BICYCLIC HETEROCYCLES, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS, THEIR USE AND PROCESSES FOR PREPARING THEM

HETEROCYCLES BICYCLIQUES, MEDICAMENTS CONTENANT LESDITS COMPOSES, LEUR UTILISATION ET PROCEDES PERMETTANT DE LES PRODUIRE

English Abstract

The invention relates to bicyclic heterocycles of general formula (I), in
which Ra to Rc, A to E, and X are defined as referred to in Claim No. 1, to
their tautomers, their stereoisomers, and to their salts, particularly their
physiologically compatible salts with inorganic or organic acids or bases,
which have valuable pharmacological properties, in particular, an inhibitive
effect on the signal transduction imparted by tyrosine kinases. The invention
also relates to the use of said bicyclic heterocycles for treating diseases,
especially tumor diseases, disorders of the lung and of the respiratory tract,
and to the production thereof.

French Abstract

L'invention concerne des hétérocycles bicycliques de formule générale (I) dans laquelle R¿a? à R¿c?, A à E et X ont la signification mentionnée dans la revendication 1, leurs tautomères, leurs stéréoisomères et leurs sels, notamment leurs sels physiologiquement tolérables avec des acides ou des bases inorganiques ou organiques, qui présentent des propriétés pharmacologiques intéressantes, en particulier un effet inhibiteur sur la transduction de signaux induite par tyrosine-kynases. L'invention concerne en outre l'utilisation desdits hétérocycles bicycliques pour traiter des affections, en particulier des affections tumorales, des affections des poumons et des voies respiratoires, ainsi que leur mode de production.

Claims

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Claims
1. Bicyclic heterocycles of general formula
<IMG>
wherein
R a denotes a hydrogen atom or a methyl 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, while
R1 and R2, which may be identical or different, in each
case denote a hydrogen, fluorine, chlorine, bromine or
iodine atom,
a methyl, ethyl, hydroxy, methoxy, ethoxy, amino, cyano,
vinyl or ethynyl group,
an aryl, aryloxy, arylmethyl or arylmethoxy group,
a methyl or methoxy group substituted by 1 to 3 fluorine
atoms or
R1 together with R2, if they are bound to adjacent carbon
atoms, denote a -CH=CH-CH=CH, -CH=CH-NH- or -CH=N-NH group
and
R3 denotes a hydrogen, fluorine, chlorine or bromine atom,
R c denotes a hydrogen atom or a methyl group,

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X denotes a methyne group substituted by a cyano group or a
nitrogen atom,
A denotes a 1,1- or 1,2-vinylene group which may be
substituted in each case by one or two methyl groups or by a
trifluoramethyl group,
an ethynylene group or
a 1,3-butadien-1,4-ylene group optionally substituted by a
methyl or trifluoromethyl group,
B denotes an alkylene or -CO-alkylene group wherein the
alkylene moiety in each case contains 1 to 4 carbon atoms,
while the linking of the -CO-alkylene group to the adjacent
group A in each case must take place via the carbonyl group,
a -CO-O-alkylene- or -CO-NR4-alkylene group wherein the
alkylene moiety in each case contains 1 to 4 carbon atoms,
while the linking to the adjacent group A in each case must
take place via the carbonyl group, wherein
R4 denotes a hydrogen atom or a methyl or ethyl group,
or a carbonyl group,
C denotes a 2-oxo-morpholin-4-yl group substituted by the
group R5 or by the group R5 and a C1-4-alkyl group, while
R5 denotes a C3-4-alkyl, hydroxy-C1-4-alkyl, C1-4-alkoxy-
C1-4-alkyl, di-(C1-4-alkyl)-amino-C1-4-alkyl, pyrrolidino-
C1-4-alkyl, piperidino-C1-4-alkyl, morpholino-C1-4-alkyl,
4-(C1-4-alkyl)-piperazino-C1-4-alkyl, C1-4-alkylsulphanyl-
C1-4-alkyl, C1-4-alkylsulphinyl-C1-4-alkyl, C1-4-alkylsulphonyl-
C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxycarbonyl-C1-4-alkyl,
aminocarbonyl-C1-4-alkyl, C1-4-alkyl-aminocarbonyl-C1-4-alkyl,

