Note: Descriptions are shown in the official language in which they were submitted.
CA 02417050 2003-01-22
Boehringer Ingelheim Pharma KG Case 5/1298
a'-
D-55216 Ingelheim/Rhein Foreign filing text
73887fft
Bicyclic heterocycles, pharmaceutical compositions containing
these compounds, their use and processes for preparing them
The present invention relates to bicyclic heterocycles of
general formula ~Ra\ /H
N
NH - CO - CH = CH - (CH2 ) n - Rb
N R . (I)
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.
In the above general formula I
Ra denotes a benzyl or 1-phenylethyl group or a phenyl group
substituted by the groups R. and R2, where
R1 denotes a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl, cyano or ethynyl group and
R2 denotes a hydrogen or fluorine atom,
Rb denotes an R30-CO-CH2-N-CHZ-CHZ-OH group optionally
substituted at the methylene groups by 1 or 2 methyl or ethyl
groups, where
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' ' - 2 -
R3 represents a hydrogen atom or a C1_4-alkyl group,
a 2-oxo-morpholin-4-yl group which may be substituted by 1 or
2 methyl or ethyl groups, or
a N-[(1,3-dioxolan-2-yl)-methyl]-methylamino group,
R. denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxyethoxy,
2-ethoxyethoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,
cyclopropylmethoxy,,cyclobutylmethoxy, cyclopentylmethoxy,
cyclohexylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-
3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or
tetrahydropyranylmethoxy group and
n denotes an integer from the range from 1 to 3 with the
proviso that the following compounds
4-[ (3-bromophenyl) amino]-6- ({4-[N- (1, 3-dioxolan-2-yl-
methyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-methoxy-
quinazoline,
4-[ (3-bromophenyl) amino]-6-{[4- (2-oxo-morpholin-4-yl) -1-
oxo-2-buten-1-yl]amino}-7-methoxyquinazoline,
4-[ (3-bromophenyl) amino]-6-[ (4-{N-
[(tert.butyloxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-
2-buten-1-yl)amino]-7-methoxyquinazoline,
4 - [ (3-bromophenyl) amino]-6- ({4-[N- (carboxymethyl) -N- (2-
hydroxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-
methoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2-oxo-morpholin-
4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-
methoxyquinazoline,
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- 3 -
4-[ (3-chloro-4-fluorophenyl) amino] -6-[ (4-{N-[ (ethoxy-
carbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-l-
yl)amino]-7-cyclopropylmethoxyquinazoline,
4 - [ ( 3 -chloro-4 - f luorophenyl ) amino]-6 -[ (4 - {N-[ (ethoxy-
carbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)amino}-l-oxo-2-
buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline,
4-[ (3-chloro-4-fluorophenyl) amino]-6-{[4- (2, 2-dimethyl-6-
oxomorpholin-4-yl)-,1-oxo-2-buten-1-y1]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-
oxomorpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4 - [ (3-chloro-4-fluorophenyl) amino]-6-{[4- (5-methyl-2-
oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
(R) -4-[(3-chloro-4-fluorophenyl) amino]-6-[ (4-{N-[1- (ethoxy-
carbonyl)-ethyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)-
amino]-7-cyclopropylmethoxyquinazoline and
(R) -4 -[ (3 -chloro-4 - f luorophenyl ) amino]-6- {[4 - (3 -methyl-2 -
oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline
are excluded.
Preferred compounds of the above general formula I are those
wherein
Ra denotes a benzyl or 1-phenylethyl group or a phenyl group
substituted by the groups R1 and R2, where
R. denotes a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl, cyano or ethynyl group and
R2 denotes a hydrogen or fluorine atom,
a
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- 4 -
Rb denotes an R30-CO-CH2-N-CHZ-CH2-OH group optionally
substituted at the methylene groups by 1 or 2 methyl or ethyl
groups, where
R3 represents a hydrogen atom or a C1_4-alkyl group,
a 2-oxo-morpholin-4-yl group which may be substituted by 1 or
2 methyl or ethyl groups, or
~
an N-[(1,3-dioxolan-2-yl)-methyl]-methylamino group,
Rc denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxyethoxy,
2-ethoxyethoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,
cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy,
cyclohexylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-
3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or
tetrahydropyranylmethoxy group and
n denotes an integer from the range from 1 to 3 with the
proviso that the following compounds
4-[ (3-bromophenyl) amino]-6- ({4-[N- (1, 3-dioxolan-2-yl-
methyl)-N-methylamino]-i-oxo-2-buten-l-yl}amino)-7-
methoxyquinazoline,
4-[(3-bromophenyl) amino]-6-{[4- (2-oxo-morpholin-4-yl) -1-
oxo-2-buten-1-yl]amino}-7-methoxyquinazoline,
4-[(3-bromophenyl) amino]-6-[ (4-{N-
[(tert.butyloxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-
2-buten-1-yl)amino]-7-methoxyquinazoline,
4 -[ (3 -bromophenyl ) amino] - 6 - ({4 -[N- ( carboxymethyl ) -N- (2 -
hydroxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-
methoxyquinazoline,
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4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2-oxo-morpholin-
4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-[ (4-{N-[ (ethoxy-
carbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-l-
yl)amino]-7-cyclopropylmethoxyquinazoline,
4-[ (3-chloro-4-fluorophenyl) amino]-6-[ (4-{N-[ (ethoxy-
carbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)amino}-1-oxo-2-
buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline,
4-[ (3-chloro-4-fluorophenyl) amino]-6-{[4- (2, 2-dimethyl-6-
oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (5, 5-dimethyl-2-
oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (5-methyl-2-
oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
(R) -4-[ (3-chloro-4-fluorophenyl) amino]-6-[ (4-{N-[1- (ethoxy-
carbonyl)-ethyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)-
amino]- 7 -cyclopropylmethoxyquinazoline,
(R) -4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (3-methyl-2-
oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline, ,
4- [ (3-chloro-4-fluorophenyl) amino] -6- [ (4- [N- (1, 3-dioxolan-
2-ylmethyl)-N-methylamino]-1-oxo-2-buten-1-yl)amino]-7-cyclo-
propylmethoxy-quinazoline,
4- (3-chloro-4-fluorophenyl) amino] -6- { [4- (3-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-
methoxy-quinazoline and
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4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-
methoxy-quinazoline
are excluded,
the tautomers, the stereoisomers and the salts thereof.
Particularly preferred compounds of the above general formula
I are those wherein,
R. denotes a benzyl or 1-phenylethyl group or a phenyl group
substituted by the groups R1 and R2, where
R1 denotes a fluorine, chlorine or bromine atom, a methyl
or ethynyl group and
R2 denotes a hydrogen or fluorine atom,
Rb denotes an R30-CO-CH2-N-CH2-CH2-OH group substituted at the
methylene groups by 1 or 2 methyl or ethyl groups, where
R3 represents a C1_4-alkyl- group,
a 2-oxo-morpholin-4-yl group which is substituted by 1 or 2
~ 25 methyl or ethyl groups,
Rc denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxyethoxy,
cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy,
cyclobutylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-
yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy
group and
n denotes the number 1 or 2 with the proviso that the
following compounds
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4-[ (3-chloro-4-fluorophenyl) amino] -6-[ (4-{N-[ (ethoxy-
carbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)amino}-1-oxo-2-
buten-l-yl)amino]-7-cyclopropylmethoxyquinazoline,
4-[ (3-chloro-4-fluorophenyl) amino]-6-{[4- (2, 2-dimethyl-6-
oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (5, 5-dimethyl-2-
oxomorpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5-methyl-2-
oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
(R) -4-[(3-chloro-4-fluorophenyl) amino]-6-[ (4-{N-[1- (ethoxy-
carbonyl)-ethyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)-
amino]-7-cyclopropylmethoxyquinazoline,
(R) -4 -[ (3 -chloro-4 -f luorophenyl ) amino]-6 - {[4 - (3 -methyl-2 -
oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxo-
:20 morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
J quinazoline and
4 - [ ( 3 - chloro- 4 - f luorophenyl ) amino] - 6 - { [4 - ( 6 -methyl - 2 -
oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
quinazoline
are excluded,
particularly those wherein
Ra denotes a benzyl or 1-phenylethyl group or a phenyl group
substituted by the groups R1 and R2, where
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R1 denotes a fluorine, chlorine or bromine atom and
R2 denotes a hydrogen or fluorine atom,
Rb denotes a 2-oxo-morpholin-4-yl group which is substituted by
1 or 2 methyl or ethyl groups,
Rc denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxyethoxy,
cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,
tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group and
~ n denotes the number 1, with the proviso that the following
compounds
4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (2, 2-dimethyl-6-
oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (5, 5-dimethyl-2-
oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (5-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclopropylmethoxy-
quinazoline,
(R) -4-[(3-chloro-4-fluorophenyl)amino]-6-{[4- (3-methyl-2-
oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (3-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclopropylmethoxy-
quinazoline and
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
quinazoline
are excluded,
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the tautomers, the stereoisomers and the salts thereof.
