BICYCLIC HETEROCYCLES, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS, THEIR USE AND PROCESSES FOR THE PREPARATION THEREOF

HETEROCYCLES BICYCLIQUES, MEDICAMENTS CONTENANT CES COMPOSES, LEUR UTILISATION ET LEUR PROCEDE DE PRODUCTION

English Abstract

The present invention relates to bicyclic heterocycles of general formula
(see formula I)
wherein
R a is H or alkyl; R b is optionally substituted phenyl, benzyl or phenethyl;
R c is H,
halo, -OH, optionally substituted alkoxy, etc.; A is imino or alkylimino; B is
carbonyl
or sulphonyl; C' is optionally substituted alkenylene; D is alkylene; E is an
optionally substituted heterocylic group wherein two hydrogen atoms or carbon
atoms of the cyclic skeleton are replaced with an alkylene bridge; and X is
substituted methyne, the tautomers, the stereoisomers, the mixtures and the
salts
thereof, particularly the physiologically acceptable salts thereof with
inorganic or
organic acids 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, as well as
benign
prostatic hyperplasia (BPH), diseases of the lungs and respiratory tract, and
the
preparation thereof.

French Abstract

La présente invention concerne des hétérocycles bicycliques de la formule générale (I), où R?a¿, R?b¿, R?c¿, A, B, C, D, E et X ont la définition donnée dans la revendication 1, leurs tautomères, leurs stéréo-isomères, leurs mélanges et leurs sels, notamment leurs sels physiologiquement compatibles avec des acides inorganiques ou organiques ayant de précieuses caractéristiques pharmacologiques, notamment une action inhibitrice sur la transduction de signaux transmise par la tyrosine-kinase. L'invention concerne également leur utilisation pour le traitement de maladies, notamment de maladies tumorales et de l'hypertrophie de la prostate (BPH), de maladies des poumons et des voies respiratoires, ainsi que leur production.

Claims

42
CLAIMS:
1. A compound, which is a bicyclic heterocycle of general formula
<IMG>
a tautomer thereof, a stereoisomer thereof, a mixture of stereoisomers thereof
or a
salt thereof,
wherein
R a denotes a hydrogen atom or a C1-4-alkyl group,
R b denotes a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl
nucleus is
substituted in each case by the groups R1 to R3, wherein
R1 and R2 independently denote hydrogen, fluorine, chlorine,
bromine, iodine,
C1-4-alkyl, hydroxy, C1-4-alkoxy, C2-3-alkenyl, C2-3-alkynyl,
aryl, aryloxy, arylmethyl, arylmethoxy,
heteroaryl, heteroaryloxy, heteroarylmethyl, heteroarylmethoxy,
methyl or methoxy substituted by 1 to 3 fluorine atoms,
cyano, nitro or amino; and
R3 denotes hydrogen, fluorine, chlorine, bromine,
methyl or trifluoromethyl;
R c denotes hydrogen, fluorine, chlorine, bromine,
hydroxy, C1-4-alkyloxy,

43
methoxy substituted by 1 to 3 fluorine atoms,
ethyloxy substituted by 1 to 5 fluorine atoms,
C2-4-alkyloxy substituted by R4, wherein
R4 denotes hydroxy, C1-3-alkyloxy, C3-6-cycloalkyloxy, C3-6-cycloalkyl-
C1-3-alkyloxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, bis-(2-
C1-3-alkyloxy-ethyl)-amino, bis-(3-C1-3-alkyloxy-propyl)-amino,
pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl,
homomorpholin-4-yl, piperazin-1-yl, 4-(C1-3-alkyl)-piperazin-1-yl,
homopiperazin-1-yl or 4-(C1-3-alkyl)-homopiperazin-1-yl,
C2-4-alkyloxy substituted by E,
C3-7-cycloalkyloxy, C3-7-cycloalkyl-C1-4-alkyloxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,
tetrahydrofuranyl-C1-4-alkyloxy, tetrahydropyranyl-C1-4-alkyloxy,
pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy,
1-(C1-3-alkyl)-pyrrolidin-3-yloxy, 1-(C1-3-alkyl)-piperidin-3-yloxy, 1-(C1-3-
alkyl)-
piperidin-4-yloxy,
C1-4-alkoxy substituted by pyrrolidinyl, piperidinyl or homopiperidinyl
substituted in
the 1 position by the group R5, wherein
R5 denotes hydrogen or C1-3-alkyl,
or C1-4-alkoxy substituted by morpholinyl or homomorpholinyl substituted in
the 4
position by the group R5, wherein R5 is as hereinbefore defined;
A denotes imino or C1-4-alkylimino;
B denotes carbonyl or sulphonyl;
C' denotes 1,3-allenylene, 1,1-vinylene or 1,2-vinylene optionally substituted
in
each case by one or two methyl groups or by a trifluoromethyl group,

44
ethynylene or
1,3-butadien-1,4-ylene optionally substituted by one or two methyl groups or
by a
trifluoromethyl group;
D denotes a straight-chain or branched C1-4-alkylene group;
E denotes a pyrrolidin-1-yl group wherein two hydrogen atoms on the carbon
skeleton are replaced by a straight-chain alkylene bridge, wherein the bridge
comprises 2 to 6 carbon atoms if the two hydrogen atoms are located on the
same
carbon atom, 1 to 5 carbon atoms if the two hydrogen atoms are located on
adjacent carbon atoms, or 2 to 4 carbon atoms if the two hydrogen atoms are
located on carbon atoms which are separated by one atom, wherein the
pyrrolidin-
1-yl group is optionally additionally substituted by one or two C1-3-alkyl
groups,
a piperidin-1-yl or homopiperidin-1-yl group, wherein in each case two
hydrogen
atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge,
wherein the bridge comprises 2 to 6 carbon atoms if the two hydrogen atoms are
located on the same carbon atom, 1 to 5 carbon atoms if the two hydrogen atoms
are located on adjacent carbon atoms, 1 to 4 carbon atoms if the two hydrogen
atoms are located on carbon atoms which are separated by one atom, or 1 to 3
carbon atoms if the two hydrogen atoms are located on carbon atoms which are
separated by two atoms, wherein the piperidin-1-yl and homopiperidin-1-yl
groups
are each optionally additionally substituted by one or two C1-3-alkyl groups,
a piperazin-1-yl or homopiperazin-1-yl group, wherein in each case two
hydrogen
atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge,
wherein the bridge comprises 2 to 6 carbon atoms if the two hydrogen atoms are
located on the same carbon atom, 1 to 5 carbon atoms if the two hydrogen atoms
are located on adjacent carbon atoms, 1 to 4 carbon atoms if the two hydrogen
atoms are located on carbon atoms which are separated by one atom, or 1 to 3
carbon atoms if the two hydrogen atoms are located on carbon atoms which are
separated by two atoms, wherein the piperazin-1-yl and homopiperazin-1-yl
groups are each optionally additionally substituted by one or two C1-3-alkyl
groups,
or