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di-(C1-4-alkyl)aminocarbonyl-C1-4-alkyl, pyrrolidinocarbonyl-
C1-4-alkyl, piperidinocarbonyl-C1-4-alkyl, morpho-
linocarbonyl-C1-4-alkyl or a 4-(C1-4-alkyl)-pipera-
zinocarbonyl-C1-4-alkyl group,
a 2-oxo-morpholin-4-yl group substituted by two groups R5,
where R5 is as hereinbefore defined and the two groups R5 may
be identical or different,
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of
a methylene group are replaced by a -(CH2)m, -CH2-Y-CH2,
-CH2-Y-CH2-CH2, -CH2CH2-Y-CH2CH2- or -CH2CH2-Y-CH2CH2CH2- bridge
optionally substituted by one or two C1-2-alkyl groups, while
m denotes the number 2, 3, 4, 5 or 6 and
Y denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl
or C1-4-alkylimino group,
a 2-oxo-morpholin-4-yl group, wherein a hydrogen atom in the 5
position together with a hydrogen atom in the 6 position is
replaced by a -(CH2)n, -CH2-Y-CH2, -CH2-Y-CH2CH2- or -CH2CH2-Y-CH2-
bridge, while
Y is as hereinbefore defined and
n denotes the number 2, 3 or 4,
or, if D together with E denotes a group R d, it may also denote
a 2-oxo-morpholin-4-yl group which may be substituted by 1 to
4 C1-2-alkyl groups,
D denotes a -O-C1-6-alkylene group, while the alkylene moiety is
linked to the group E, or
an oxygen atom, while this may not be linked to a nitrogen
atom of the group E, and

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E denotes an amino group substituted by 2 C1-4-alkyl groups,
wherein the alkyl groups may be identical or different and
each alkyl moiety may be substituted from the 2 position by a
C1-4-alkoxy or di-(C1-4-alkyl)-amino group or by a 4- to 7-
membered alkyleneimino group, while in the abovementioned 6-
to 7-membered alkyleneimino groups in each case a methylene
group may be replaced in the 4 position by an oxygen or
sulphur atom or by a sulphinyl, sulphonyl- or N-(C1-4-alkyl)-
imino group,
a 4- to 7-membered alkyleneimino group optionally substituted
by 1 to 4 methyl groups,
a 6- to 7-membered alkyleneimino group optionally substituted
by 1 or 2 methyl groups, wherein in each case a methylene
group in the 4 position is replaced by an oxygen or sulphur
atom or by a sulphinyl, sulphonyl- or N-(C1-4-alkyl)-imino
group,
an imidazolyl group optionally substituted by 1 to 3 methyl
groups,
a C5-7-cycloalkyl group, wherein a methylene group is replaced
by an oxygen or sulphur atom or by a sulphinyl, sulphonyl or
N-(C1-4-alkyl)-imino group, or
D together with E denotes a hydrogen atom,
a C1-6-alkoxy group optionally substituted from the 2 position
by a hydroxy- or C1-4-alkoxy group,
a C3-7-cycloalkoxy- or C3-7-cycloalkyl-C1-4-alkoxy group,
or a group R d, where

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R d denotes a C2-6-alkoxy group which is substituted from the
2 position by a C4-7-cycloalkoxy- or C3-7- cycloalkyl-
C1-3-alkoxy group,
a C4-7-cycloalkoxy- or C3-7-cycloalkyl-C1-6-alkoxy group
wherein the cycloalkyl moiety in each case is substituted
by a C1-4-alkyl, C1-4-alkoxy, di-(C1-4-alkyl)-amino,
pyrrolidino, piperidino, morpholino, piperazino,
4-(C1-2-alkyl)-piperazino, C1-4-alkoxy-C1-2-alkyl, di-
(C1-4-alkyl)-amino-C1-2-alkyl, pyrrolidino-C1-2-alkyl,
piperidino-C1-2-alkyl, morpholino-C1-2-alkyl, piperazino-
C1-2-alkyl- or 4-(C1-2-alkyl)-piperazino-C1-2-alkyl group,
while the abovementioned cycloalkyl moieties may
additionally be substituted by a methyl or ethyl group,
while, unless otherwise stated, by the aryl moieties mentioned
in the definition of the abovementioned groups is meant a
phenyl group which may be mono- or disubstituted by R6, while
the substituents may be identical or different and
R6 denotes a fluorine, chlorine, bromine or iodine atom, a
C1-2-alkyl, trifluoromethyl or C1-2-alkoxy group, or
two groups R6, if they are bound to adjacent carbon atoms,
together represent a C3-4-alkylene, methylenedioxy or
1,3-butadien-1,4-ylene group,
the tautomers, stereisomers and salts thereof.
2. Bicyclic heterocycles of general formula I according to
claim 1, wherein
R a denotes a hydrogen atom,
R b denotes a benzyl or 1-phenylethyl group or a phenyl group
substituted by the groups R1 and R2, while