Most particularly preferred compounds of the above general
formula I are those wherein
Ra denotes a 1-phenylethyl or a 3-chloro-4-fluorophenyl group,
Rb denotes a 2-oxo-morpholin-4-yl group which is substituted by
1 or 2 methyl groups, or
a 2-oxo-morpholin-4-yl group which is substituted by an ethyl
group,
Rc denotes a hydrogen atom, a methoxy, 2-methoxyethoxy,
cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,
tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group and
n denotes the number 1, with the proviso that the following
compounds
4-[(3-chloro-4-fluorophenyl) amino] -6-{[4- (2, 2-dimethyl-6-
oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[ (3-chloro-4-fluorophenyl) amino]-6-{[4- (5, 5-dimethyl-2-
oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (5-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
quinazoline,
(R) -4 -[ (3 -chloro-4 - f luorophenyl) amino]- 6 - {[4 - (3-methyl-2-
oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-
cyclopropylmethoxyquinazoline,
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4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (3-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
quinazoline and
4-[(3-chloro-4-fluorophenyl) amino]-6-{[4- (6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
quinazoline
are excluded,
the tautomers, the stereoisomers and the salts thereof.
~
The following compounds are mentioned by way of example as
being particularly preferred compounds of general formula I:
4- [ (3-chloro-4-fluorophenyl) amino] -6- [ (4- {N- [ (l, 3-
dioxolan-2-yl)methyl]-N-methyl-amino}-1-oxo-2-buten-l-
yl)amino]-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((S)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclo-
propylmethoxy-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7-cyclo-
propylmethoxy-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (S) -3-methyl-
2-oxo-morpholin-4-yl)-l-oxo-2-buten-1-yl]amino}-7-cyclo-
propylmethoxy-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (5, 5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-(2-methoxy-
ethoxy)-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (S) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclobutyl-
oxy-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6-( [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyl-
oxy-quinazoline,
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4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (5, 5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyl-
oxy-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (5, 5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclo-
pentyloxy-quinazoline,
4- [ (R) - (1-phenyl-ethyl) amino] -6-{ [4- (5, 5-dimethyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (5, 5-dimethyl-
2-oxo-morpholin-4-y1)-1-oxo-2-buten-1-yl]amino}-7=[(R)-
(tetrahydrofuran-3-yl)oxy]-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (S) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahydrofuran-3-yl)oxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahydrofuran-3-yl)oxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-
(tetrahydrofuran-3-yl)oxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
[(tetrahydropyran-4-yl)oxy]-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-
methoxy-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (2, 2-dimethyl-
6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetra-
hydropyran-4-yl)oxy]-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (5, 5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (5, 5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetra-
hydrofuran-2-yl)methoxy]-quinazoline,
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4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (5, 5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetra-
hydrofuran-3-yl)oxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(6-ethyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-
methoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((S)-6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (S) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetra-
hydrofuran-3-yl)oxy]-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (5, 5-dimethyl-
2-oxo-morpholin-4-yl)-i-oxo-2-buten-1-yl]amino}-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,
4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-l-oxo-2-buten-1-yl]amino}-7-[(tetra-
hydropyran-4-yl)oxy]-quinazoline and
4- [ (R) - (1-phenyl-ethyl) amino] -6- { [4- ( (S) -6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,
the tautomers, the stereoisomers and the salts thereof.
The compounds of general formula I may be prepared by the
following methods, for example:
a) reacting a compound of general formula
Ra\ /H
N
NH2
N~
N Rc
CA 02417050 2003-01-22
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wherein
Ra and R,, are as hereinbefore defined, with a compound of
general formula
Z1-CO-CH=CH- (CH2) n-Rb , (III)
wherein
Rb and n are as hereinbefore defined and
Z1 represents a leaving group such as a halogen atom, e.g. a
chlorine or bromine-atom, or a hydroxy group.
The reaction is optionally carried out in a solvent or mixture
of solvents such as methylene chloride, dimethylformamide,
acetonitrile, toluene, chlorobenzene, tetrahydrofuran,
methylene chloride/tetrahydrofuran or dioxan, optionally in
the presence of an inorganic or organic base and optionally in
the presence of a dehydrating agent, expediently at
temperatures between -50 and 150 C, preferably at temperatures
between -20 and 80 C.
With a compound of general formula III wherein Z1 denotes a
leaving group, the reaction is optionally carried out in a
solvent or mixture of solvents such as methylene chloride,
dimethylformamide, acetonitrile, toluene, chlorobenzene,
tetrahydrofuran, methylene chloride/tetrahydrofuran or dioxan
conveniently in the presence of a tertiary organic base such
as triethylamine, pyridine or 2-dimethylaminopyridine, or
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 and 150 C, preferably at
temperatures between -20 and 80 C.
With a compound of general formula III wherein Z. denotes a
hydroxy group, the reaction is preferably carried out in the
presence of a dehydrating agent, e.g. in the presence of
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isobutyl chloroformate, thionyl chloride, trimethyl
chlorosilane, phosphorus trichloride, phosphorus pentoxide,
hexamethyldisilazane, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or
1-hydroxy-benzotriazole 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, dioxan,
toluene, chlorobenzene, dimethylsulphoxide, ethylene glycol
diethylether or sulpholane and optionally in the presence of a
reaction accelerator such as 4-dimethylaminopyridine at
temperatures between -50 and 150 C, but preferably at
temperatures between -20 and 80 C.
b) reacting a compound of general formula
Ra\ /H
N
NH - CO CH = CH - (CH2 ) n - Z2
I~ I
N
Rc , (IV)
optionally formed in the reaction mixture,
wherein
Ra, Rc and n are as hereinbefore defined and
Z2 denotes a leaving group such as a halogen atom or a
substituted sulphonyloxy group such as a chlorine or bromine
atom, a methanesulphonyloxy or p-toluenesulphonyloxy group or
a hydroxy group, with a compound of general formula
H - Rb , (V)
wherein
Rb is as hereinbefore defined.
The reaction is expediently carried out in a solvent such as
isopropanol, acetonitrile, butanol, tetrahydrofuran, dioxan,
CA 02417050 2003-01-22
15 -
toluene, chlorobenzene, dimethylformamide, dimethylsulphoxide,
methylene chloride, ethylene glycol monomethyl ether, ethylene
glycol diethyl ether or sulpholane, or in a mixture of
solvents, optionally in the presence of an inorganic base,
e.g. sodium carbonate or potassium hydroxide, or a tertiary
organic base, e.g. triethylamine or 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 and 150 C, but preferably at
temperatures between -10 and 100 C. The reaction may, however,
~ also be carried out without a solvent or in an excess of the
compound of general formula V used.
If Z. in a compound of general formula IV denotes a hydroxy
group, the reaction is preferably carried out in the presence
of an activating agent, e.g. in the presence of thionyl
chloride or phosphorus trichloride, conveniently in a solvent
such as acetonitrile, methylene chloride, tetrahydrofuran,
dioxan, toluene, chlorobenzene or ethylene glycol diethyl
ether and optionally in the presence of a reaction accelerator
such as sodium iodide at temperatures between -50 and 150 C,
but preferably at temperatures between -20 and 80 C.