45
a morpholin-4-yl or homomorpholin-4-yl group, wherein in each case two
hydrogen atoms on the carbon skeleton are replaced by a straight-chain
alkylene
bridge, wherein the bridge comprises 2 to 6 carbon atoms if the two hydrogen
atoms are located on the same carbon atom, 1 to 5 carbon atoms if the two
hydrogen atoms are located on adjacent carbon atoms, 1 to 4 carbon atoms if
the
two hydrogen atoms are located on carbon atoms which are separated by one
atom, or 1 to 3 carbon atoms if the two hydrogen atoms are located on carbon
atoms which are separated by two atoms, wherein the morpholin-4-yl and
homomorpholin-4-yl groups are each optionally additionally substituted by one
or
two C1-3-alkyl groups;
and
X denotes methyne substituted by cyano or nitrogen;
wherein the aryl groups mentioned in the definitions of the above groups are
in
each case phenyl which is mono- or independently disubstituted by R6, wherein
R6 denotes hydrogen, fluorine, chlorine, bromine, iodine C1-3-alkyl,
hydroxy, C1-3-alkyloxy, difluoromethyl, trifluoromethyl,
difluoromethoxy, trifluoromethoxy or cyano,
and wherein the heteroaryl groups mentioned in the definitions of the above
groups are independently pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, mono-
or
independently disubstituted by R6; and
unless otherwise stated, the abovementioned alkyl groups are straight-chained
or
branched.
2. A compound according to claim 1, wherein
R a denotes hydrogen;
R b denotes phenyl substituted by the groups R1 to R3, wherein
R1 denotes hydrogen, fluorine, chlorine, bromine,
methyl, trifluoromethyl, ethynyl,

46
phenyloxy or phenylmethoxy, wherein the phenyl moiety thereof is
optionally substituted by fluorine or chlorine,
pyridinyloxy or pyridinylmethoxy, wherein the pyridinyl moiety thereof
is optionally substituted by methyl or trifluoromethyl;
R2 denotes hydrogen, fluorine or chlorine and
R3 denotes hydrogen;
R c denotes hydrogen, C1-3-alkyloxy, C4-6-cycloalkyloxy, C3-6-cycloalkyl-C1-2-
alkyloxy-group, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-
4-yloxy, tetrahydrofuranyl-C1-2-alkyloxy, tetrahydropyranyl-C1-2-alkyloxy,
ethyloxy substituted in the 2 position by R4, wherein
R4 denotes hydroxy, C1-3-alkyloxy, amino, C1-3-alkylamino, di-
(C1-3-alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl,
piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-
yl, piperazin-1-yl, 4-(C1-3-alkyl)-piperazin-1-yl, homopiperazin-1-yl,
or 4-(C1-3-alkyl)-homopiperazin-1-yl,
propyloxy substituted in the 3 position by R4, or
butyloxy substituted in the 4 position by R4;
A denotes imino;
B denotes carbonyl or sulphonyl;
C' denotes 1,1-vinylene, 1,2-vinylene or ethynylene;
D denotes methylene, 1,1-ethylene or 1,2-ethylene;
E denotes a piperidin-1-yl group wherein two hydrogen atoms on the carbon
skeleton are replaced by a straight-chain alkylene bridge, wherein the bridge
comprises 2 to 5 carbon atoms if the two hydrogen atoms are located on the
same
carbon atom, 1 to 4 carbon atoms if the two hydrogen atoms are located on
adjacent carbon atoms, 1 to 3 carbon atoms if the two hydrogen atoms are
located

47
on carbon atoms which are separated by one atom, or 1 or 2 carbon atoms if the
two hydrogen atoms are located on carbon atoms which are separated by two
atoms, wherein the piperidin-1-yl group is optionally additionally substituted
by one
or two C1-3-alkyl groups,
a piperazin-1-yl group wherein two hydrogen atoms on the carbon skeleton are
replaced by a straight-chain alkylene bridge, wherein the bridge comprises 2
to 5
carbon atoms if the two hydrogen atoms are located on the same carbon atom, 1
to 4 carbon atoms if the two hydrogen atoms are located on adjacent carbon
atoms, 1 to 3 carbon atoms if the two hydrogen atoms are located on carbon
atoms which are separated by one atom, or 1 or 2 carbon atoms if the two
hydrogen atoms are located on carbon atoms which are separated by two atoms,
wherein the piperazin-1-yl group is optionally additionally substituted by one
or two
C1-3-alkyl groups, or
a morpholin-4-yl group wherein two hydrogen atoms on the carbon skeleton are
replaced by a straight-chain alkylene bridge, wherein the bridge comprises 2
to 5
carbon atoms if the two hydrogen atoms are located on the same carbon atom, 1
to 4 carbon atoms if the two hydrogen atoms are located on adjacent carbon
atoms, 1 to 3 carbon atoms if the two hydrogen atoms are located on carbon
atoms which are separated by one atom, or 1 or 2 carbon atoms if the two
hydrogen atoms are located on carbon atoms which are separated by two atoms,
wherein the morpholin-4-yl group is optionally additionally substituted by one
or
two C1-3-alkyl groups,
and
X represents nitrogen;
wherein, unless otherwise stated, the abovementioned alkyl groups are straight-
chain or branched.
3. A compound according to claim 1, wherein
R a denotes hydrogen;

48
R b denotes 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-
fluoro-phenyl;
R c denotes hydrogen; methoxy, ethyloxy, 2-(methoxy)ethyloxy, 3-(morpholin-4-
yl)propyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,
cyclopropylmethoxy,
cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-
ylmethoxy or tetrahydropyran-4-ylmethoxy;
A denotes imino;
B denotes carbonyl;
C' denotes 1,2-vinylene;
D denotes methylene;
E denotes 2-aza-bicyclo[2.2.1]hept-2-yl, 2,5-diaza-bicyclo[2.2.1]hept-2-yl, 5-
methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,
2-
aza-bicyclo[2.2.2]oct-2-yl, 3-aza-bicyclo[3.2.1]oct-3-yl, 8-aza-
bicyclo[3.2.1]oct-8-
yl, 3,8-diaza-bicyclo[3.2.1]oct-3-yl, 8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-
yl, 3,8-
diaza-bicyclo[3.2.1]oct-8-yl, 3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl, 3-oxa-
8-
aza-bicyclo[3.2.1]oct-8-yl or 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl;
and
X denotes nitrogen.
4. A compound according to claim 1, wherein
R a denotes hydrogen;
R b denotes 3-chloro-4-fluoro-phenyl;
R c denotes tetrahydrofuran-3-yloxy, cyclopentyloxy or cyclopropylmethoxy;
A denotes imino;
B denotes carbonyl;