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R1 denotes a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl, cyano or ethynyl group and
R2 denotes a hydrogen or fluorine atom,
R c denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a 1,2-vinylene group,
B denotes a C1-4-alkylene group,
C denotes a 2-oxo-morpholin-4-yl group substituted by the
group R5 or by t he group R5 and a C1-4-alkyl group, while
R5 denotes a C3-4-alkyl, C1-2-alkoxy-C1-4-alkyl, di-(C1-2-
alkyl)-amino-C1-4-alkyl, pyrrolidino-C1-4-alkyl, piperidino-
C1-4-alkyl, morpholino-C1-4-alkyl, 4-(C1-2-alkyl)-piperazino-
C1-4-alkyl, C1-2-alkylsulphanyl-C1-4-alkyl, C1-2-alkylsulphinyl-
C1-4-alkyl, C1-2-alkylsulphonyl-C1-4-alkyl, cyano-C1-4-alkyl,
C1-2-alkoxycarbonyl-C1-4-alkyl, aminocarbonyl-C1-4-alkyl,
C1-2-alkyl-aminocarbonyl-C1-4-alkyl, di-(C1-2-alkyl)-
aminocarbonyl-C1-4-alkyl, pyrrolidinocarbonyl-C1-4-alkyl,
piperidinocarbonyl-C1-4-alkyl, morpholinocarbonyl-C1-4-alkyl-
or a 4-(C1-2-alkyl)-piperazinocarbonyl-C1-4-alkyl group,
a 2-oxo-morpholin-4-yl group substituted by two groups R5,
while R5 is as hereinbefore defined and the two groups R5 may
be identical or different,
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of
a methylene group are replaced by a -(CH2)m, -CH2-Y-CH2,
-CH2-Y-CH2-CH2- or -CH2CH2-Y-CH2CH2-bridge, while
m denotes the number 2, 3, 4 or 5 and
Y denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl
or C1-2-alkylimino group,

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a 2-oxo-morpholin-4-yl group, wherein a hydrogen atom in the 5
position together with a hydrogen atom in the 6 position is
replaced by a -(CH2)n, -CH2-Y-CH2, -CH2-Y-CH2CH2- or -CH2CH2-Y-CH2-
bridge, where
Y is as hereinbefore defined and
n denotes the number 2, 3 or 4,
or, if D together with E denotes a group R d, it may also denote
a 2-oxo-morpholin-4-yl group which may be substituted by 1 or
2 methyl or ethyl groups,
D denotes a -O-C1-4-alkylene group, while the alkylene moiety is
linked to the group E, and
E denotes a dimethylamino, diethylamino, pyrrolidino,
piperidino, morpholino, 4-methyl-piperazino- or 4-ethyl-
piperazino group or
D together with E denotes a hydrogen atom,
a methoxy, ethoxy, 2-methoxy-ethoxy, 3-methoxy-propyloxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,
tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or
tetrahydropyranylmethoxy group,
a cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclo-
propylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or
cyclohexylmethoxy group or
a group R d, where
R d denotes a 2-(cyclobutyloxy)-ethoxy, 2-(cyclopentyloxy)-
ethoxy, 2-(cyclopropylmethoxy)-ethoxy or 2-(cyclobutyl-
methoxy)-ethoxy group,

