 129.degree. C.; mass spectrum (ESI.sup.+):
m/z=510, 512 [M+H].sup.+.
(2)
4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]-6-[(vinyl-
carbonyl)amino]quinazoline
[0152] Melting point: 174.degree. C.; mass spectrum (ESI.sup.+):
m/z=496, 498 [M+H].sup.+.
(3)
4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)oxy]-6-[(vinylcarb-
onyl)amino]quinazoline
[0153] Melting point: 166.degree. C.; mass spectrum (ESI.sup.+):
m/z=482, 484 [M+H].sup.+.
(4)
4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)oxy]-6-[(1-oxo-2-b-
uten-1-yl)amino]quinazoline
[0154] R.sub.f value: 0.67 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=40:10:0.5);
mass spectrum (ESI.sup.+): m/z=496, 498 [M+H].sup.+.
(5)
4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]-6-[(1-oxo-
-2-buten-1-yl)amino]quinazoline
[0155] R.sub.f value: 0.45 (aluminium oxide, activity III; ethyl
acetate/methanol=4:1); mass spectrum (EI): m/z=509, 511
[M].sup.+.
(6)
4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(3-
-ethoxycarbonyl-1-oxo-2-propen-1-yl)-amino]quinazoline
[0156] R.sub.f value: 0.28 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=596, 598 [M+H].sup.+.
(7)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyl-
oxy]-6-[(vinylcarbonyl)amino]quinazoline
[0157] R.sub.f value: 0.33 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=498, 500 [M+H].sup.+.
(8)
4-[(R)-(1-Phenylethyl)amino]-7-[2-(azetidin-1-yl)-ethoxy]-6-[(vinylcar-
bonyl)amino]quinazoline
[0158] R.sub.f value: 0.60 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.-): m/z=416 [M-H].sup.-.
(9)
4-[(R)-(1-Phenylethyl)amino]-7-[2-(4-methyl-perhydro-1,4-diazepin-1-yl-
)-ethoxy]-6-[(vinylcarbonyl)amino]quinazoline
[0159] R.sub.f value: 0.37 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.-): m/z=473 [M-H].sup.-.
(10)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(4-methyl-perhydro-1,4-diazep-
in-1-yl)propyloxy]-6-[(vinylcarbonyl)amino]quinazoline
[0160] R.sub.f value: 0.29 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.+): m/z=513, 515 [M+H].sup.+.
(11)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(azetidin-1-yl)propyloxy]-6-[-
(vinylcarbonyl)amino]quinazoline
[0161] R.sub.f value: 0.39 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1);
mass spectrum (ESI.sup.-): m/z=454, 456 [M-H].sup.-.
Example 2
4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(1-oxo-
-2,4-hexadien-1-yl)amino]quinazoline
[0162] To 31 mg of sorbic acid in 1 ml of tetrahydrofuran are added
40 .mu.l of isobutyl chloroformate followed by 45 .mu.l of
N-methylmorpholine whilst cooling with an ice bath. The white
suspension is stirred for one minute, then a solution of 100 mg of
6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]q-
uinazoline in 1.5 ml of pyridine is added. The ice bath is removed
and the reaction mixture is stirred overnight. For working up, it
is poured onto 20 ml of ice water, stirred for 30 minutes and
adjusted to pH 9-10 with a few drops of 2 N sodium hydroxide
solution. The aqueous phase is extracted with methylene chloride,
the combined organic phases are dried over sodium sulfate and
concentrated by evaporation. The resin-like crude product is
purified by chromatography over an aluminium oxide column (activity
III) with methylene chloride/methanol (99.5:0.5). Yield: 62 mg (52%
of theory); R.sub.f value: 0.29 (aluminium oxide, activity III;
methylene chloride/methanol=98:2); mass spectrum (EI): m/z=563, 565
[M].sup.+.
[0163] The following compounds are obtained analogously to Example
2:
(1)
4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(1-
-oxo-2-buten-1-yl)amino]quinazoline
[0164] R.sub.f value: 0.26 (aluminium oxide, activity III;
methylene chloride/methanol=98:2); mass spectrum (ESI.sup.+):
m/z=538, 540 [M+H].sup.+.
(2)
4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(3-
-phenyl-1-oxo-2-propen-1-yl)amino]quinazoline
[0165] R.sub.f value: 0.26 (aluminium oxide, activity III;
methylene chloride/methanol=98:2); mass spectrum (EI): m/z=599, 601
[M].sup.+.