~ 25 The compound of formula IV may also be prepared in a one-pot
process from the compound of formula II and a corresponding
carboxylic acid derivative and further reacted directly.
c) cyclising a compound of general formula
Ra\ /H
N
NH - CO - CH = CH - (CHZ ) n - Rb'
N R , (VI)
c
optionally formed in the reaction mixture
CA 02417050 2003-01-22
16 -
wherein
Ra, R. and n are as hereinbefore defined and
Rb' denotes an optionally substituted N-(carboxymethyl)-N-
(2-hydroxyethyl) -amino or N-(C1_4-alkyloxycarbonylmethyl)-N-
(2-hydroxyethyl)-amino group which can be converted by
cyclisation into an optionally substituted 2-oxo-morpholin-
4-yl group.
The reaction is optionally carried out in a solvent or mixture
of solvents such as-methylene chloride, aceton,itrile,
dimethylformamide, dimethylsulphoxide, sulpholane, benzene,
toluene, chlorobenzene, tetrahydrofuran,
benzene/tetrahydrofuran or dioxan, expediently in the presence
of an anhydrous acid such as trifluoroacetic acid,
methanesulphonic acid or sulphuric acid or 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-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or
triphenylphosphine/carbon tetrachloride, at temperatures
between -20 and 200 C, but preferably at temperatures between
-10 and 160 C.
~ 25
If according to the invention a compound of general formula I
is obtained which contains an optionally substituted 2-oxo-
morpholin-4-yl group, this may be converted by hydrolysis into
a corresponding compound which contains an optionally
substituted N-(carboxymethyl)-N-(2-hydroxyethyl)-amino group.
The optional subsequent hydrolysis is carried out, for example,
by hydrolysis in an aqueous solvent, e.g. in water,
isopropanol/water, acetic acid/water, tetrahydrofuran/water or
dioxan/water, in the presence of an acid such as
trifluoroacetic acid, hydrochloric acid or sulphuric acid or in
the presence of an alkali metal base such as sodium hydroxide,
CA 02417050 2003-01-22
- 17 -
at temperatures between 0 and 120 C, preferably at temperatures
between 10 and 100 C.
In the reactions described hereinbefore, any reactive groups
present such as hydroxy, carboxy, phosphono or imino groups may -
be protected during the reaction by conventional protecting
groups which are cleaved again after the reaction.
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,
and
protecting groups for an imino group may be a formyl, acetyl,
trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,
benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl
group.
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
)25 dioxan/water, in the presence of an acid such as
trifluoroacetic acid, hydrochloric acid or sulphuric 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 and 120 C,
preferably at temperatures between 10 and 100 C.
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 and 100 C,
CA 02417050 2003-01-22
18 -
but preferably at ambient temperatures between 20 and 60 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.
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, dioxan,
methanol or diethyl,ether.
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 and
120 C or by treating with sodium hydroxide solution, optionally
in the presence of a solvent such as tetrahydrofuran at
temperatures between 0 and 50 C.
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.
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. Al-
linger N. L. and Eliel E. L. 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
crystallisation, and, if these compounds are obtained in
CA 02417050 2003-01-22
- 19 -
racemic form, they may subsequently be resolved into the
enantiomers as mentioned above.
The enantiomers are preferably separated by column separation
on chiral phases or by recrystallisation 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,
camphorsulphonic 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.
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
~ 25 acids. Acids which may be used for this purpose include for
example hydrochloric acid, hydrobromic acid, sulphuric acid,
methanesulphonic acid, phosphoric acid, fumaric acid, succinic
acid, lactic acid, citric acid, tartaric acid or maleic acid.
The compounds of general formulae II to VI 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 VI I I ) .
As already mentioned hereinbefore, the compounds of general
formula I according to the invention and the physiologically
acceptable salts thereof have valuable pharmacological
CA 02417050 2003-01-22
- 20 -
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 dimerisation or tyrosine kinase
itself. It is also possible that the transmission of signals
to components located further down is blocked.
The biological properties of the new compounds were
investigated as follows:
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. von Ruden, T. et al. in
EMBO J. 7, 2749-2756 (1988) and Pierce, J. H. et al. in
Science 239, 628-631 (1988)).
The starting material used for the F/L-HERc cells was the cell
line FDC-P1, the production of which has been described by
Dexter, T. M. et al. in J. Exp. Med. 152, 1036-1047 (1980).
~ 25 Alternatively, however, other growth-factor-dependent cells
may also be used (cf. for example Pierce, J. H. et al. in
Science 239, 628-631 (1988), Shibuya, H. et al. in Cell 70,
57-67 (1992) and Alexander, W. S. et al. in 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 von Ruden, T. et al.,
EMBO J. 7, 2749-2756 (1988), except that the retroviral vector
LXSN (cf. Miller, A. D. et al. in BioTechniques 7, 980-990
(1989)) was used for the expression of the EGF-R cDNA and the
line GP+E86 (cf. Markowitz, D. et al. in J. Virol. 62, 1120-
1124 (1988)) was used as the packaging cell.
CA 02417050 2003-01-22
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The test was performed as follows:
F/L-HERc cells were cultivated in RPMI/1640 medium
(BioWhittaker), supplemented with 10 % foetal calf serum (FCS,
Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard
antibiotics and 20 ng/ml of human EGF (Promega), at 37 C and
5% CO2. In order to investigate the inhibitory activity of the
compounds according to the invention, 1.5 x 104 cells per well
were cultivated in triplicate in 96-well dishes in the above
medium (200 l), tll'e 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. Karasuyama, H. et al. in Eur. J. Immunol. 18, 97-104
(1988)). The compounds according to the invention were
dissolved in 100% dimethylsulphoxide (DMSO) and added to the
cultures in various dilutions, the maximum DMSO concentration
being 1%. The cultures were incubated for 48 hours at 37 C.
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 96TM 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% (IC50) was derived therefrom. The following results
were obtained:
Compound Inhibition of EGF-dependent
(Example No.) proliferation IC50 [nM]
2 15
2 (1) 9
1(2) 0.02
The compounds of general formula I according to the invention
thus inhibit signal transduction by tyrosine kinases, as
CA 02417050 2003-01-22
- 22 -
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 tumours, particularly tumours of
epithelial and neuroepithelial origin, metastasisation and the
abnormal proliferation of vascular endothelial cells
(neoangiogenesis).
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, al-antitrypsin deficiency, or
coughs, pulmonary emphysema, pulmonary fibrosis and
hyperreactive airways.
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, Crohn's disease, ulcerative
~ 25 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, and
also for treating nasal polyps and polyps of the.
gastrointestinal tract of various origins such as villous or
adenomatous polyps of the large intestine, but also polyps in
familial polyposis coli, in intestinal polyps in Gardner's
syndrome, in polyps throughout the entire gastro-intestinal
tract in Peutz-Jeghers Syndrome, in inflammatory pseudopolyps,
in juvenile polyps, in colitis cystica profunda and in
pneumatosis cystoides intestinales.
CA 02417050 2003-01-22
- 23 -
In addition, the compounds of general formula I and the
physiologically acceptable salts thereof may be used to treat
kidney diseases, particularly in cystic changes as in cystic
kidneys, for treating renal cysts which may be idiopathic in
origin or occur in syndromes such as tubercular sclerosis, in
von Hippel-Lindau syndrome, in nephrophthisis and spongy
kidney and 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 haematopoietic cells, etc.
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
~ 25 as substances with a secretolytic, broncholytic and/or anti-
inflammatory 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, or anti-inflammatory
substances. These combinations may be administered either
simultaneously or sequentially.
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.
CA 02417050 2003-01-22
- 24 -
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.