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the tautomers, stereoisomers and salts thereof.
3. Bicyclic heterocycles of general formula I according to
claim 1, wherein
R a denotes a hydrogen atom,
R b denotes a 1-phenylethyl, 3-methylphenyl, 3-chlorophenyl,
3-bromophenyl- or 3-chloro-4-fluorophenyl group,
R c denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a 1,2-vinylene group,
B denotes a methylene group,
C denotes a 2-oxo-morpholin-4-yl group which is substituted by
a methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl,
dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl,
diethylaminoethyl, cyanomethyl or cyanoethyl group,
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of
a methylene group are replaced by a -CH2CH2, -CH2CH2CH2,
-CH2CH2CH2CH2, -CH2CH2CH2CH2CH2, -CH2-O-CH2CH2, -CH2-NCH3-CH2CH2,
-CH2-NC2H5-CH2CH2, -CH2CH2-O-CH2CH2, -CH2CH2-NCH3-CH2CH2- or
-CH2CH2-NC2H5-CH2CH2- bridge,
a 2-oxo-morpholin-4-yl group, wherein a hydrogen atom in the 5
position together with a hydrogen atom in the 6 position is
replaced by a -CH2CH2CH2, -CH2CH2CH2CH2, -CH2-O-CH2, -CH2-NCH3-CH2,
-CH2-NC2H5-CH2, -CH2-O-CH2CH2, -CH2-NCH3-CH2CH2, -CH2-NC2H5-CH2CH2,
-CH2CH2-O-CH2, -CH2CH2-NCH3-CH2- or -CH2CH2-NC2H5-CH2- bridge,

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or, if D together with E denotes a group R d, it may also denote
a 2-oxo-morpholin-4-yl group which is substituted by 1 or 2
methyl groups, and
D together with E denotes a hydrogen atom,
a methoxy, ethoxy, 2-methoxy-ethoxy, 3-methoxy-propyloxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or
tetrahydrofuranylmethoxy group,
a cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy,
cyclobutylmethoxy or cyclopentylmethoxy group or
a group R d, where
R d denotes a 2-(cyclobutyloxy)-ethoxy, 2-(cyclopentyloxy)-
ethoxy, 2-(cyclopropylmethoxy)-ethoxy or
2-(cyclobutylmethoxy)-ethoxy group,
the tautomers, stereoisomers and salts thereof.
4. Bicyclic heterocycles of general formula I according to
claim 1, wherein
R a denotes a hydrogen atom,
R b denotes a 3-chloro-4-fluorophenyl group,
R c denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a 1,2-vinylene group,
B denotes a methylene group,

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C denotes a 2-oxo-morpholin-4-yl group which is substituted by
a methoxymethyl or methoxyethyl group, or
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of
a methylene group are replaced by a -CH2CH2-O-CH2CH2- bridge,
and
D together with E denotes a hydrogen atom, a methoxy or
cyclopropylmethoxy group,
the tautomers, stereoisomers and salts thereof.
5. The following compounds of general formula I according to
claim 1:
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxy-
methyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-
7-cyclopropylmethoxy-quinazoline,
(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(2-oxo-1,9-
dioxa-4-aza-spiro[5.5]undec-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxy-quinazoline and
(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-({4-[2-(2-methoxy-
ethyl)-6-oxo-morpholin-4-yl]-1-oxo-2-buten-1-yl}amino)-
7-cyclopropylmethoxy-quinazoline,
the tautomers, stereisomers and salts thereof.
6. Physiologically acceptable salts of the compounds according
to at least one of claims 1 to 5 with inorganic or organic
acids or bases.
7. Pharmaceutical compositions containing a compound according
to at least one of claims 1 to 5 or a physiologically
acceptable salt according to claim 6 optionally together with
one or more inert carriers and/or diluents.

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8. Use of a compound according to at least one of claims 1 to 6
for preparing a pharmaceutical composition which is suitable
for the treatment of benign or malignant tumours, for
preventing and treating diseases of the respiratory tract and
lungs, for treating polyps, diseases of the gastro-intestinal
tract, bile duct and gall bladder as well as the kidneys and
skin.
9. Process for preparing a pharmaceutical composition according
to claim 7, characterised in that a compound according to at
least one of claims 1 to 6 is incorporated in one or more inert
carriers and/or diluents by a non-chemical method.
10. Process for preparing the compounds of general formula I
according to claims 1 to 6, characterised in that
a) a compound of general formula
<IMG>
optionally formed in a reaction mixture
wherein
R a to R c, A, B, D, E and X are defined as in claims 1 to 5 and
Z1 denotes a leaving group,
is reacted with a compound of general formula
H - C ,(III)
wherein
C is defined as in claims 1 to 5 hereinbefore, or

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b) a compound of general formula
<IMG>
optionally formed in a reaction mixture
wherein
R a to R c, A, B, D, E and X are defined as in claims 1 to 5 and
C' denotes a correspondingly substituted N-(carboxymethyl)-N-
(2-hydroxyethyl)-amino or N-(C1-4-alkyloxycarbonymethyl)-N-
(2-hydroxyethyl)-amino group which can be converted into a
group C by cyclising, is cyclised, and
if necessary any protecting group used in the reactions
described above is cleaved again and/or
if desired a compound of general formula I thus obtained is
resolved into its stereoisomers and/or
a compound of general formula I thus obtained is converted into
the salts thereof, particularly, for pharmaceutical use, into
the physiologically acceptable salts thereof.