(3)
4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(1-
-oxo-2-butyn-1-yl)amino]quinazoline
[0166] R.sub.f value: 0.40 (aluminium oxide, activity III;
methylene chloride/methanol=98:2); mass spectrum (ESI.sup.+):
m/z=536, 538 [M+H].sup.+.
Example 3
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten--
1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0167] To a solution of 640 mg of 4-bromo-2-butenoic acid in 10 ml
of methylene chloride are added, at ambient temperature, 0.67 ml of
oxalyl chloride and one drop of dimethylformamide. The reaction
mixture is stirred for about another half hour at ambient
temperature, until the development of gas has ceased. The acid
chloride formed is substantially freed from solvent in vacuo using
a rotary evaporator. Then the crude product is dissolved in 10 ml
of methylene chloride and added dropwise, whilst cooling with an
ice bath, to a mixture of 1.00 g of
6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxyquinazolin-
e and 1.60 ml of Hunig base in 50 ml of tetrahydrofuran. The
reaction mixture is stirred for 1.5 hours in an ice bath and for a
further 2 hours at ambient temperature. Then 2.90 ml of
diethylamine are added and the mixture is stirred for 2.5 days at
ambient temperature. To work it up, the reaction mixture is
filtered and the filtrate is concentrated by evaporation. The
filter residue is purified by chromatography over a silica gel
column with ethyl acetate/methanol (19:1). Yield: 550 mg (40% of
theory); melting point: 114.degree. C.; mass spectrum (ESI.sup.+):
m/z=498, 500 [M+H].sup.+.
[0168] The following compounds are obtained analogously to Example
3:
(1)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0169] R.sub.f value: 0.53 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.-): m/z=510, 512
[M-H].sup.-.
(2)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-ethylpiperazin-1-yl)-1-oxo-
-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0170] R.sub.f value: 0.44 (silica gel, ethyl
acetate/methanol/concentrated aqueous ammonia solution=9:1:0.1);
mass spectrum (EI): m/z=538, 540 [M].sup.+.
(3)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,6-dimethyl-morpholin-4-yl)-
-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0171] Melting point: 160.degree. C.; mass spectrum (ESI.sup.+):
m/z=540, 542 [M+H].sup.+.
(4)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0172] Melting point: 137.degree. C.; mass spectrum (ESI.sup.+):
m/z=470, 472 [M+H].sup.+.
(5)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(1-oxido-thiomorpholin-4-yl)--
1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0173] Melting point: 239.degree. C.; mass spectrum (ESI.sup.+):
m/z=544, 546 [M+H].sup.+.
(6)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclobutyloxyquinazoline
[0174] R.sub.f value: 0.45 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=512, 514
[M+H].sup.+.
(7)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentyloxyquinazoline
[0175] Melting point: 143.degree. C.; R.sub.f value: 0.45 (silica
gel, ethyl acetate/methanol=9:1).
(8)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten--
1-yl]amino}-7-cyclobutyloxyquinazoline
[0176] Melting point: 111.degree. C.; R.sub.f value: 0.21 (silica
gel, ethyl acetate/methanol=9:1).
(9)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten--
1-yl]amino}-7-cyclopentyloxyquinazoline
[0177] Melting point: 105.degree. C.; R.sub.f value: 0.23 (silica
gel, ethyl acetate/methanol=9:1).
(10)
4-[(R)-(1-Phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-y-
l]amino}-7-cyclobutyloxyquinazoline
[0178] R.sub.f value: 0.33 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=488
[M+H].sup.+.
(11)
4-[(R)-(1-Phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-y-
l]amino}-7-cyclopropylmethoxyquinazoline
[0179] R.sub.f value: 0.37 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=488
[M+H].sup.+.
(12)
4-[(R)-(1-Phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-y-
l]amino}-7-cyclopentyloxyquinazoline
[0180] R.sub.f value: 0.35 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=502
[M+H].sup.+.
(13)
4-[(R)-(1-Phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]-
amino}-7-cyclobutyloxyquinazoline
[0181] R.sub.f value: 0.26 (silica gel, ethyl
acetate/methanol=4:1); mass spectrum (ESI.sup.+): m/z=474
[M+H].sup.+.
(14)
4-[(R)-(1-Phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]-
amino}-7-cyclopentyloxyquinazoline
[0182] R.sub.f value: 0.31 (silica gel, ethyl
acetate/methanol=4:1); mass spectrum (ESI.sup.+): m/z=488
[M+H].sup.+.