49
C' denotes 1,2-vinylene;
D denotes methylene;
E denotes 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl group, a 3-oxa-8-aza-
bicyclo[3.2. 1 ]oct-8-yl group or an 8-oxa-3-aza-bicyclo[3.2. 1 ]oct-3-yl;
and
X denotes nitrogen.
5. A compound, which is 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1S,4S)-2-
oxa-
5-aza-bicyclo[2.2.1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
quinazoline, or a salt thereof.
6. A compound, which is 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1S,4S)-2-
oxa-
5-aza-bicyclo[2.2.1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-
quinazoline, or a salt thereof.
7. A compound, which is 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1S,4S)-2-
oxa-
5-aza-bicyclo[2.2.1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahydrofuran-3-
yl)oxy]-quinazoline, or a salt thereof.
8. A compound, which is 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(3-oxa-8-aza-
bicyclo[3.2.1 ]oct-8-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-
yl)oxy]-
quinazoline, or a salt thereof.
9. A compound, which is 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1R,4R)-2-
oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahydrofuran-3-yl)oxy]-quinazoline, or a salt thereof.
10. A compound, which is 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(8-oxa-3-
aza-
bicyclo[3.2.1 ]oct-3-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-
yl)oxy]-
quinazoline, or a salt thereof.
11. A compound, which is 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1R,4R)-2-
oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-
(tetrahydrofuran-3-yl)oxy]-quinazoline, or a salt thereof.

50
12. A compound, which is 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1S,4S)-2-
oxa-5-aza-bicyclo[2.2.1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-
(tetrahydrofuran-3-yl)oxy]-quinazoline, or a salt thereof.
13. A compound according to any one of claims 1 to 12 in the form of a
physiologically acceptable salt with an inorganic or organic acid or base.
14. A pharmaceutical composition comprising a compound as defined in any one
of claims 1 to 13 and a pharmaceutically acceptable carrier or diluent.
15. A use of a compound as defined in any one of claims 1 to 13 in preparation
of
a pharmaceutical composition for treating a benign or malignant tumor.
16. A use of a compound as defined in any one of claims 1 to 13 in preparation
of
a pharmaceutical composition for preventing or treating a disease of the
airways
or lungs.
17. A use of a compound as defined in any one of claims 1 to 13 in preparation
of
a pharmaceutical composition for treating a disease of the gastrointestinal
tract,
the bile duct or the gall bladder.
18. A use of a compound as defined in any one of claims 1 to 13 for treating a
benign or malignant tumor.
19. A use of a compound as defined in any one of claims 1 to 13 for preventing
or
treating a disease of the airways or lungs.
20. A use of a compound as defined in any one of claims 1 to 13 for treating a
disease of the gastrointestinal tract, the bile duct or the gall bladder.
21. A compound as defined in any one of claims 1 to 13 for treating a benign
or
malignant tumor.
22. A compound as defined in any one of claims 1 to 13 for preventing or
treating
a disease of the airways or lungs.
23. A compound as defined in any one of claims 1 to 13 for treating a disease
of
the gastrointestinal tract, the bile duct or the gall bladder.

51
24. A pharmaceutical composition according to claim 14 for treating a benign
or
malignant tumor.
25. A pharmaceutical composition according to claim 14 for preventing or
treating
a disease of the airways or lungs.
26. A pharmaceutical composition according to claim 14 for treating a disease
of
the gastrointestinal tract, the bile duct and gall bladder.
27. A process for preparing a pharmaceutical composition as defined in claim
14,
wherein a compound as defined in any one of claims 1 to 13 is admixed with a
pharmaceutically acceptable carrier or diluent.
28. A process for preparing a compound of general formula I as defined in
claim 1, wherein
a) a compound of general formula
<IMG>
wherein
R a, R b, R c, A, B and X are defined as in claim 1 and R7 and R8,
independently
denote C1-4-alkyl,
is reacted with a compound of general formula
OHC'- D - E, (III)
wherein
C', D and E are as defined in claim 1; or
b) a compound of general formula

52
<IMG>
wherein
R a, R b, R c, A, B, C', D and X are defined as in claim 1 and Z' denotes a
leaving
group
is reacted with a compound of general formula
H - E, (V)
wherein E is as defined in claim 1, and
if necessary any protecting group used in the reactions defined above is
cleaved
again and/or
if desired a compound of general formula I thus obtained is resolved into the
stereoisomers thereof and/or
a compound of general formula I thus obtained is converted into a salt
thereof.
29. A process according to claim 28, wherein the leaving group is halogen or
substituted sulphonyloxy.
30. A process according to claim 29, wherein the halogen is chlorine or
bromine.
31. A process according to claim 29, wherein the substituted sulphonyloxy is
methane sulphonyloxy or p-toluenesulphonyloxy.
32. A process according to any one of claims 28 to 31, wherein the salt is a
pharmaceutically acceptable salt.

Description

CA 02484395 2010-04-27
25771-966
1
Bicyclic heterocycles, pharmaceutical compositions containing these
compounds, their use and processes for the preparation thereof
The present invention relates to bicyclic heterocycles of general formula
R R
N
A-B-C'D-E
IXI ~ ~
N RC
(I),
the tautomers, the stereoisomers, the mixtures 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,
as well as benign prostatic hyperplasia (BPH), diseases of the lungs and
respiratory tract, and the preparation thereof.
In the above general formula I
Ra denotes a hydrogen atom or a C1 -alkyl group,
Rb denotes a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl
nucleus is substituted in each case by the groups R1 to R3, while
R1 and R2, which may be identical or different, in each case denote a
hydrogen, fluorine, chlorine, bromine or iodine atom,
a C14-alkyl, hydroxy, C1 -alkoxy, C2_3-alkenyl or C2_3-alkynyl group,
an aryl, aryloxy, arylmethyl or arylmethoxy group,

CA 02484395 2004-10-18
2
a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy
group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms or
a cyano, nitro or amino group, and
R3 denotes a hydrogen, fluorine, chlorine or bromine atom,
a methyl or trifluoromethyl group,
R` denotes a hydrogen atom or a fluorine, chlorine or bromine atom,
a hydroxy or C1_4-alkyloxy group,
a methoxy group substituted by I to 3 fluorine atoms,
an ethyloxy group substituted by 1 to 5 fluorine atoms,
a C2_4-alkyloxy group which is substituted by a group R4, where
R4 denotes a hydroxy, C1_3-alkyloxy, C3_6-cycloalkyloxy, C3_6-cycloalkyl-
C1_3-alkyloxy, amino, C1.3-alkylamino, di-(C1_3-alkyl)amino, bis-(2-C1.3-
alkyloxy-ethyl)-amino, bis-(3-C1_3-alkyloxy-propyl)-amino, pyrrolidin-1-yl,
piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,
piperazin-1-yl, 4-(C1-3-alkyl)-piperazin-1-yl, homopiperazin-1-yl or 4-
(C1_3-alkyl)-homopiperazin-1-yl group,
a C2-4-alkyloxy group which is substituted by the group E, where E is defined
as hereinafter,
a C3.7-cycloalkyloxy or C3.7-cycloalkyl-C1 -alkyloxy group,