Description

CA 02417907 2003-O1-30
s
73889fft
Boehringer Ingelheim Pharma KG Case 5/1303
D-55216 Ingelheim/Rhein Foreign filing text
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 \ /Rb
N
NR~ - CO - A - B - C
X~ /
\ I . (I)
N D - E
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, especially 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 hydrogen atom or a methyl 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 RZ, which may be identical or different, in each
case denote a hydrogen, fluorine, chlorine, bromine or
iodine atom,

CA 02417907 2003-O1-30
,.
-
a methyl, ethyl, hydroxy, methoxy, ethoxy, amino, cyano,
vinyl or ethynyl group,
an aryl, aryloxy, arylmethyl or arylmethoxy group,
a methyl or methoxy group substituted by 1 to 3 fluorine
atoms or
R1 together with R2, if they are bound to adjacent carbon
atoms, denote a -CH=CH-CH=CH, -CH=CH-NH- or -CH=N-NH group
and
R~ denotes a hydrogen, fluorine, chlorine or bromine atom,
R~ denotes a hydrogen atom or a methyl group,
X denotes a methyne group substituted by a cyano group or a
nitrogen atom,
A denotes a 1,1- or 1,2-vinylene group which may be
substituted in each case by one or two methyl groups or by a
trifluorornethyl group,
an ethynylene group or
a 1,3-butadien-1,4-ylene group optionally substituted by a
methyl or trifluoromethyl group,
B denotes an alkylene or -CO-alkylene group wherein the
alkylene moiety in each case contains 1 to 4 carbon atoms,
while the linking of the -CO-alkylene group to the adjacent
group A in each case must take place via the carbonyl group,
a -CO-O-alkylene- or -CO-NR4-alkylene group wherein the
alkylene moiety in each case contains 1 to 4 carbon atoms,
while the linking to the adjacent group A in each case must
take place via the carbonyl group, wherein

CA 02417907 2003-O1-30
- 3 -
R4 denotes a hydrogen atom or a methyl ar ethyl group,
or a carbonyl group,
C denotes a 2-oxo-morpholin-4-yl group substituted by the
group RS or by the group RS and a Cl_4-alkyl group, while
RS denotes a C3_4-alkyl, hydroxy-Cl_4-alkyl, Cl_4-alkoxy-
C~_Q-alkyl, di- (Cl_4-alkyl) -amino-Cl_4-alkyl, pyrrolidino-
Cl_4-alkyl, piperidino-Cl_4-alkyl, rnorpholino-Cl_4-alkyl,
4- (Cl_~-alkyl) -piperazino-Cl_4-alkyl, Cl_4-alkylsulphanyl-
Cl_4-alkyl, Cl_~-alkylsulphinyl-Cl_4-alkyl, Cl_4-alkylsulphonyl-
Cl_4-alkyl, cyano-Cl_4-alkyl, Cl_4-alkoxycarbonyl-Cl_4-alkyl,
aminocarbonyl-Cl_4-alkyl, Cl_4-alkyl-aminocarbonyl-Cl_4-alkyl,
di- (Cl_4-alkyl) aminocarbonyl-Cl_4-alkyl, pyrrolidinocarbonyl-
C1_4-alkyl, piperidinocarbonyl-Cl_4-alkyl,
morpholinocarbonyl-C1_4-alkyl or a 4-(Cl_4-alkyl)-piperazino-
carbonyl-Cl_4-alkyl group,
a 2-oxo-morpholin-4-yl group substituted by two groups RS,
where RS is as hereinbefore defined and the two groups RS may
be identical or different,
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of
a methylene group are replaced by a - (CHZ) m, -CHZ-Y-CH2 ,
-CHZ-Y-CH2-CHZ, -CHZCHZ-Y-CH2CH2- or -CHZCHz-Y-CH2CHZCH2- bridge
optionally substituted by one or two C1_2-alkyl groups, while
m denotes the number 2, 3, 4, 5 or 6 and
Y denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl
or Cl_4-alkylimino group,
a 2-oxo-morpholin-4-yl group, wherein a hydrogen atom in the 5
position together with a hydrogen atom in the 6 position is
replaced by a - (CH2) n, -CHZ-Y-CH2, -CH2-Y-CHaCH2- or -CH2CH2-Y-CHZ-
bridge, while