(15)
4-[(R)-(1-Phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]-
amino}-7-cyclopropylmethoxyquinazoline
[0183] R.sub.f value: 0.15 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=474
[M+H].sup.+.
(16)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(1-methylpiperid-
in-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0184] R.sub.f value: 0.28 (silica gel, ethyl
acetate/methanol/concentrated aqueous ammonia solution=80:20:2);
mass spectrum (ESI.sup.+): m/z=553, 555 [M+H].sup.+.
(17)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)-2-methoxymethylpyrrolid-
in-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0185] R.sub.f value: 0.33 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=540, 542
[M+H].sup.+.
(18)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)-2-methoxymethylpyrrolid-
in-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0186] Melting point: 120.degree. C.; mass spectrum (ESI.sup.+):
m/z=540, 542 [M+H].sup.+.
(19)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[bis-(2-methoxyethyl)amino]--
1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0187] R.sub.f value: 0.51 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=558, 560
[M+H].sup.+.
(20)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)a-
mino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0188] R.sub.f value: 0.33 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=528, 530
[M+H].sup.+.
(21)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(piperidin-1-yl)-1-oxo-2-but-
en-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0189] R.sub.f value: 0.22 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=510, 512
[M+H].sup.+.
(22)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methylpiperidin-1-yl)-1-o-
xo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0190] R.sub.f value: 0.21 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=524, 526
[M+H].sup.+.
(23)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(pyrrolidin-1-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0191] R.sub.f value: 0.10 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.+): m/z=496, 498
[M+H].sup.+.
(24)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylmethylpiperazi-
n-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0192] Melting point: 117.degree. C.; mass spectrum (ESI.sup.+):
m/z=565, 567 [M+H].sup.+.
(25)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methylpyrrolidin-1-yl)-1--
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0193] Melting point: 108.degree. C.-110.degree. C.; R.sub.f value:
0.27 (silica gel, ethyl acetate/methanol=9:1).
(26)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-
-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0194] R.sub.f value: 0.29 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.-): m/z=538, 540
[M-H].sup.-.
(27)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(cis-2,6-dimethylpiperidin-1-
-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0195] R.sub.f value: 0.27 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.-): m/z=536, 538
[M-H].sup.-.
(28)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,5-dimethylpyrrolidin-1-yl-
)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0196] R.sub.f value: 0.36 (silica gel, ethyl
acetate/methanol=9:1); mass spectrum (ESI.sup.-): m/z=522, 524
[M-H].sup.-.
(29)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
[0197] R.sub.f value: 0.35 (silica gel, ethyl
acetate/methanol/concentrated aqueous ammonia solution=9:1:0.1);
mass spectrum (ESI.sup.-): m/z=526, 528 [M-H].sup.-.
(30)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline
[0198] Melting point: 119.degree. C.; mass spectrum (ESI.sup.-):
m/z=512, 514 [M-H].sup.-.
(31)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-diethylaminomethylpiperid-
in-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0199] R.sub.f value: 0.20 (silica gel, methylene
chloride/methanol=9:1); mass spectrum (ESI.sup.-): m/z=593, 595
[M-H].sup.-.
(32)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-methyl-N-cyclopropylmethy-
l-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0200] R.sub.f value: 0.73 (silica gel, methylene
chloride/methanol=9:1); mass spectrum (ESI.sup.+): m/z=510, 512
[M+H].sup.+.
(33)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxypropyl-
)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0201] The N-methyl-N-(2-methoxypropyl)amine used was prepared by
reaction of 2-methoxypropionic acid chloride with methylamine and
subsequent reduction with lithium aluminium hydride; melting point:
123.degree. C.-125.degree. C.; R.sub.f value: 0.66 (silica gel,
methylene chloride/methanol=9:1).
(34)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(3-methoxypropyl-
)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0202] R.sub.f value: 0.66 (silica gel, methylene
chloride/methanol=9:1); mass spectrum (ESI.sup.+): m/z=528, 530
[M+H].sup.+.
(35)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methoxypiperidin-1-yl)-1--
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0203] Melting point: 129.degree. C.-130.degree. C.; R.sub.f value:
0.20 (silica gel, ethyl acetate/methanol=9:1); mass spectrum
(ESI.sup.-): m/z=538, 540 [M-H].sup.-.