The following Examples are intended to illustrate the present
invention without restricting it:
CA 02417050 2003-01-22
- 25 -
Preparation of the starting compounds:
Example I
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropyl-
methoxy-quinazoline
36.02 g of 4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropyl-
methoxy-6-nitro-quinazoline are suspended in a mixture of 1080
ml of ethanol, 144 ml of glacial acetic acid and 360 ml of
water and refluxed, during which time the substance goes into
solution. 20.70 g of iron powder are then carefully added in
batches. After 30 minutes the reaction is complete and the
reaction mixture is evaporated to dryness. The residue is
taken up in 1200 ml of methylene chloride/methanol (9:1) and
made alkaline with 33% ammonia solution. The iron slurry is
suction filtered through and washed with 500 ml of methylene
chloride/methanol (9:1). The brown filtrate is filtered
through a silica gel packing, washed with a total of 2000 ml
of methylene chloride/methanol (9:1) and concentrated by
evaporation. The flask residue is suspended with 140 ml of
diethylether, suction filtered and air dried.
Yield: 29.70 g (89 % of theory),
Melting point: 208 C
Mass spectrum (ESI') : m/z = 359, 361 [M+H] +
~ 25
The following compounds are obtained analogously to Example I:
(1) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-(2-methoxy-
ethoxy)-quinazoline
Rf value: 0.48 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI`) : m/z = 363, 365 [M+H] +
(2) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-
cyclobutyloxy-quinazoline
Melting point: 238 C
Mass spectrum (ESI') : m/z = 359, 361 [M+H] +
CA 02417050 2003-01-22
= - 26 -
(3) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopentyl-
oxy-quinazoline
Melting point: 204 C
Mass spectrum (ESI+) : m/z = 373, 375 [M+H]+
(4) 6-Amino-4-[(R)-(l-phenyl-ethyl)amino]-quinazoline
Rf value: 0.12 (silica gel, ethyl acetate)
Mass spectrum (EI): m/z = 264 [M]'
(5) 6-Amino-4- [ (3-c'hloro-4-fluorophenyl) amino] -7- [ (R) - (tetra-
hydrofuran-3-yl)oxy]-quinazoline
Rf value: 0.27 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 375, 377 [M+H] `
(6) 6-Amino-4- [ (3-chloro-4-fluorophenyl) amino] -7- [ (S) - (tetra-
hydrofuran-3-yl)oxy]-quinazoline
Rf value: 0.27 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 373, 375 [M-H] -
(7) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydro-
pyran-4-yl)oxy]-quinazoline
Rf value: 0.41 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 387, 389 [M-H] -
,.~ .
(8) 6-Amino-4- [ (R) - (1-phenyl-ethyl) amino] -7-cyclopropyl-
methoxy-quinazoline
Rf value: 0.54 (silica gel, ethyl acetate)
Mass spectrum (ESI`) : m/z = 335 [M+H] +
(9) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydro-
furan-2-yl)methoxy]-quinazoline
Melting point value: 162-164 C
Mass spectrum (ESI-) : m/z = 387, 389 [M-H] -
(10) 6-Amino-4-[(R)-(l-phenyl-ethyl)amino]-7-methoxy-
quinazoline
CA 02417050 2003-01-22
27 -
Rf value: 0.42 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI') : m/z = 295 [M+H] +
(11) 6-Amino-4-[(3-chloro-4-fluoro-phenyl)amino]-7-
[(tetrahydrofuran-3-yl)methoxy]-quinazoline
Rf value: 0.40 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 387, 389 [M-H]-
(12) 6-Amino-4-[(3-chloro-4-fluoro-phenyl)amino]-7-
[(tetrahydropyran-4-yl)methoxy]-quinazoline
Rf value: 0.41 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 403, 405 [M+H]+
Example II
4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-
6-nitro-guinazoline
29.36 g of cyclopropylmethanol are dissolved in 310 ml of N,N-
dimethylformamide and cooled to about 10 C in an ice bath.
Then 41.58 g potassium tert. butoxide are added in batches,
while the temperature should stay below 15 C. The reaction
mixture is then stirred for another 30 minutes at 10 C, then
31.19 g of 4-[(3-chloro-4-fluorophenyl)amino]-7-fluoro-6-
nitro-quinazoline are added in batches, while again the
temperature should not exceed 15 C. The dark red reaction
mixture is stirred for another hour at 15 C. For working up
the mixture is poured onto 2.5 1 of water and neutralised with
2N hydrochloric acid. The yellowish precipitate formed is
suction filtered, washed with water and dried at 50 C in a
drying cupboard.
Yield: 36.02 g (100 % of theory),
Melting point: 204 C
Mass spectrum (ESI') : m/z = 389, 391 [M+H] +
CA 02417050 2003-01-22
- 28 -
The following compounds are obtained analogously to Example
II:
(1) 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-methoxy-ethoxy)-
6-nitro-quinazoline
Melting point: 208 C
Mass spectrum (ESI+) : m/z = 393, 395 [M+H] +
(2) 4-[(3-chloro-4-,fluorophenyl)amino]-7-cyclobutyloxy-6-
nitro-quinazoline
Melting point: 235 C
Mass spectrum (ESI+) : m/z = 389, 391 [M+H] `
(3) 4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopentyloxy-
6-nitro-quinazoline
Melting point: 230 C
Mass spectrum (ESI') : m/z = 403, 405 [M+H]+
(4) 4- [ (3-chloro-4-fluorophenyl) amino] -6-nitro-7- [ (R) - (tetra-
hydrofuran-3-yl)oxy]-quinazoline
Melting point: 244 C
Mass spectrum (ESI+) : m/z = 405, 407 [M+H] +
(5) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(S)-(tetra-
hydrofuran-3-yl)oxy]-quinazoline
Rf value: 0.45 (silica gel, ethyl acetate)
Mass spectrum (ESI+) : m/z = 405, 407 [M+H] `
(6) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydro-
pyran-4-yl)oxy]-quinazoline
Rf value: 0.41 (silica gel, ethyl acetate)
Mass spectrum (ESI-) : m/z = 417, 419 [M-H] -
(7) 4-[(R)-(1-phenyl-ethyl)amino]-7-cyclopropylmethoxy-
6-nitro-quinazoline
Rf value: 0.24 (silica gel, cyclohexane/ethyl acetate = 1:1)
CA 02417050 2003-01-22
- 29 -
Mass spectrum (ESI-) : m/z = 363 [M-H] -
(8) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetra-
hydrofuran-2-yl)methoxy]-quinazoline
Rf value: 0.47 (silica gel, ethyl acetate)
Mass spectrum (ESI-) : m/z = 417, 419 [M-H] -
(9) 4-[(R)-(1-phenyl-ethyl)amino]-7-methoxy-6-nitro-
quinazoline
(The reaction is c4rried out with sod-ium methoxide in
tetrahydrofuran)
Rf value: 0.17 (silica gel, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (ESI-) : m/z = 323 [M-H] -
(10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-nitro-7-
[(tetrahydrofuran-3-yl)methoxy]-quinazoline
Rf value: 0.41 (silica gel, ethyl acetate)
Mass spectrum (ESI-) : m/z = 417, 419 [M-H]-
(11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-nitro-7-
[(tetrahydropyran-4-yl)methoxy]-quinazoline
(The reaction is carried out with sodium hydride in
~ tetrahydrofuran.)
Rf value: 0.78 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 431, 433 [M-H]-
Example III
tert. butyl (S)-(2-hydroxy-propylamino)-acetate
5.91 ml of tert. butyl bromoacetate are added dropwise within
30 minutes to a mixture of 15.00 g of (S)-(+)-1-amino-2-
propanol and 6.97 ml of diisopropylethylamine in 100 ml of
N,N-dimethylformamide, while cooling with an ice bath. Then
the cooling bath is removed and the reaction mixture is
stirred overnight at ambient temperature. For working up the
CA 02417050 2003-01-22
- 30 -
solvent is distilled off in vacuo, the flask residue is
dissolved in 50 ml water and saturated with 15 g of sodium
chloride. The aqueous phase is extracted several times with
ethyl acetate. The extracts are combined, washed with 20 ml of
saturated sodium chloride solution, dried over magnesium
sulphate and concentrated by evaporation. The oily yellowish
crude product is reacted further without any more
purification.