CA 02417907 2003-O1-30
- 4 -
Y is as hereinbefore defined and
n denotes the number 2, 3 or 4,
or, if D together with E denotes a group Rd, it may also denote
a 2-oxo-morpholin-4-yl group which may be substituted by 1 to
4 Cl_2-alkyl groups,
D denotes a -O-C1_6-alkylene group, while the alkylene moiety is
linked to the group, E, or
an oxygen atom, while this may not be linked to a nitrogen
atom of the group E, and
E denotes an amino group substituted by 2 C1_4-alkyl groups,
wherein the alkyl groups may be identical or different and
each alkyl moiety may be substituted from the 2 position by a
Cl_g-alkoxy or dl- (C1_4-alkyl) -amino group or by a 4- to 7-
membered alkyleneimino group, while in the abovementioned 6-
to 7-membered alkyleneimino groups in each case a methylene
group may be replaced in the 4 position by an oxygen or
sulphur atom or by a sulphinyl, sulphonyl- or N-(C1_4-alkyl)-
imino group,
a 4- to 7-membered alkyleneimino group optionally substituted
by 1 to 4 methyl groups,
a 6- to 7-membered alkyleneimino group optionally substituted
by 1 or 2 methyl groups, wherein in each case a methylene
group in the 4 position is replaced by an oxygen or sulphur
atom or by a sulphinyl, sulphonyl- or N-(C1_4-alkyl?-imino
group,
an imidazolyl group optionally substituted by 1 to 3 methyl
groups,

CA 02417907 2003-O1-30
a CS_.,-cycloalkyl group, wherein a methylene group is replaced
by an oxygen or sulphur atom or by a sulphinyl, sulphonyl or
N- (Cl_4-alkyl) -imino group, or
D together with E denotes a hydrogen atom,
a Cl_6-alkoxy group optionally substituted from the 2 position
by a hydroxy- or C1_4-alkoxy group,
a C3_.,-cycloalkoxy- or C3_.,-cycloalkyl-Cl_4-alkoxy group,
or a group Rd, where
Rd denotes a CZ_6-alkoxy group which is substituted from the
2 position by a C4_.,-cycloalkoxy- or C3_,- cycloalkyl-
Cl_3-alkoxy group,
a C4_.,-cycloalkoxy- or C3_7-cycloalkyl-Cl_s-alkoxy group
wherein the cycloalkyl moiety in each case is substituted
by a Cl_4-alkyl, C1_4-alkoxy, di- (C1_4-alkyl) -amino,
pyrrolidino, piperidino, morpholino, piperazino,
4- (Cl_2-alkyl) -piperazino, Cl_4-alkoxy-Cl_2-alkyl, di-
(Cl_4-alkyl) -amino-Cl_2-alkyl, pyrrolidino-Cl_2-alkyl,
piperidino-Cl_2-alkyl, morpholino-Cl_2-alkyl, piperazino-
C1_2-alkyl- or 4- (Cl_2-alkyl) -piperazino-Cl_2-alkyl group,
while the abovementioned cycloalkyl moieties may
additionally be substituted by a methyl or ethyl group,
while, unless otherwise stated, by the aryl moieties mentioned
in the definition of the abovementioned groups is meant a
phenyl group which may be mono- or disubstituted by R6, while
the substituents may be identical or different and
R6 denotes a fluorine, chlorine, bromine or iodine atom, a
Cl_2-alkyl, trifluoromethyl or Cl_2-alkoxy group, or