(36)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-hydroxypiperidin-1-yl)-1--
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0204] R.sub.f value: 0.30 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution=9:1:0.1);
mass spectrum (ESI.sup.-): m/z=524, 526 [M-H].sup.-.
(37)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline
[0205] R.sub.f value: 0.47 (silica gel, methylene
chloride/methanol=9:1); mass spectrum (ESI.sup.-): m/z=528, 530
[M-H].sup.-.
(38)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-
-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoli-
ne
[0206] Melting point: about 145.degree. C. (decomp.); R.sub.f
value: 0.23 (silica gel, methylene chloride/methanol=15:1); Mass
spectrum (ESI.sup.+): m/z=540, 542 [M+H].sup.+.
(39)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-
-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0207] The starting N-methyl-N-(3-tetrahydrofuranyl)amine was
prepared by reaction of tetrahydrofuran-3-carboxylic acid with
diphenyl phosphonate azide in benzyl alcohol and subsequent
reduction of the obtained 3-(benzyloxycarbonylamino)tetrahydrofuran
with lithium aluminium hydride. Melting point: 157.degree.
C.-159.degree. C.; R.sub.f value: 0.23 (silica gel, methylene
chloride/methanol=15:1); mass spectrum (ESI.sup.+): m/z=526, 528
[M+H].sup.+.
(40)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(1-methoxy-2-pro-
pyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0208] The starting N-methyl-N-(1-methoxy-2-propyl)amine was
prepared by reductive amination of methoxyacetone with methylamine
hydrochloride and sodium triacetoxyborohydride in the presence of
sodium acetate. The reaction was carried out in tetrahydrofuran.
R.sub.f value: 0.38 (silica gel, ethyl acetate/methanol=9:1); mass
spectrum (ESI.sup.+): m/z=528, 530 [M+H].sup.+.
[0209] The following compounds may also be obtained analogously to
the above Examples and other methods known from the literature:
[0210] (1)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0211] (2)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dibutylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0212] (3)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(piperidin-1-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline [0213] (4)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,6-dimethylmorpholin-4-yl)-1-o-
xo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0214] (5)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methylpiperazin-1-yl)-1-oxo-2-
-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0215] (6)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylmethylpiperazin-1--
yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0216] (7)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylpiperazin-1-yl)-1--
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0217] (8)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methylsulfonylpiperazin-1-yl)-
-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0218]
(9)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-acetylpiperazin-1-yl)-1-oxo-2-
-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0219] (10)
4-[(3-Chloro-4-fluorophenyl)amino]-6-[(4-{4-[(N,N-dimethylamino)carbonyl]-
piperazin-1-yl}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
[0220] (11)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(pyrrolidin-1-yl)-1-oxo-2-buten--
1-yl]amino}-7-cyclopropylmethoxyquinazoline [0221] (12)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0222] (13)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropylmethyl-N-methylami-
no)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0223] (14)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buty-
n-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0224] (15)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-butyn-
-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0225] (16)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(piperidin-1-yl)-1-oxo-2-butyn-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline [0226] (17)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-butyn-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline [0227] (18)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methylpiperazin-1-yl)-1-oxo-2-
-butyn-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0228] (19)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methylsulfonylpiperazin-1-yl)-
-1-oxo-2-butyn-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0229]
(20)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1,4-dioxo-2-but-
en-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0230] (21)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(3-N,N-dimethylamino-propan-1-y-
l)amino]-1,4-dioxo-2-buten-1-yl}amino]-7-cyclopropylmethoxyquinazoline
[0231] (22)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({2-[(N,N-diethylamino)methyl]-1-oxo-
-2-propen-1-yl}amino]-7-cyclopropylmethoxyquinazoline [0232] (23)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methoxymethylpyrrolidin-1-yl)-
-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline [0233]
(24)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-
-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline [0234]
(25)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline [0235]
(26)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclobutylmethoxyquinazoline [0236] (27)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentylmethoxyquinazoline [0237] (28)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclohexylmethoxyquinazoline [0238] (29)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-(2-cyclopropylethoxy)quinazoline [0239] (30)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-(3-cyclopropylpropyloxy)quinazoline [0240] (31)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(tetrahydrofuran-3-yl)piperid-
in-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0241] (32)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(morpholin-4-yl)piperidi-
n-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0242] (33)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(tetrahydrofuran-3-yl)pi-
perazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0243] (34)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(tetrahydrofuran-2-ylmethyl)p-
iperazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0244] (35)
4-[(3-Chloro-4-fluorophenyl)amino]-6-[(4-{N-methyl-N-[1-(tetrahydrofuran--
3-yl)piperidin-4-yl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyq-
uinazoline [0245] (36)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)-2-methoxymethylpyrrolidin-1-