Yield: 7.80 g (103 0 of theory),
Rf value: 0.42 (silica gel, methylene. chloride/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 190 [M+H] `
The following compounds are obtained analogously to Example
III:
(1) tert. butyl (R)-(2-hydroxy-propylamino)-acetate
Rf value: 0.42 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 190 [M+H] +
(2) tert. butyl (2-hydroxy-1,l-dimethyl-ethylamino)-acetate
R. value: 0.67 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 204 [M+H] +
~ 25
Example IV
4-[(R)-(1-phenyl-ethyl)amino]-6-nitro-quinazoline
A mixture of 6.40 ml of (R)-(1-phenyl-ethyl)amine and 8.70 ml
of diisopropylethylamine in 30 ml methylene chloride is added
dropwise to 9.00 g of 4-chloro-6-nitro-quinazoline in 70 ml
methylene chloride while cooling with an ice bath. The mixture
is allowed to come up to ambient temperature, then it is
stirred for about another 48 hours. For working up the
reaction mixture is washed with water, 10% citric acid and
again with water. The organic phase is dried over magnesium
sulphate and concentrated by evaporation. The solid
CA 02417050 2003-01-22
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evaporation residue is stirred with about 100 ml methanol,
suction filtered and washed with a little methanol.
Yield: 8.44 g (67 0 of theory),
Rf value: 0.33 (silica gel, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (ESI-) : m/z = 293 [M-H] -
The following compound is obtained analogously to Example IV:
(1) 4-[(R)-(l-phenyl-ethyl)amino]-7-fluoro-6-nitro-quinazoline
Rf value: 0.52 (silica gel, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (ESI-) : m/z = 311 [M-H]-
Example V
ethyl (2-hydroxy-2-methyl-propylamino)-acetate
100.00 g of sodium carbonate are added to 50.00 g of glycine
ethyl ester hydrochloride in 100 ml of saturated potassium
carbonate solution while cooling. The resulting mass is
extracted several times with a total of about 600 ml of
diethyl ether. The combined ether extracts are dried over
sodium sulphate and evaporated to dryness. 28.60 g of glycine
ethyl ester are left. This is mixed with 26.00 ml of
isobutylene oxide and 40 ml of absolute ethanol and heated to
90 C for 6 hours in a Roth bomb. After cooling to ambient
temperature the reaction mixture is evaporated to dryness,
leaving a runny oil.
Yield: 45.80 g (73 % of theory),
Mass spectrum (ESI+) : m/z = 176 [M+H]'
The following compound is obtained analogously to Example V:
(1) [N-benzyl-N-(2-hydroxy-butyl)-amino]-acetic acid (by
reacting benzylglycine with 1,2-epoxybutane in 1N sodium
hydroxide solution)
Mass spectrum (ESI-) : m/z = 236 [M-H] -
CA 02417050 2003-01-22
32 -
Example VI
methyl (2-hydroxy-butyl-amino)-acetate hydrochloride
2.85 g of (2-hydroxy-butyl-amino)-acetic acid in 100 ml of
methanol are cooled in an ice-acetone cooling bath, then 7.27
ml of thionyl chloride are added dropwise within 20 minutes.
The reaction mixture is left overnight to come back to ambient
temperature and then evaporated to dryness. Methanol is added
several times to the residue and this is then concentrated by
evaporation. The crude product is reacted further without any
more purification.
Yield: 3.83 g (100 % of theory),
Rf value: 0.85 (Reversed phase ready-made TLC plate (E. Merck),
methanol/5% sodium chloride solution = 6:4)
Mass spectrum (ESI') : m/z = 162 [M+H] +
Example VII
(2-hydroxy-butyl-amino)-acetic acid
4.60 g of [N-benzyl-N-(2-hydroxy-butyl)-amino]-acetic acid are
dissolved in a mixture of methanol and water (7:1) and
hydrogenated in the presence-of palladium (10% on activated
charcoal) as catalyst for about 2.5 hours at ambient
temperature until the calculated amount of hydrogen has been
taken up. For working up the catalyst is filtered off and the
filtrate evaporated down in vacuo, leaving a white solid.
Yield: 2.77 g (97 % of theory),
Rf value: 0.86 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/trifluoroacetic acid = 50:50:1)
Mass spectrum (ESI-) : m/z = 146 [M-H]
Example VIII
Ethyl (2-hydroxy-l,1-dimethyl-ethylamino)-acetate
hydrochloride
63.00 g of tert. butyl(2-hydroxy-1,l-dimethyl-ethylamino)-
acetate are placed in 500 ml of ethanol. Then while cooling
CA 02417050 2003-01-22
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with an ice bath about 200 g of hydrogen chloride are
introduced over a period of about four hours. The reaction
mixture is stirred overnight at ambient temperature. For
working up it is concentrated by evaporation and stirred with
toluene. Then the toluene is distilled off. A viscous oil
remains, which is reacted further without any more
purification.
Rf value: 0.16 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 176 [M+H] +
Preparation of the final compounds:
Example 1
4- [ (3-chloro-4-fluorophenyl) amino] -6- [ (4-{N-
[(tert.butyloxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-l-yl)-
amino}-1-oxo-2-buten-l-yl)amino]-7-cyclopropylmethoxy-
guinazoline
0.67 ml of oxalyl chloride is pipetted into 644 mg of
bromocrotonic acid in 15 ml methylene chloride, then one drop
of N,N-dimethylformamide is added. The reaction mixture is
stirred for about an hour at ambient temperature until the
development of gas has ended and then evaporated to dryness.
~ 25 The crude bromocrotonic acid chloride is taken up in 10 ml of
methylene chloride and while cooling with an ice bath added
dropwise within five minutes to a solution of 1.00 g of 6-
amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-
quinazoline and 2.5 ml of diisopropylethylamine in 30 ml of
tetrahydrofuran. The reaction mixture is stirred for one hour
while cooling with an ice bath, then for two hours at ambient
temperature. 2.64 g of tert. butyl (S)-(2-hydroxy-
propylamino)-acetate, dissolved in 5 ml methylene chloride,
are then added. The reaction mixture is stirred overnight at
ambient temperature and then for a further five hours at 60 C.
For working up it is evaporated to dryness. The flask residue
is taken up in ethyl acetate, washed with 5% citric acid,
CA 02417050 2003-01-22
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water and saturated sodium chloride solution, dried over
magnesium sulphate and concentrated by evaporation. The crude
product is purified by chromatography over a silica gel column
with ethyl acetate as eluant.