CA 02484395 2010-04-27
25771-966
3
a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetra hyd ropyra n-4-yl
oxy
group,
a tetrahydrofuranyl-C1_4-alkyloxy or tetrahydropyranyl-C1_4-alkyloxy group,
a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy-group,
a 1-(C1.3-alkyl)-pyrrolidin-3-yloxy, 1-(C1_3-alkyl)-piperidin-3-yloxy or
1-(C1_3-alkyl)-piperidin-4-yloxy-group,
a C1-4-alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or
homopiperidinyl group substituted in the 1 position by the group R5, where
R5 denotes a hydrogen atom or a C1.3-alkyl group,
or a C1-4-alkoxy group which is substituted by a morpholinyl or
homomorpholinyl group substituted in the 4 position by the group R5, where
R5 is as hereinbefore defined,
A denotes an imino or C1..4-alkylimino group,
B denotes a carbonyl or sulphonyl group,
C'denotes a 1,3-allenylene, 1,1-vinylene 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 which may be substituted by one or two
methyl groups or by a trifluoromethyl group,
D denotes a straight-chain or branched C1-0-alkylene group,

CA 02484395 2004-10-18
4
E denotes a pyrrolidin-1-yl group wherein two hydrogen atoms on the carbon
skeleton are replaced by a straight-chain alkylene bridge, this bridge
containing 2 to 6 carbon atoms if the two hydrogen atoms are located on the
same carbon atom, or 1 to 5 carbon atoms if the two hydrogen atoms are
located on adjacent carbon atoms, or 2 to 4 carbon atoms if the two hydrogen
atoms are located on carbon atoms which are separated by one atom, while
the abovementioned pyrrolidin-1-yl groups may each additionally be
substituted by one or two C1_3-alkyl groups,
a piperidin-1-yl or homopiperidin-1-yl group, wherein in each case two
hydrogen atoms on the carbon skeleton are replaced by a straight-chain
alkylene bridge, this bridge containing 2 to 6 carbon atoms if the two
hydrogen
atoms are located on the same carbon atom, or 1 to 5 carbon atoms if the two
hydrogen atoms are located on adjacent carbon atoms, or 1 to 4 carbon
atoms if the two hydrogen atoms are located on carbon atoms which are
separated by one atom, or 1 to 3 carbon atoms if the two hydrogen atoms are
located on carbon atoms which are separated by two atoms, while the
abovementioned piperidin-1-yl- and homopiperidin-1-yl groups may each
additionally be substituted by one or two C1.3-alkyl groups,
a piperazin-1-yl or homopiperazin-1-yl group, wherein in each case two
hydrogen atoms on the carbon skeleton are replaced by a straight-chain
alkylene bridge, this bridge containing 2 to 6 carbon atoms if the two
hydrogen
atoms are located on the same carbon atom, or 1 to 5 carbon atoms if the two
hydrogen atoms are located on adjacent carbon atoms, or I to 4 carbon
atoms if the two hydrogen atoms are located on carbon atoms which are
separated by one atom, or I to 3 carbon atoms if the two hydrogen atoms are
located on carbon atoms which are separated by two atoms, while the
abovementioned piperazin-1-yl- and homopiperazin-1-yl groups may each
additionally be substituted by one or two C1.3-alkyl groups,
a morpholin-4-yl or homomorpholin-4-yl group, wherein in each case two
hydrogen atoms on the carbon skeleton are replaced by a straight-chain

CA 02484395 2004-10-18
alkylene bridge, this bridge containing 2 to 6 carbon atoms if the two
hydrogen
atoms are located on the same carbon atom, or 1 to 5 carbon atoms if the two
hydrogen atoms are located on adjacent carbon atoms, or 1 to 4 carbon
atoms if the two hydrogen atoms are located on carbon atoms which are
separated by one atom, or 1 to 3 carbon atoms if the two hydrogen atoms are
located on carbon atoms which are separated by two atoms, while the
abovementioned morpholin-4-yl- and homomorpholin-4-yl may each
additionally be substituted by one or two C1_3-alkyl groups,
and
X denotes a methyne group substituted by a cyano group or a nitrogen atom,
whilst by the aryl groups mentioned in the definition of the above groups is
meant in each case a phenyl group which is mono- or disubstituted by R6,
while the substituents may be identical or different and
R6 denotes a hydrogen atom, a fluorine, chlorine, bromine or iodine
atom or a C1.3-alkyl, hydroxy, C1_3-alkyloxy, difluoromethyl,
trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group,
by the heteroaryl groups mentioned in the definition of the above groups is
meant a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, while the
abovementioned heteroaryl groups are each mono- or disubstituted by the
group R6, while the substituents may be identical or different and R6 is as
hereinbefore defined, and
unless otherwise stated, the abovementioned alkyl groups may be straight-
chained or branched.
Preferred compounds of the above general formula I are those wherein
Ra denotes a hydrogen atom,

CA 02484395 2004-10-18
6
Rb denotes a phenyl group substituted by the groups R1 to R3, where
R1 denotes a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl or ethynyl group,
a phenyloxy or phenylmethoxy group, wherein the phenyl moiety of the
abovementioned groups is optionally substituted by a fluorine or
chlorine atom, or
a pyridinyloxy or pyridinylmethoxy group, wherein the pyridinyl moiety
of the abovementioned groups is optionally substituted by a methyl or
trifluoromethyl group,
R2 denotes a hydrogen, fluorine or chlorine atom and
R3 denotes a hydrogen atom,
Rc denotes a hydrogen atom,
a C1.3-alkyloxy group,
a C4_6-cycloalkyloxy or C3_6-cycloalkyl-C1_2-alkyloxy-group,
a tetrahydrofuran-3-yloxy, tetra hydropyran-3-yloxy, tetrahydropyran-4-yloxy,
tetra hydrofuranyl-C1_2-alkyloxy or tetra hydropyranyl-C1_2-alkyloxy group,
an ethyloxy group which is substituted in the 2 position by a group R4, where
R4 denotes a hydroxy, C1.3-alkyloxy, amino, C1.3-alkylamino, di-
(C1_3-alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-
1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-
1-yl, 4-(C1.3-alkyl)-piperazin-1-yl, homopiperazin-l-yl, or 4-(C1.3-alkyl)-
homopiperazin-1-yl group,