-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline [0246]
(37)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)-2-methoxymethylpyrrolidin-1-
-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline [0247]
(38)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[bis-(2-methoxyethyl)amino]-1-ox-
o-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline [0248] (39)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline [0249] (40)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)--N-methyl-N-(1-methoxy-2-pr-
opyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline
[0250] (41)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)--N-methyl-N-(1-methoxy-
-2-propyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline
[0251] (42)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(1-methoxy-2-propyl)-
amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0252] (43)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxypropy-
l)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0253] (44)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(3-methoxypropy-
l)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0254] (45)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofura-
n-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0255] (46)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)--N-methyl-N-(tetrahydrofura-
n-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline
[0256] (47)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)--N-methyl-N-(tetrahydr-
ofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline
[0257] (48)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-y-
l)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0258] (49)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyra-
n-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline
[0259] (50)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylpiperazin-1-y-
l)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0260] (51)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylmethylpiperazin-1--
yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0261]
(52)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0262] (53)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropylmethyl-N-methyl-am-
ino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0263]
(54)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-2-y-
lmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0264] (55)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)--N-methyl-N-(tetrahydrofura-
n-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline
[0265] (56)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)--N-methyl-N-(tetrahydrofura-
n-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline
[0266] (57)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(pyrrolidin-1-yl)-1-oxo-2-buten--
1-yl]amino}-7-cyclobutyloxyquinazoline [0267] (58)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methylpyrrolidin-1-yl)-1-oxo--
2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0268] (59)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,5-dimethylpyrrolidin-1-yl)-1--
oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0269] (60)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(piperidin-1-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclobutyloxyquinazoline [0270] (61)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methylpiperidin-1-yl)-1-oxo-2-
-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0271] (62)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,6-dimethylpiperidin-1-yl)-1-o-
xo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0272] (63)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-hydroxy-piperidin-1-yl)-1-oxo-
-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0273] (64)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methoxy-piperidin-1-yl)-1-oxo-
-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0274] (65)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(2-methoxyethyl)piperazin-1-y-
l]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline [0275] (66)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-morpholin-4-yl)-1-oxo--
2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0276] (67)
4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(3,5-dimethyl-morpholin-4-yl)-1--
oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline [0277] (68)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amin-
o]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-3-yloxy)quinazoline
[0278] (69)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl-
)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydropyran-4-yloxy)quinazoline
[0279] (70)
4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amin-
o]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-2-ylmethoxy)quinazoline
[0280] (71)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(azetidin-1-yl)propyloxy]-6-[(vin-
ylcarbonyl)amino]quinazoline [0281] (72)
4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(4-methyl-homopiperazin-1-yl)prop-
yloxy]-6-[(vinylcarbonyl)amino]quinazoline.
Example 4
Coated Tablets Containing 75 mg of Active Substance
1 Tablet Core Contains:
TABLE-US-00002 [0282] active substance 75.0 mg calcium phosphate
93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg
hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg
230.0 mg
Preparation:
[0283] The active substance is mixed with calcium phosphate, corn
starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half
the specified amount of magnesium stearate. Blanks 13 mm in
diameter are produced in a tablet-making machine and these are then
rubbed through a screen with a mesh size of 1.5 mm using a suitable
machine and mixed with the rest of the magnesium stearate. This
granulate is compressed in a tablet-making machine to form tablets
of the desired shape. Weight of core: 230 mg; die: 9 mm, convex.
The tablet cores thus produced are coated with a film consisting
essentially of hydroxypropylmethylcellulose. The finished
film-coated tablets are polished with beeswax. Weight of coated
tablet: 245 mg.
Example 5
Tablets Containing 100 mg of Active Substance
Composition:
1 Tablet Contains:
TABLE-US-00003 [0284] active substance 100.0 mg lactose 80.0 mg
corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate
2.0 mg 220.0 mg
Method of Preparation:
[0285] The active substance, lactose and starch are mixed together
and uniformly moistened with an aqueous solution of the
polyvinylpyrrolidone. After the moist composition has been screened
(2.0 mm mesh size) and dried in a rack-type drier at 50.degree. C.
it is screened again (1.5 mm mesh size) and the lubricant is added.