Yield: 1.10 g (64 % of theory),
Rf value: 0.54 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 612, 614 [M-H]-
The following compounds are obtained analogously to Example 1:
(1) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tert.butyl-
oxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-l-yl)-amino}-1-oxo-
2-buten-l-yl)amino]-7-cyclopropylmethoxy-quinazoline
Rf value: 0.54 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 612, 614 [M-H]-
(2) 4- [ (3-chloro-4-fluorophenyl)amino] -6- [ (4-{N- [ (1,3-
dioxolan-2-yl)methyl]-N-methyl-amino}-1-oxo-2-buten-l-
yl)amino]-7-cyclopropylmethoxy-quinazoline
Melting point: 121 C
Mass spectrum (EI): m/z = 541, 543 [M]+
(3) 4- [ (3-chloro-4-fluorophenyl)amino] -6- [ (4-{N- [ (S) -1-
(ethoxycarbonyl)-ethyl]-N-(2-hydroxy-ethyl)-amino}-1-oxo-2-
buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline
(The starting material ethyl (S)-2-(2-hydroxy-ethylamino)-
propionate is obtained by reacting ethyl (R)-2-
(trifluoromethylsulphonyloxy)-propionate with 2-amino-ethanol
in methylene chloride)
Mass spectrum (EI): m/z = 585, 587 [M]+
(4) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-(2-methoxy-
ethoxy)-quinazoline
CA 02417050 2003-01-22
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(Ethyl (2-hydroxy-1,1-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.40 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 558, 560 [M+H]'
(5) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tert.butyl-
oxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-1-yl)-amino}-1-oxo-
2-buten-1-yl)amino]-7-cyclobutyloxy-quinazoline
Rf value: 0.52 (sil,ica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 612, 614 [M-H]-
(6) 4- [ (3-chloro-4-fluorophenyl) amino] -6- [ (4-{N- [ (tert.butyl-
oxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-i-oxo-
2-buten-1-yl)amino]-7-cyclobutyloxy-quinazoline
Rf value: 0.52 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 612, 614 [M-H]-
(7) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-
2-oxo-morpholin-4-yl)-i-oxo-2-buten-l-yl]amino}-7-cyclo-
butyloxy-quinazoline
(Ethyl (2-hydroxy-l,1-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.42 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI') : m/z = 554, 556 [M+H] +
(8) 4- [ (3-chloro-4-fluorophenyl)amino] -6-{ [4- (5,5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclo-
pentyloxy-quinazoline
(Ethyl (2-hydroxy-1,l-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.42 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI') : m/z = 568, 570 [M+H]'
CA 02417050 2003-01-22
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(9) 4- [ (R) - (1-phenyl-ethyl) amino] -6-{ [4- (5, 5-dimethyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(Ethyl (2-hydroxy-l,1-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.48 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 485 [M-H] -
(10) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(R)-
(tetrahydrofuran-3-yl)oxy]-quinazoline
~ (Ethyl (2-hydroxy-l,1-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.36 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 568, 570 [M-H] -
(11) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tert.butyl-
oxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-1-yl)-amino}-1-oxo-
2-buten-1-yl) amino] -7- [ (S) - (tetrahydrofuran-3-yl) oxy] -
quinazoline
Rf value: 0.44 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 628, 630 [M-H]
~
(12) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tert.butyl-
oxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-1-oxo-
2-buten-l-yl) amino] -7- [ (S) - (tetrahydrofuran-3-yl) oxy] -
quinazoline
Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 628, 630 [M-H] -
(13) 4- [ (3-chloro-4-fluorophenyl) amino] -6- [ (4-{N- [ (tert.butyl-
oxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-1-oxo-
2-buten-1-yl) amino] -7- [ (R) - (tetrahydrofuran-3-yl) oxy] -
quinazoline
Rf value: 0.40 (silica gel, methylene chloride/methanol = 95:5)
CA 02417050 2003-01-22
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Mass spectrum (ESI-) : m/z = 628, 630 [M-H]
(14) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetra-
hydropyran-4-yl)oxy]-quinazoline
(Ethyl (2-hydroxy-1,1-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.54 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 582, 584 [M-H] (15) 4- [ (R) - (1-phenyl-ethyl)
amino] -6- { [4- (5, 5-dimethyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-
methoxy-quinazoline
(Ethyl (2-hydroxy-1,1-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.31 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 528 [M-H]-
(16) 4- [ (3-chloro-4-fluorophenyl) amino] -6- [ (4- {N-
[(ethoxycarbonyl)methyl]-N-(2-hydroxy-2-methyl-prop-1-yl)-
amino}-1-oxo-2-buten-1-yl)amino]-7-[(tetrahydropyran-4-
yl)oxy]-quinazoline
~ 25 Rf value: 0.28 (silica gel, methylene chloride/methanol = 95:5)
(17) 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- (5, 5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline
(Ethyl (2-hydroxy-1,1-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.30 (silica gel, methylene chloride/methanol = 15:1)
Mass spectrum (ESI+) : m/z = 514, 516 [M+H]+
CA 02417050 2003-01-22
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(18) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-
2-oxo-morpholin-4-yl)-l-oxo-2-buten-1-yl]amino}-7-[(tetra-
hydrofuran-2-yl)methoxy]-quinazoline
(Ethyl (2-hydroxy-l,l-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.32 (silica gel, methylene chloride/methanol = 15:1)
Mass spectrum (EI ) : m/z = 583, 585 [M] +
(19) 4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (5, 5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(S)-
(tetrahydrofuran-3-yl)oxy]-quinazoline
(Ethyl (2-hydroxy-1,1-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.32 (silica gel, methylene chloride/methanol = 15:1)
Mass spectrum (ESI-) : m/z = 568, 570 [M-H] -
(20) 4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- (6-ethyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-
methoxy-quinazoline
(A mixture of cyclised and open-ring product is obtained which
is converted into the cyclised product by subsequent treatment
with methanesulphonic acid)
Rf value: 0.65 (silica gel, methylene chloride/methanol = 15:1)
Mass spectrum (ESI-) : m/z = 552, 554 [M-H] -
(21) 4- [ (R) - (1-phenyl-ethyl) amino] -6- [ (4- {N- [ (tert.butyloxy-
carbonyl)methyl]-N-((S)-2-hydroxy-prop-1-yl)-amino}-i-oxo-
2-buten-1-yl)amino]-7-methoxy-quinazoline
Rf value: 0.54 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI") : m/z = 548 [M-H] -
(22) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tert.butyl-
oxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-l-yl)-amino}-1-oxo-
CA 02417050 2003-01-22
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2-buten-l-yl) amino] -7- [ (R) - (tetrahydrofuran-3-yl) oxy] -
quinazoline
Rf value: 0.44 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 628, 630 [M-H] -
(23) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(Ethyl (2-hydroxy-1,1-dimethyl-ethylamino)-acetate
hydrochloride is used as starting material. The cyclised
product is obtained)
Rf value: 0.25 (silica gel, methylene chloride/methanol = 15:1)
Mass spectrum (ESI-) : m/z = 482, 484 [M-H] -
(24) 4- [ (3-chloro-4-fluorophenyl) amino] -6- [ (4- {N- [ (tert.butyl-
oxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-l-yl)-amino}-i-oxo-
2-buten-1-yl)amino]-quinazoline
Rf value: 0.29 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 542, 544 [M-H] -
(25) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tert.butyl-
oxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-l-yl)-amino}-1-oxo-
2-buten-l-yl)amino]-7-[(tetrahydropyran-4-yl)oxy]-quinazoline
Rf value: 0.29 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 642, 644 [M-H] -
(26) 4- [ (R) - (1-phenyl-ethyl) amino] 6- [ (4- {N- [ (tert.butyl-
oxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-l-yl)-amino}-1-oxo-
2-buten-1-yl)amino]-quinazoline
Rf value: 0.61 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 518 [M-H] -
(27) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-[(tert.-
butyloxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-1-
oxo-2-buten-l-yl)amino]-7-cyclopentyloxy-quinazoline
Rf value: 0.53 (silica gel, ethyl acetate)
Mass spectrum (ESI-) : m/z = 626 [M-H]-
CA 02417050 2003-01-22
- 40 -
(28) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-[(tert.-
butyloxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-1-
oxo-2-buten-1-yl)amino]-7-methoxy-quinazoline
Rf value: 0.42 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 574, 576 [M+H]+
(29) 4-[(R)-(1-Phenyl-ethyl)amino]-6-[(4-{N-[(tert.-
butyloxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-1-
oxo-2-buten-1-yl)amino]-quinazoline
~ Rf value: 0.60 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 520 [M+H] +
(30) 4-[(R)-(1-Phenyl-ethyl)amino]-6-[(4-{N-[(tert.-
butyloxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-1-
oxo-2-buten-1-yl)amino]-7-methoxy-quinazoline
Rf value: 0.54 (siica gel, ethyl cetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 548 [M-H]-
(31) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-[(tert.-
butyloxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-1-
oxo-2-buten-1-yl)amino]-7-[(tetrahydrofuran-3-yl)methoxy]-
quinazoline
Rf value: 0.41 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 644, 646 [M+H]+
(32) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(2,2-dimethyl-
6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
[(tetrahydrofuran-3-yl)methoxy]-quinazoline
(Ethyl (2-hydroxy-2-methyl-propylamino)-acetate is used as the
starting material. The reaction yields the already cyclised
product.)
Rf value: 0.28 (silica gel, ethyl acetate/methanol = 9:1)
CA 02417050 2003-01-22
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Mass spectrum (ESI+) : m/z = 584, 586 [M+H]+
(33) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(5,5-dimethyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
[(tetrahydrofuran-3-yl)methoxy]-quinazoline
(Ethyl (2-Hydroxy-1,1-dimethyl-ethylamino)-acetate is used as
the starting material. The reaction yields the already
cyclised product.)