CA 02484395 2010-04-27
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7
a propyloxy group which is substituted in the 3 position by a group R4, where
R4 is as hereinbefore defined, or
a butyloxy group which is substituted in the 4 position by a group R4 where R4
is as hereinbefore defined,
A denotes an imino group,
B denotes a carbonyl or sulphonyl group,
C'denotes a 1,1-vinylene, 1,2-vinylene or ethynylene group,
D denotes a methylene, 1,1-ethylene or 1,2-ethylene group,
E denotes a piperidin-1-yl group wherein two hydrogen atoms on the carbon
skeleton are replaced by a straight-chain alkylene bridge, this bridge
containing 2 to 5 carbon atoms if the two hydrogen atoms are located on the
same carbon atom, or 1 to 4 carbon atoms if the two hydrogen atoms are
located on adjacent carbon atoms, or 1 to 3 carbon atoms if the two hydrogen
atoms are located on carbon atoms which are separated by one atom, or 1 or
2 carbon atoms if the two hydrogen atoms are located on carbon atoms which
are separated by two atoms, while the abovementioned piperidin-1-yi groups
may each additionally be substituted by one or two C1_3-alkyl groups,
a piperazin-1-yl group wherein two hydrogen atoms on the carbon skeleton
are replaced by a straight-chain alkylene bridge, this bridge containing 2 to
5
carbon atoms if the two hydrogen atoms are located on the same carbon
atom, or 1 to 4 carbon atoms if the two hydrogen atoms are located on
adjacent carbon atoms, or 1 to 3 carbon atoms if the two hydrogen atoms are
located on carbon atoms which are separated by one atom, or 1 or 2 carbon
atoms if the two hydrogen atoms are located on carbon atoms which are
separated by two atoms, while the abovementioned piperazin-1-yl groups may
each additionally be substituted by one or two C1_3-alkyl groups, or

CA 02484395 2004-10-18
8
a morpholin-4-yl group wherein two hydrogen atoms on the carbon skeleton
are replaced by a straight-chain alkylene bridge, this bridge containing 2 to
5
carbon atoms if the two hydrogen atoms are located on the same carbon
atom, or 1 to 4 carbon atoms if the two hydrogen atoms are located on
adjacent carbon atoms, or 1 to 3 carbon atoms if the two hydrogen atoms are
located on carbon atoms which are separated by one atom, or 1 or 2 carbon
atoms if the two hydrogen atoms are located on carbon atoms which are
separated by two atoms, while the abovementioned morpholin-4-yl groups
may each additionally be substituted by one or two CI_3-alkyl groups,
and
X represents a nitrogen atom,
while, unless otherwise stated, the abovementioned alkyl groups may be
straight-chain or branched,
their tautomers, their stereoisomers, their mixtures and their salts.
Particularly preferred compounds of the above general formula I are those
wherein
Ra denotes a hydrogen atom,
Rb denotes a 3-ethynyiphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chioro-
4-fluoro-phenyl group,
R` denotes a hydrogen atom,
a methoxy, ethyloxy, 2-(methoxy)ethyloxy, 3-(morpholin-4-yl)propyloxy, cyclo-
butyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy,
cyclopentylmethoxy, tetra hyd rofu ra n-3-yloxy, tetrahydropyran-3-yloxy,

CA 02484395 2010-04-27
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9
tetra hydropyran-4-yloxy, tetra hyd rofu ran-2-yl methoxy, tetra hyd rofu ran-
3-
ylmethoxy or tetrahydropyran-4-ylmethoxy group,
A denotes an imino group,
B denotes a carbonyl group,
C'denotes a 1,2-vinylene group,
D denotes a methylene group,
E denotes a 2-aza-bicyclo[2.2.1]hept-2-yl, 2,5-diaza-bicyclo[2.2.1]hept-2-yl,
5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl, 2-oxa-5-aza-bicyclo[2.2.I]hept-5-
yl, 2-aza-bicyclo[2.2.2]oct-2-yl, 3-aza-bicyclo[3.2.1 ]oct-3-yl, 8-aza-
bicyclo[3.2.1 ]oct-8-yl, 3,8-diaza-bicyclo[3.2.1 ]oct-3-yl, 8-methyl-3,8-diaza-
bicyclo[3.2.1 ]oct-3-yl, 3,8-diaza-bicyclo[3.2.1 ]oct-8-yl, 3-methyl-3,8-diaza-
bicyclo[3.2.1]oct-8-yl, 3-oxa-8-aza-bicyclo[3.2. 1 ]oct-8-yl or 8-oxa-3-aza-
bicyclo[3.2.1 ]oct-3-yl group
and
X denotes a nitrogen atom,
their tautomers, their stereoisomers, their mixtures and their salts.
Most particularly preferred compounds of general formula I are those wherein
Ra denotes a hydrogen atom,
Rb denotes a 3-chloro-4-fluoro-phenyl group,
R` denotes a tetrahydrofuran-3-yloxy, cyclopentyloxy or cyclopropylmethoxy
group,
A denotes an imino group,

CA 02484395 2010-04-27
25771-966
B denotes a carbonyl group,
C'denotes a 1,2-vinylene group,
D denotes a methylene group,
E denotes a 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl group, a 3-oxa-8-aza-
bicyclo[3.2.1]oct-8-yl group or an 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl group
and
X denotes a nitrogen atom,
their tautomers, their stereoisomers, their mixtures and their salts.
The following are mentioned as examples of particularly preferred compounds
of general formula I:
(a) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-
bicyclo[2.2.1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxy-qu inazoline,
(b) 4-[(3-chloro-4-fl uoro-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-
bicyclo[2.2.1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-
quinazoline,
(c) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-
bicyclo[2.2. 1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahyd rofu ran-3-yl )oxy]-qu inazoline,
(d) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(3-oxa-8-aza-
bicyclo[3.2.1 ]oct-8-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahyd rofuran-3-yl )oxy]-q u i nazol i n e,

CA 02484395 2004-10-18
11
(e) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1 R,4R)-2-oxa-5-aza-
bicyclo[2.2. 1]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tet ra h yd rof u ra n-3-y l )oxy] -quinazoline ,
(f) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(8-oxa-3-aza-
bicyclo[3.2.1 ]oct-3-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahydrofuran-3-yl)oxy]-qu inazoline,
(g) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1 R,4R)-2-oxa-5-aza-
bicyclo[2.2.1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-
(tetrahydrofuran-3-yl)oxy]-quinazoline and
(h) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-
bicyclo[2.2.1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-
(tetrahydrofuran-3-yl)oxy]-qu inazoline,
and the salts thereof.
The compounds of general formula I may be prepared for example by the
following methods:
a) reacting a compound of general formula
RAN Rb O~ O-R7
f-P
A-B O- R8
X
N R
(ll)
wherein
Ra, Rb, Rc, A, B and X are as hereinbefore defined and R7 and R8, which may
be identical or different, denote C1_4-alkyl groups,