,
3
CA 02417907 2003-O1-30
- 6 -
two groups R6, if they are bound to adjacent carbon atoms,
together represent a C3_4-alkylene, methylenedioxy or
1,3-butadien-1,4-ylene group.
Preferred compounds of the above general formula I are those .
wherein
Ra denotes a hydrogen atom,
Rb denotes a benzyl,or 1-phenylethyl group or a phenyl group
substituted by thegroups R1 and R2, while
R1 denotes a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl, cyano or ethynyl group and
R2 denotes a hydrogen or fluorine atom,
R~ denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a 1,2-vinylene group,
B denotes a Cl_4-alkylene group,
C denotes a 2-oxo-morpholin-4-yl group substituted by the
group RS or by the group RS and a Cl_4-alkyl group, while
RS denotes a C3_a-alkyl, Cl_Z-alkoxy-C~_4-alkyl, di- (Cl_2-
alkyl) -amino-Cl_4-alkyl, pyrrolidina-Cl_4-alkyl, piperidino-
Cl_4-alkyl, morpholino-Cl_4-alkyl, 4- (Cl_2-alkyl) -piperazino-
Cl_4-alkyl, C~_2-alkylsulphanyl-Cl_~-alkyl, Cl_2-alkylsulphinyl-
Cl_4-alkyl, Cl_2-alkylsulphonyl-Cl_4-alkyl, cyano-Cl_4-alkyl,
C1_2-alkoxycarbonyl-Cl_4-alkyl, aminocarbonyl-Cl_4-alkyl,
Cl_z-alkyl-aminocarbonyl-Cl_~-alkyl, di- (Cl_2-alkyl) -
aminocarbonyl-Cl_~-alkyl, pyrrolidinocarbonyl-Cl_4-alkyl,
piperidinocarbonyl-C1_4-alkyl, morpholinocarbonyl-C1_4-alkyl-
or a 4- (C1_2-alkyl) -piperazinocarbonyl-Cl_4-alkyl group,

CA 02417907 2003-O1-30
_ 7 _
a 2-oxo-morpholin-4-yl group substituted by two groups R5,
while RS is as hereinbefore defined and the two groups RS may
be identical or different,
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of
a methylene group are replaced by a - (CHz)m, -CHZ-Y-CH2,
-CHI-Y-CHZ-CHZ- or -CHZCHZ-Y-CHZCHZ-bridge, while
m denotes the number 2, 3, 4 or 5 and
Y denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl
or Cl_z-alkylimino group,
a 2-oxo-morpholin-4-yl group, wherein a hydrogen atom in the 5
position together with a hydrogen atom in the 6 position is
replaced by a - (CH2)n, -CH2-Y-CHz, -CHZ-Y-CHZCH2- or -CHZCHZ-Y-CHZ-
bridge, where
Y is as hereinbefore defined and
n denotes the number 2, 3 or 4,
or, if D together with E denotes a group Rd, it may also denote
a 2-oxo-morpholin-4-yl group which may be substituted by 1 or
2 methyl or ethyl groups,
D denotes a -O-C1_4-alkylene group, while the alkylene moiety is
linked to the group E, and
E denotes a dimethylamino, diethylamino, pyrrolidino,
piperidino, morpholino, 4-methyl-piperazino- or 4-ethyl-
piperazino group or
D together with E denotes a hydrogen atom,
a methoxy, ethoxy, 2-methoxy-ethoxy, 3-methoxy-propyloxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,

CA 02417907 2003-O1-30
-
tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or
tetrahydropyranylmethoxy group,
a cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclo-
propylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or
cyclohexylmethoxy group or
a group Rd, where
Rd denotes a 2-~cyclobutyloxy)-ethoxy, 2-(cyclopentyloxy)-
ethoxy, 2-(cyclopropylmethoxy)-ethoxy or 2-(cyclobutyl-
methoxy)-ethoxy group,
the tautomers, stereoisomers and salts thereof.
Particularly preferred compounds of the above general formula
I are those wherein
Ra denotes a hydrogen atom,
Rb denotes a 1-phenylethyl, 3-methylphenyl, 3-chlorophenyl,
3-bromophenyl- or 3-chloro-4-fluorophenyl group,
R~ denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a 1,2-vinylene group,
B denotes a methylene group,
C denotes a 2-oxo-morpholin-4-yl group which is substituted by
a methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl,
dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl,
diethylaminoethyl, cyanomethyl or cyanoethyl group,