Rf value: 0.26 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (EI): m/z = 583, 585 [M]+
~
(34) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-[(tert.-
butyloxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-1-
oxo-2-buten-l-yl)amino]-7-[(tetrahydropyran-4-yl)methoxy]-
quinazoline
Rf value: 0.52 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 656, 658 [M-H]-
(35) 4-Benzylamino-6-[(4-{N-((tert.-butyloxycarbonyl)methyl]-
N-((R)-2-hydroxy-prop-l-yl)-amino}-1-oxo-2-buten-l-yl)amino]-
7-cyclopropylmethoxy-quinazoline
~ (The preparation of the starting material has already been
described elsewhere: WO 0051991 Al)
Rf value: 0.50 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 576 [M+H]+
(36) 4-[(3-chloro-4-fluoro-phenyl)amino]- 6-[(4-{N-[(tert.-
butyloxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-l-yl)-amino}-1-
oxo-2-buten-l-yl)amino]-7-[(tetrahydropyran-4-yl)methoxy]-
quinazoline
Rfvalue: 0.49 (aluminium oxide, ethyl acetate)
Mass spectrum (ESI+) : m/z = 658, 660 [M+H]+
CA 02417050 2003-01-22
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Example 2
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((S)-6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-
methoxy-guinazoline
A mixture of 700 mg of 4-[(3-chloro-4-fluorophenyl)amino]-
6-[(4-{N-[(tert.butyloxycarbonyl)methyl]-N-((S)-2-hydroxy-
prop-l-yl)-amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropyl-
methoxy-quinazoline and 228 mg of p-toluenesulphonic acid-
hydrate in 20 ml of' acetonitrile is refluxed for five hours.
Then a further 200 mg of p-toluenesulphonic acid-hydrate are
added and the mixture is refluxed for a further five hours.
For working up the reaction mixture is evaporated to dryness.
The flask residue is divided between ethyl acetate and
saturated sodium carbonate solution. The organic phase is
separated off, washed with saturated sodium carbonate
solution, water and saturated sodium chloride solution, dried
over magnesium sulphate and concentrated by evaporation. The
oily residue is crystallised by stirring with 15 ml of diethyl
ether.
Melting point: 173-175 C
Mass spectrum (ESI') : m/z = 540, 542 [M+H]'
The following compounds are obtained analogously to Example 2:
(1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7-cyclo-
propylmethoxy-quinazoline
Rf value: 0.54 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 540, 542 [M+H]+
(2) 4- [ (3-chloro-4-fluorophenyl)amino] -6-{ [4- ( (S) -3-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclo-
propylmethoxy-quinazoline
(The reaction is carried out with methanesulphonic acid in
acetonitrile)
CA 02417050 2003-01-22
= - 43 -
Melting point: 182 C
Mass spectrum (ESI+) : m/z = 540, 542 [M+H] `
(3) 4- [ (3-chloro-4-fluorophenyl)amino] -6-{ [4- ( (S) -6-methyl-
2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7-cyclo-
butyloxy-quinazoline
(The reaction is carried out with methanesulphonic acid in
acetonitrile)
Rf value: 0.54 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI'') : m/z =. 540, 542 [M+H] +
(4) 4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclo-
butyloxy-quinazoline
(The reaction is carried out with methanesulphonic acid in
acetonitrile)
Rf value: 0.54 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 540, 542 [M+H]'
(5) 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (S) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(S)-
(tetrahydrofuran-3-yl)oxy]-quinazoline
(The reaction is carried out with methanesulphonic acid in
acetonitrile)
Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (EI): m/z = 555, 557 [M]'
(6) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(S)-
(tetrahydrofuran-3-yl)oxy]-quinazoline
(The reaction is carried out with methanesulphonic acid in
acetonitrile)
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 556, 558 [M+H] +
CA 02417050 2003-01-22
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(7) 4- [ (3-chloro-4-fluorophenyl)amino] -6-{ [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-
(tetrahydrofuran-3-yl)oxy]-quinazoline
(The reaction is carried out with methanesulphonic acid in
acetonitrile)
Melting point: 230 C
Mass spectrum (EI): m/z = 555, 557 [M]'
(8) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2,2-dimethyl-
6-oxo-morpholin-4-~il)-i-oxo=2-buten-l-yl]amino}-7-[(tetra-
hydropyran-4-yl)oxy]-quinazoline
~ (The reaction is carried out with methanesulphonic acid in
acetonitrile)
Rf value: 0.33 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI") : m/z = 582, 584 [M-H] -
(9) 4- [ (R) - (l-phenyl-ethyl) amino] -6-{ [4- ( (S) -6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-methoxy-
quinazoline
(The reaction is carried out with methanesulphonic acid in
acetonitrile)
Rf value: 0.52 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 474 [M-H]
(10) 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (S) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(R)-(tetra-
hydrofuran-3-yl)oxy]-quinazoline
(The reaction is carried out with methanesulphonic acid in
acetonitrile)
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 554, 556 [M-H] -
(11) 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(The reaction is carried out with trifluoroacetic acid in
acetonitrile).
CA 02417050 2003-01-22
= - 45 -
Rf value: 0.34 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 470, 472 [M+H]+
(12) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetra-
hydropyran-4-yl)oxy]-quinazoline
(The reaction is carried out with trifluoroacetic acid in
acetonitrile)
Rf value: 0.38 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI'+) : m/z .= 570, 572 [M+H]'
(13) 4- [ (R) - (1-phenyl-ethyl)amino] -6-{ [4- ( (S) -6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(The reaction is carried out with trifluoroacetic acid in
acetonitrile)
Rt value: 0.50 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 444 [M-H] -
(14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopentyloxy-quinazoline
Rf value: 0.38 (silica gel, ethyl acetate)
Mass spectrum (ESI+) : m/z = 554, 556 [M+H]+
-~
(15) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-methoxy-
quinazoline
Rf value: 0.13 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 500, 502 [M+H]+
(16) 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-quinazoline
Rf value: 0.34 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 446 [M+H]+
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46 -
(17) 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline
Rf value: 0.48 (silica gel, ethyl acetate/methanol = 4:1)
Mass spectrum (ESI+): m/z = 476 [M+H]+
(18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-ylJamino}-7-
[(tetrahydrofuran-3-yl)methoxy]-quinazoline
Rf value: 0.48 (silica gel, ethy acetate/methanol = 4:1)
Mass spectrum (ESI-) : m/z = 568, 570 [M-H]
(19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
[(tetrahydropyran-4-yl)methoxy]-quinazoline
melting point: 196 C
Mass spectrum (ESI+): m/z = 584, 586 [M+H]+
(20) 4-Benzylamino-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-
1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline
~ Rf value: 0.41 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+): m/z = 502 [M+H]+
(21) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((S)=6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
[(tetrahydropyran-4-yl)methoxy]-quinazoline
melting point: 196-199 C
Mass spectrum (ESI+) : m/z = 584, 586 [M+H]+
CA 02417050 2003-01-22
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Example 3
4- [ (3-chloro-4-fluorophenyl) amino] -6- ( {4- [N- (carboxymethyl) -
N-((R)-2-hydroxy-prop-1-yl)-amino]-1-oxo-2-buten-l-yl}amino)-
7-cyclopropylmethoxy-ctuinazoline
100 mg of 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (R) -6-
methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxy-quinazoline are mixed with 1.63 ml of water
and 0.37 ml of iN hydrochloric acid. The reaction mixture is
stirred for three laours at 60 C and then left to stand
overnight at ambient temperature. For working up 0.37 ml 1N
~ sodium hydroxide solution are added and the mixture is cooled
in an ice bath, whereupon a light-coloured precipitate is
deposited. This is suction filtered, washed with cold water
and dried.