CA 02484395 2010-04-27
25771-966
12
with a compound or general formula
OHC'- D - E, (III)
wherein
C, D and E are as hereinbefore defined.
The reaction is expediently carried out in a solvent or mixture of solvents
such
as tetrahydrofuran, tetra hydrofuran/water, acetonitrile, acetonitrile/water,
dioxane, ethyleneglycol dimethyl ether, isopropanol, methylene chloride,
dimethylformamide or sulpholane optionally in the presence of an inorganic or
organic base, e.g. sodium carbonate, potassium hydroxide or 1,8-
diazabicyclo[5.4.0]undec-7-ene and optionally in the presence of a lithium
salt
such as lithium chloride at temperatures between -50 and 150 C, but
preferably at temperatures between -20 and 80 C. The reaction may also be
carried out with a reactive derivative of the compound of general formula III,
for example the hydrate or a hemiacetal.
b) reacting a compound of general formula
RRb
N
A-B-C D-Z'
N Rc (IV)
wherein Ra, Rb, R`, A, B, C', D and X are as hereinbefore defined and Z'
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,
with a compound of general formula

CA 02484395 2004-10-18
13
H - E, (V)
wherein E is as hereinbefore defined.
The reaction is expediently carried out in a solvent such as isopropanol,
butanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide,
sulpholane, toluene or methylene chloride or mixtures thereof, optionally in
the presence of an inorganic or organic base, e.g. sodium carbonate,
potassium carbonate, potassium hydroxide, triethylamine or N-ethyl-
diisopropylamine and optionally in the presence of a reaction accelerator such
as an alkali metal iodide at temperatures between -20 and 150 C, but
preferably at temperatures between 0 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.
In the reactions described hereinbefore, any reactive groups present such as
hydroxy, amino, alkylamino 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, trityl, benzyl or tetrahydropyranyl group.
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, for example.
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 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

CA 02484395 2004-10-18
14
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, 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. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6,
Wiley Interscience, 1971) into their optical antipodes and compounds of

CA 02484395 2004-10-18
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 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 may be a (+)- or (-)-menthyloxycarbonyl, for
example.
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, sulphuric
acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid,
lactic acid, citric acid, tartaric acid or maleic acid.
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

CA 02484395 2004-10-18
16
bonding, receptor dimerisation or tyrosine kinase itself. It is also possible
that
the transmission of signals to components located downstream is blocked.
The biological properties of the new compounds were investigated as follows:
The inhibition of human EGF-receptor kinase was determined using the cyto-
plasmic tyrosine kinase domain (methionine 664 to alanine 1186 based on the
sequence published in Nature 309 (1984), 418). For this the protein was
expressed in Sf9 insect cells as GST fusion protein using the Baculovirus
expression system.
The enzyme activity was measured in the presence or absence of the test
compounds in serial dilutions. The polymer pEY (4:1) obtained from SIGMA
was used as the substrate. Biotinylated pEY (bio-pEY) was added as the
tracer substrate. 100 pl of reaction solution contained 10 pl of the inhibitor
in
50% DMSO, 20 pl of the substrate solution (200 mM HEPES pH 7.4, 50 mM
magnesium acetate, 2.5 mg/ml poly(EY), 5 pg/mi bio-pEY) and 20 pl of
enzyme preparation. The enzyme reaction was started by the addition of 50 pl
of a 100 pM ATP solution in 10 mM of magnesium chloride. The dilution of the
enzyme preparation was adjusted so that the incorporation of phosphate in
the bio-pEY was linear in terms of time and quantity of enzyme. The enzyme
preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM
common salt, 0.05% Triton X-100, 1 mM DTT and 10% glycerol.
The enzyme assays were carried out at ambient temperature over a period of
30 minutes and ended by the addition of 50 pl of a stopping solution (250 mM
EDTA in 20 mM HEPES pH 7.4). 100 pl were placed on a streptavidin-coated
microtitre plate and incubated for 60 minutes at ambient temperature. Then
the plate was washed with 200 pl of a wash solution (50 mM Tris, 0.05%
Tween 20). After the addition of 100 pl of an HRPO-labelled anti-PY antibody
(PY20H Anti-PTyr:HRP made by Transduction Laboratories, 250 ng/ml) the
preparation was incubated for 60 minutes. Then the microtitre plate was
washed three times with 200 pl of wash solution. The samples were then
combined with 100 pl of a TMB-peroxidase solution (A:B = 1:1, Kirkegaard

CA 02484395 2004-10-18
17
Perry Laboratories). After 10 minutes the reaction was stopped. The extinction
was measured at OD450nm with an ELISA reader. All the results were
measured three times.
The data were adapted by iterative calculation using an analytical programme
for sigmoid curves (Graph Pad Prism Version 3.0) with a variable Hill pitch.
All
the iterative data produced had a correlation coefficient of more than 0.9 and
the upper and lower values of the curves showed a spread of at least a factor
of 5. The active substance concentration which inhibits the activity of EGF
receptor kinase by 50% (IC50) was derived from the curves.
The following results were obtained:
Compound Inhibition of EGF-receptor
(Example No.) kinase
IC50 [nM]
1 1.5
1(1) 0.5
2 0.5
2(2) 0.5
2(3) 2
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 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

CA 02484395 2004-10-18
18
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
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.
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), benign prostatic hyperplasia (BPH),
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. vinbiastine), 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 (e.g. ambroxol,

CA 02484395 2004-10-18
19
N-acetylcysteine) , broncholytic (e.g. tiotropium or ipratropium or fenoterol,
salmeterol, salbutamol) and/or anti-inflammatory activity (e.g. theophylline
or
glucocorticoids). 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.
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.
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.