The finished mixture is compressed to form tablets. Weight of
tablet: 220 mg; diameter: 10 mm, biplanar, facetted on both sides
and notched on one side.
Example 6
Tablets Containing 150 mg of Active Substance
Composition:
1 Tablet Contains:
TABLE-US-00004 [0286] active substance 50.0 mg powdered lactose
89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg
polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg
Preparation:
[0287] The active substance mixed with lactose, corn starch and
silica is moistened with a 20% aqueous polyvinylpyrrolidone
solution and passed through a screen with a mesh size of 1.5 mm.
The granules, dried at 45.degree. C., are passed through the same
screen again and mixed with the specified amount of magnesium
stearate. Tablets are pressed from the mixture. Weight of tablet:
300 mg; die: 10 mm, flat.
Example 7
Hard Gelatine Capsules Containing 150 mg of Active Substance
1 Capsule Contains:
TABLE-US-00005 [0288] active substance 50.0 mg corn starch (dried)
approx. 80.0 mg lactose (powdered) approx. 87.0 mg magnesium
stearate 3.0 mg approx. 420.0 mg
Preparation:
[0289] The active substance is mixed with the excipients, passed
through a screen with a mesh size of 0.75 mm and homogeneously
mixed using a suitable apparatus. The finished mixture is packed
into size 1 hard gelatine capsules. Capsule filling: approx. 320
mg; capsule shell: size 1 hard gelatine capsule.
Example 8
Suppositories Containing 150 mg of Active Substance
1 Suppository Contains:
TABLE-US-00006 [0290] active substance 150.0 mg polyethyleneglycol
1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene
sorbitan monostearate 840.0 mg 2,000.0 mg
Preparation:
[0291] After the suppository mass has been melted the active
substance is homogeneously distributed therein and the melt is
poured into chilled molds.
Example 9
Suspension Containing 50 mg of Active Substance
100 ml of Suspension Contain:
TABLE-US-00007 [0292] active substance 1.00 g
carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05
g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g
70% sorbitol solution 20.00 g flavoring 0.30 g dist. water ad 100
ml
Preparation:
[0293] The distilled water is heated to 70.degree. C. The methyl
and propyl p-hydroxybenzoates together with the glycerol and sodium
salt of carboxymethylcellulose are dissolved therein with stirring.
The solution is cooled to ambient temperature and the active
substance is added and homogeneously dispersed therein with
stirring. After the sugar, the sorbitol solution and the flavoring
have been added and dissolved, the suspension is evacuated with
stirring to eliminate air. 5 ml of suspension contain 50 mg of
active substance.
Example 10
Ampoules Containing 10 mg Active Substance
Composition:
TABLE-US-00008 [0294] active substance 10.0 mg 0.01 N hydrochloric
acid q.s. double-distilled water ad 2.0 ml
Preparation:
[0295] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 2 ml ampoules.
Example 11
Ampoules Containing 50 mg of Active Substance
Composition:
TABLE-US-00009 [0296] active substance 50.0 mg 0.01 N hydrochloric
acid q.s. double-distilled water ad 10.0 ml
Preparation:
[0297] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 10 ml ampoules.
Example 12
Capsules for Powder Inhalation Containing 5 mg of Active
Substance
1 Capsule Contains:
TABLE-US-00010 [0298] active substance 5.0 mg lactose for
inhalation 15.0 mg 20.0 mg
Preparation:
[0299] The active substance is mixed with lactose for inhalation.
The mixture is packed into capsules in a capsule-making machine
(weight of the empty capsule approx. 50 mg). Weight of capsule:
70.0 mg; size of capsule=3.
Example 13
Solution for Inhalation for Hand-Held Nebulizers Containing 2.5 mg
Active Substance
1 Spray Contains:
TABLE-US-00011 [0300] active substance 2.500 mg benzalkonium
chloride 0.001 mg 1N hydrochloric acid q.s. ethanol/water (50/50)
ad 15.000 mg
Preparation:
[0301] The active substance and benzalkonium chloride are dissolved
in ethanol/water (50/50). The pH of the solution is adjusted with
1N hydrochloric acid. The resulting solution is filtered and
transferred into suitable containers for use in hand-held
nebulizers (cartridges). Contents of the container: 4.5 g.
* * * * *