Yield: 60 mg (58 g of theory),
Mass spectrum (ESI-) : m/z = 556, 558 [M-H] -
The folowing compounds are obtained analogously to Example 3:
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-({4-[N-
(carboxymethyl)-N-(2-hydroxy-2-methyl-prop-l-yl)-amino]-1-oxo-
2-buten-l-yl}amino)-7-cyclopropylmethoxy-quinazoline
} (The preparation of the starting material has already been
described elsewhere: WO 0051991 Al)
Rf value: 0.62 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/trifluoroacetic acid = 50:50:1)
Mass spectrum (ESI-) : m/z = 570, 572 [M-H]-
(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-({4-[N-
(carboxymethyl)-N-(1,1-dimethyl-2-hydroxy-ethyl)-amino]-1-oxo-
2-buten-l-yl}amino)-7-cyclopropylmethoxy-quinazoline
(The preparation of the starting material has already been
described elsewhere: WO 0051991 Al)
CA 02417050 2003-01-22
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melting point: 163-166 C
Mass spectrum (ESI-) : m/z = 570, 572 [M-H]-
Example 4
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-
[(methoxycarbonyl)methyl]-N-((R)-2-hydroxy-prop-1-yl)-amino}-
1-oxo-2-buten-l-yl)amino]-7-cyclopropylmethoxy-
quinazoline
Obtained by treating a methanolic solution of 4-[(3-chloro-4-
fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
yl)-1-oxo-2-buten-l-yl]amino}-7-cyclopropylmethoxy-quinazoline
with ethereal hydrochloric acid at room temperature.
Rf value: 0.37 (silica gel, methylene chloride/methanol = 20:1)
Mass spectrum (ESI ): m/z = 570, 572 [M-H]
The following compounds may also be obtained analogously to
the above Examples and other methods known from the
literature:
(1) 4- [ (3-bromo-phenyl) amino] -6-{ [4- ( (S) -3-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-quinazoline
(2) 4- [ (3-bromo-phenyl) amino] -6-{ [4- ( (R) -6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-quinazoline
(3) 4-[(3-bromo-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(4) 4-[(3-methyl-phenyl)amino]-6-{[4-((S)-3-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-quinazoline
(5) 4- [ (3-methyl-phenyl) amino] -6-{ [4- ( (R) -6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
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(6) 4- [ (3-methyl-phenyl) amino] -6-{ [4- (5, 5-dimethyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(7) 4-[(3-ethynyl-phenyl)amino]-6-{[4-((S)-3-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(8) 4- [ (3-ethynyl-phenyl)amino] -6-{ [4- ( (R) -6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(9) 4- [ (3-ethynyl-phenyl) amino] -6-{ [4- (5, 5-dimethyl-2-oxo-
~ morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(10) 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (S) -3-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(11) 4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (S) -3-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline
(12) 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (S) -3-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-(2-methoxy-
ethoxy)-quinazoline
~
(13) 4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (S) -3-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-
(tetrahydrofuran-3-yl)oxy]-quinazoline
(14) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((S)-3-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahydrofuran-3-yl)oxy]-quinazoline
(15) 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (S) -3-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-[(R)-
(tetrahydrofuran-2-yl)methoxy]-quinazoline
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(16) 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (S) -3-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahydrofuran-2-yl)methoxy]-quinazoline
(17) 4- [ (3-chloro-4-fluorophenyl)amino] -6-{ [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
[(tetrahydrofuran-3-yl)methoxy]-quinazoline
(18) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetra-
hydropyran-4-yl)methoxy]-quinazoline
(19) 4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetra-
hydropyran-2-yl)methoxy]-quinazoline
(20) 4- [ (3-trifluoromethyl-phenyl) amino] -6-{ [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline
(21) 4- [ (3-cyano-phenyl)amino] -6-{ [4- ( (R) -6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline
(22) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(23) 4- [ (3-chloro-4-fluorophenyl)amino] -6-{ [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline
(24) 4- [ (3-chloro-4-fluorophenyl)amino] -6-{ [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-(2-methoxy-
ethoxy)-quinazoline
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(25) 4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetra-
hydropyran-4-yl)oxy]-quinazoline
(26) 4- [ (3-chloro-4-fluorophenyl) amino] -6- { [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetra-
hydrofuran-2-yl)methoxy]-quinazoline
(27) 4- [ (3-chloro-4-flizorophenyl) amino] -6- { [4- ( (R) -6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahydrofuran-2-yl)methoxy]-quinazoline
(28) 4- [ (R) - (1-phenyl-ethyl) amino] -6-{ [4- ( (R) -6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(29) 4- [ (R) - (1-phenyl-ethyl)amino] -6-{ [4- ( (S) -3-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline
(30) 4- [ (R) - (1-phenyl-ethyl) amino] -6-{ [4- ( (S) -3-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline
~(31) 4- [ (R) - (1-phenyl-ethyl) amino] -6-{ [4- ( (R) -6-methyl-2-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-
quinazoline
(32) 4- [ (3-chloro-4-fluorophenyl) amino] -6-{ [4- ( (S) -3-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-
quinazoline
(33) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-
2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-
quinazoline
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Example 5
Coated tablets containing 75 mg of active substance
1 tablet core contains:
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 mcT
230.0 mg
Preparation:
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 6
Tablets containing 100 mg of active substance
Composition:
1 tablet contains:
active substance 100.0 mg
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53 -
lactose 80.0 mg
corn starch 34.0 mg
polyvinylpyrrolidone 4.0 mg
magnesium stearate 2.0 mg
220.0 mg
Method of Preparation:
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 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 7
Tablets containing 150 mct of active substance
Composition:
~ 25 1 tablet contains:
active substance '150.0 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:
The active substance mixed with lactose, corn starch and silica
is moistened with a 2011 aqueous polyvinylpyrrolidone solution
CA 02417050 2003-01-22
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and passed through a screen with a mesh size of 1.5 mm. The
granules, dried at 45 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 8
Hard aelatine capsules containing 150 mg of active substance
~ 1 capsule contains:
active substance 450.0 mg
corn starch (dried) approx. 80.0 mg
lactose (powdered) approx. 87.0 mg
magnesium stearate 3.0 ma
approx. 420.0 mg
Preparation:
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.
~ 25 Capsule filling: approx. 320 mg
Capsule shell: size 1 hard gelatine capsule.
Example 9
Suppositories containing 150 mg of active substance
1 suppository contains:
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
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55 -
Preparation:
After the suppository mass has been melted the active substance
is homogeneously distributed therein and the melt is poured
into chilled moulds.
Example 10
Suspension containi,ng 50 mg of active substance
100 ml of suspension contain:
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
70o sorbitol solution 20.00 g
flavouring 0.30 g
dist. water ad 100 ml
Preparation:
~ 25 The distilled water is heated to 70 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
flavouring have been added and dissolved, the suspension is
evacuated with stirring to eliminate air.
5 ml of suspension contain 50 mg of active substance.
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Example 11
Ampoules containincr 10 mg active substance
Composition:
active substance 10.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml
Preparation=
The active substance is dissolved in the necessary amount of
0.01 N HC1, made isotonic with common salt, filtered sterile
and transferred into 2 ml ampoules.
Example 12
Ampoules containing 50 mg of active substance
Composition:
active substance 50.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml
~ 25
Preparation=
The active substance is dissolved in the necessary amount of
0.01 N HC1, made isotonic with common salt, filtered sterile
and transferred into 10 ml ampoules.
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Example 13
Capsules for powder inhalation containing 5 mg of active
substance
1 capsule contains:
active substance 5.0 mg
lactose for inhalation 15.0 mg
20.0 mg
Preparation: 0
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 14
Solution for inhalation for hand-held nebulisers containincr
2.5 mg active substance
1 spray contains:
active substance 2.500 mg
J 25 benzalkonium chloride 0.001 mg
1N hydrochloric acid q.s.
ethanol/water (50/50) ad 15.000 mg
Preparation:
The active substance and benzalkonium chloride are dissolved
in ethanol/water (50/50). The pH of the solution is adjusted
with iN hydrochloric acid. The resulting solution is filtered
and transferred into suitable containers for use in hand-held
nebulisers (cartridges).
Contents of the container: 4.5 g