CA 02484395 2004-10-18
The following Examples are intended to illustrate the present invention
without
restricting it:
Preparation of the starting compounds:
Example I
4-[(3-chloro-4-fluoro-phenyl)aminol-6-[(diethoxy-phosphoryl)-acetylaminol-7-
RS)-(tetrahydrofu ran-3-yl)oxyl-guinazoline
60.07 g of diethoxyphosphorylacetic acid are placed in 750 ml N,N-
dimethylformamide and at ambient temperature combined with 48.67 g of
N,N'-carbonyldiimidazole. After the development of gas has ended 90.00 g of
4-[(3-chloro-4-fluoro-phenyl)amino]-6-amino-[(S)-(tetrahydrofu ran-3-yl)oxy]-
quinazoline are added and the reaction mixture is stirred for about 4-5 hours
at ambient temperature until the reaction is complete. The reaction mixture is
then heated gently in a water bath and two batches of 750 ml of water are
added. The thick suspension is stirred overnight and the next morning another
350 ml of water are added. The suspension is cooled in the ice bath, stirred
for another hour and suction filtered. The filter cake is washed with 240 ml
of
N,N-dimethylformamide/water (1:2) and 240 ml of diisopropylether and dried
at 40 C in a circulating air drier.
Yield: 117.30 g (88 % of theory)
Rf value: 0.37 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+): m/z = 553, 555 [M+H]+
The following compound is obtained analogously to Example I:
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(diethoxy-phosphoryl)-acetylamino]-
7-[(R)-(tetrahydrofuran-3-yl)oxy]-quinazoline
Mass spectrum (ESI+): m/z = 553, 555 [M+H]+

CA 02484395 2004-10-18
21
Example II
(1S 4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-acetaldehyde-hydrochloride
Prepared by treating (1 S,4S)-5-(2,2-dimethoxy-ethyl)-2-oxa-5-aza-
bicyclo[2.2.1]heptane with conc. hydrochloric acid in water at 80 C. The
solution obtained is further reacted directly in Example 2 and 2(5).
The following compounds are obtained analogously to Example II:
(1) (3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-yl)-acetaldehyde-hydrochloride
The solution obtained is further reacted directly in Example 2(1).
(2) (1 R,4R)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yi)-acetaldehyde-hydrochloride
The solution obtained is further reacted directly in Example 2(2) and 2(4).
(3) (8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-acetaldehyde-hydrochloride
The solution obtained is further reacted directly in Example 2(3).
Example III
(1 S 4S)-5-(2,2-dimethoxy-ethyl)-2-oxa-5-aza-bicyclo[2.2.11heptane
Prepared by reacting (1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane-
hydrochloride with bromoacetaldehyde-dimethylacetal in the presence of
potassium carbonate in N-methylpyrrolidinone at 100 C.
Rf value: 0.35 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1)
Mass spectrum (ESI+): m/z = 188 [M+H]+
The following compounds are obtained analogously to Example III:
(1) 8-(2,2-dimethoxy-ethyl)-3-oxa-8-aza-bicyclo[3.2.1 ]octane
Rf value: 0.81 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1)
(2) (1 R,4R)-5-(2,2-dimethoxy-ethyl)-2-oxa-5-aza-bicyclo[2.2.1]heptane

CA 02484395 2004-10-18
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Rf value: 0.23 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia =
90:10:1)
Mass spectrum (ESI+): m/z = 188 [M+H]+
The (1 R,4R)-2-oxa-5-aza-bicyclo[2.2.1 ]heptane-hydrochloride used is
prepared by reacting (2R,4R)-1-(tert.-butyloxycarbonyl)-2-[(4-methylphenyl-
sulphonyloxy)-methyl]-4-hydroxy-pyrrolidine (see J. Org. Chem., 1992, 57,
3783-3789) with sodium hydride in tetrahydrofuran and subsequently treating
it with hydrochloric acid in dioxane.
(3) 3-(2,2-dimethoxy-ethyl)-8-oxa-3-aza-bicyclo[3.2.1 ]octane
Rf value: 0.84 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia =
90:10:1)
Preparation of the final compounds:
Example 1
4-f(3-chloro-4-fluoro-phenyl)aminol-6-{f4-((1 S,4S)-2-oxa-5-aza-
bicyclof2.2.1lhept-5-vl)-1-oxo-2-buten-1-yllamino} 7-cyclopropylmethox --
guinazoline
F
CI \ NH
H
NI N
,10 N
N ~'O
4.50 g of bromocrotonic acid are dissolved in 40 ml of methylene chloride and
combined with 4.70 ml of oxalyl chloride. After the addition of 0.02 ml of N,N-
dimethylformamide a vigorous development of gas sets in which is finished
after about two hours. The reaction mixture is evaporated down in vacuo and
the flask residue is dissolved in 40 ml methylene chloride. This solution is
added dropwise to a mixture of 7.00 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-

CA 02484395 2004-10-18
23
6-amino-7-cyclopropylmethoxy-quinazoline and 9.60 ml of Hunig base in 80
ml of tetrahydrofuran while cooling with an ice bath. The reaction solution is
stirred for one hour in the ice bath and for another hour at ambient
temperature.
One fifth of this solution is then removed and combined with 740 mg of
(1 S,4S)-2-oxa-5-aza-bicyclo[2.2. 1 ]heptane-hydrochloride and 1 ml of Hunig
base. The reaction mixture is stirred overnight at 60 C and then evaporated
down in vacuo. The flask residue is taken up with ethyl acetate and a little
methanol and-extracted with water. The organic phase is taken up on silica
gel and chromatographed through a silica gel column with ethyl
acetate/methanol (95:5 to 70:30) as eluant. The product obtained is
crystallised from diisopropylether and suction filtered.
Yield: 850 mg (42 % of theory)
Rf value: 0.36 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+): m/z = 524, 526 [M+H]+
The following compound is obtained analogously to Example 1:
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-
bicyclo[2.2. 1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-
quinazoline
F
CI \ 1 NH
N N
0
N 0 O
6
Rf value: 0.40 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/ trifluoroacetic acid = 50:50:1)
Mass spectrum (ESI"): m/z = 536, 538 [M-H]"

CA 02484395 2004-10-18
24
Example 2
4-[(3-chloro-4-fluoro-phenyl)amino1-6-{[4-((1 S,4S)-2-oxa-5-aza-
bicyclof 2.2.1lhept-5-yl)-1-oxo-2-buten-1-yllamino}-7-f (S)-(tetrahydrofu ran-
3-
yl)oxyl-quinazoline
F
~I
CI NH H
NI NI /
`N O
O O
Col
A solution of 4.44 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(diethoxy-
phosphoryl)-acetylamino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline in 22
ml of tetrahydrofuran is added at ambient temperature to a solution of 340 mg
of lithium chloride in 22 ml of water. Then 2.73 g of potassium hydroxide
flakes are added and the reaction mixture is cooled to -3 C in a cooling bath
of ice and acetone. The solution of (1 S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-
yl)-acetaldehyde-hydrochloride obtained in Example II is then added dropwise
within 5 min at a temperature of 0 C. After the addition has ended the
reaction
mixture is stirred for another 10 min at 0 C and another 20 min at ambient
temperature. For working up 100 ml of ethyl acetate are added and the
aqueous phase is separated off. The organic phase is washed with saturated
sodium chloride solution, dried over magnesium sulphate and evaporated
down. The crude product is purified by chromatography over a silica gel
column with methylene chloride/methanol/conc. methanolic ammonia
(980:18:2 to 750:225:25) as eluant. The product obtained is brought to
crystallisation with a little diisopropylether.
Yield: 2.60 g (60 % of theory)
Rf value: 0.33 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia = 90:10:1)
Mass spectrum (ESI+): m/z = 540, 542 [M+H]+
The following compounds are obtained analogously to Example 2:

CA 02484395 2004-10-18
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(3-oxa-8-aza-bicyclo[3.2.1 ]oct-
8-
yI)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline
F /
\I
CI NH
H
N ao 0 O
Mass spectrum (ESI+): m/z = 554, 556 [M+H]+
(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1 R,4R)-2-oxa-5-aza-
bicyclo[2.2.1 ]hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahyd rofu ran-
3-
yl)oxy]-quinazoline
F /
CI \ NH
H
N \ N\ II N
O O O
N
0
Rf value: 0.08 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia =
90:10:1)
Mass spectrum (ESI'): m/z = 538, 540 [M-H]-
(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(8-oxa-3-aza-bicyclo[3.2.1 ]oct-
3-
yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline
F /
CI NH
H~~
N \ N-II~ N
N / 0 0 O
O
Rf value: 0.77 (aluminium oxide, ethyl acetate/methanol = 95:5)

CA 02484395 2004-10-18
26
Mass spectrum (ESI+): m/z = 554, 556 [M+H]+
(4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1 R,4R)-2-oxa-5-aza-
bicyclo[2.2.1 ]kept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-
yl)oxy]-quinazoline
F
CI NH
H
\ \ N\II N
N N O O
0
Mass spectrum (ESI+): m/z = 540, 542 [M+H]+
(5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-
bicyclo[2.2.1 ]hept-5-yi)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-
yl)oxy]-quinazoline
F
CI NH
H
N
NII \ \ \IN
O `JO
0
Mass spectrum (ESI+): m/z = 540, 542 [M+H]+

CA 02484395 2004-10-18
27
The following compounds may also be prepared analogously to the foregoing
Examples and other methods known from the literature:
Example No. Structure
(~) F / `
CI \ NH
H
N \ NN
N O O
(2) F /
CI \ NH
N N\~~N
O
0
1
CH3
(3) F /
~'~/~
CI NH H
N \ \ N\II N
0 0
(4) F /
CI \ NH
H
N \ \ N\II N
0 0
H
0, CH3

CA 02484395 2004-10-18
28
Example No. Structure
(5) F /
CI \ NH
H
N N~II
N 0 0 N
O
(6) F /
CI \ NH
H
N `~ N\II N
N O 0 (7) F /
CI \ NH H
N a N\II
kN O O
(8) F /
CI \ NH
H
~II N
N
kN ao 0 0

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29
Example No. Structure
(9) F /
CI NH H
INI N\ I I N
N O
(10) F /
CI ~ NH H
N N\II N
N 0 0 1-0
(11) F /
CI NH H
N N\N
,.i"a
(12) F /
CI \ NH
N \ \ N\ II N
N O 0 0

CA 02484395 2004-10-18
Example No. Structure
(13) F /
CI \ NH
H
\ \ N
N ~II N
0 0 O
(14) F /
CI \ NH
H
N \ \ N\II N
0 0 I-CO)
(15) F
C I \ NH
H
N \ N~N
e N \ / 0 IOI
O
(16) F /
CI \ NH
H
N \ \ N\II N
0
N / O O
11~0

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31
Example No. Structure
(17) F /
\I
Cl NH
H
N N\N
~N 0 0
O
(18) F /
CI \ NH
H
N N~II N
0
N O D
(19) F /
CI NH
H
N N
N
0 0
1
CH3
(20) F /
CI NH
H
INI N\ N
IOI O
N O
I-V
(21) F /
CI NH
H
N \ ~ Neil N
i 0 0
N 0

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32
Example No. Structure
(22) F / I~
CI/\/~
NH
H
k \ \ IN
/ OI O
N
O
(23) F /
CI NH
H
N \ \ N
kN / O 0 O
O
(24) F /
ZI-I
CI NH
H
INI \ NO N
N / 0
0
(25) F
CI NH
H
N \ \ NN
IIII ~N H
O 0
00,
(26) F / II
CI)\/~
NH
H
N
II \ N N
i / IOI
N O CH3
CO)

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33
Example No. Structure
(27) F
CI NH
H
N NN
O IOI H
N
0
(28) F / I~
/\/~
CI NH
H
INI NN
ONE
O CH3
CO)
(29) F /
CI NH
H
N NN
11
TI NH
O 0
0
(30) F I~
CI/\/~
NH
H
IN~~\ N, CN,
N O CH3
0
(31) F /
H
CI NH ~~~~
N NII N
V/
N O 0
0

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34
Example No. Structure
(32) F /
CI \ NH
H
N N\~~\N
O O
0
(33) F /
CI NH
H
IN N y- N
/
O 0
N
0
(34) F /
CI NH
H
INI N \ N
OO
N
O
(35) F /
CI NH
N N
O
O 0
O

CA 02484395 2004-10-18
Example No. Structure
(36) F aNH
CI H
N N"7"
0 0
O
(37) aNH
HC H
N N~~\N
N O
co)
(38) F /
F \ NH
H
N \ N\II N
kN / O 0
0
(39) /
Br \ NH
H
N \ N\II
kN / O O O
O

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36
Example 3
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 mg
230.0 mg
Preparation:
The active substance is mixed with calcium phosphate, corn starch, poly-
vinylpyrrolidone, 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.

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37
Example 4
Tablets containing 100 mg of active substance
Composition:
1 tablet contains:
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:
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 5
Tablets containing 150 mg of active substance
Composition:
1 tablet contains:
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

CA 02484395 2004-10-18
38
Preparation:
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 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 6
Hard gelatine capsules containing 150 mg of active substance
1 capsule contains:
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:
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.

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Example 7
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
2000.0 mg
Preparation:
After the suppository mass has been melted the active substance is
homogeneously distributed therein and the melt is poured into chilled moulds.
Example 8
Suspension containing 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
70% sorbitol solution 20.00 g
flavouring 0.30 g
dist. water 100 ml

CA 02484395 2004-10-18
Preparation:
The distilled water is heated to 70 C. The methyl and propyl
p-hydroxybenzoates together with the glycerol and sodium salt of
carboxymethylcelIulose 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.
Example 9
Ampoules containing 10 mg active substance
Composition:
active substance 10.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water 2.0 ml
Preparation:
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 10
Ampoules containing 50 mg of active substance
Composition:
active substance 50.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water 10.0 ml
Preparation:
The active substance is dissolved in the necessary amount of 0.01 N HCI,
made isotonic with common salt, filtered sterile and transferred into 10 ml
ampoules.

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Example 11
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:
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 12
Inhalable solution for hand-held nebulisers containing 2.5 mg active
substance
1 spray contains:
active substance 2.500 mg
benzalkonium chloride 0.001 mg
1 N hydrochloric acid q.s.
ethanol/water (50/50) 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 1 N
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

Representative Drawing