CA 02417907 2003-O1-30
_ g _
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of
a methylene group are replaced by a -CH2CH2, -CH2CHzCHz,
-CHZCHZCH2CHa, -CHZCH2CHZCHzCH2, -CHz-O-CHZCH2, -CHz-NCH3-CH2CH2,
-CHz-NC2H5-CHZCH2, -CHZCH2-O-CHZCH2, -CHzCH2-NCH3-CHzCH2- or
-CHZCH2-NCZHS-CH2CH2- bridge,
a 2-oxo-morpholin-4-yl group, wherein a hydrogen atom in the 5
position together with a hydrogen atom in the 6 position is
replaced by a -CHZCHZCH2, -CH2CHZCHZCHz, -CHZ-O-CHz, -CHZ-NCH-CHz,
-CHZ-NCZHS-CH2, -CHZ-O-CHzCH2, -CHz-NCH3-CH2CH2, -CH2-NCZHS-CHZCH2,
-CHZCHZ-O-CH2, -CHzCH2-NCH3-CH2- or -CHZCH2-NC2H5-CHz- bridge,
or, if D together with E denotes a group Rd, it may also denote
a 2-oxo-morpholin-4-yl group which is substituted by 1 or 2
methyl groups, and
D together with E denotes a hydrogen atom,
a methoxy, ethoxy, 2-methoxy-ethoxy, 3-methoxy-propyloxy,
tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or
tetrahydrofuranylmethoxy group,
a cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy,
cyclobutylmethoxy or cyclopentylmethoxy group or
a group Rd, where
Rd denotes a 2-(cyclobutyloxy)-ethoxy, 2-(cyclopentyloxy)-
ethoxy, 2-(cyclopropylmethoxy)-ethoxy or
2-(cyclobutylmethoxy)-ethaxy group,
the tautomers, stereoisomers and salts thereof.
Most particularly preferred compounds of the above general
formula I are those wherein
Ra denotes a hydrogen atom,

CA 02417907 2003-O1-30
- 1~
Rb denotes a 3-chloro-4-fluorophenyl group,
R~ denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a I,2-vinylene group,
B denotes a methyle,ne group,
C denotes a 2-oxo-morpholin-4-yl group which is substituted by
a methoxymethyl or methoxyethyl group, or
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of
a methylene group are replaced by a -CHZCH2-O-CHZCHZ- bridge,
and
D together with E denotes a hydrogen atom, a methoxy or
cyclopropylmethoxy group,
the tautomers, stereoisomers and salts thereof.
The following particularly preferred compounds of the above
general formula I are mentioned by way of example:
(1) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-{ [4- ( (R) -2-methoxy-
methyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-
7-cyclopropylmethoxy-quinazoline,
(2) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-{ [4- (2-oxo-1, 9-
dioxa-4-aza-spiro[5.5]undec-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxy-quinazoline and
(3 ) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- ( {4- [2- (2-methoxy-
_.ethyl)-6-oxo-morpholin-4-yl]-1-oxo-2-buten-1-yl}amino)-
7-cyclopropylmethoxy-quinazoline,

CA 02417907 2003-O1-30
1. I. -
the tautomers, stereoisomers and salts thereof.
The compounds of general formula I may be prepared, for
example, by the following methods:
a) reacting a compound of general formula
Ra ~
N
NR~ - CO - A - B - Zl
X ~' /
\ ~ . (II)
N D - E
optionally formed in a reaction mixture,
wherein
Ra to R~, A, B, D, E and X are as hereinbefore defined and
Z1 denotes a leaving group such as a halogen atom, e.g. a
chlorine or bromine atom, or a hydroxy group,
with a compound of general formula
H - C , (III?
wherein
C is as hereinbefore defined.
The reaction is optionally carried out in a solvent or mixture
of solvents such as acetonitrile, methylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane optionally
in the presence of an inorganic or organic base and optionally
in the presence of an activating agent, expediently at
temperatures between -50 and 150°C, preferably at temperatures
between -20 and 100°C.

CA 02417907 2003-O1-30
- 12 -
With a compound of general formula II wherein Z1 denotes a
leaving group, the reaction is optionally carried out in a
solvent or mixture of solvents such as methylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane
conveniently in the presence of a tertiary organic base such
as triethylamine or N-ethyl-diisopropylamine, wherein these
organic bases may simultaneously serve as solvent, or in the
presence of an inorganic base such as sodium carbonate or
potassium carbonate" expediently at temperatures between -50
and 150°C, preferably at temperatures between -20 and 100°C.
With a compound of general formula II wherein Z1 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, dioxane, toluene, chlorobenzene, ethylene
glycol diethyl ether or sulpholane and optionally in the
presence of a reaction accelerator such as sodium iodide at
temperatures between -SO and 150°C, but preferably at
temperatures between -20 and 100°C.
b) cyclising a compound of general formula
Ra \ /Rb ..
N
NRC - CO - A - B - C '
X '~
\ ~ ~ HIV)
N D - E
optionally formed in a reaction mixture
wherein
R$ to R~, A, B, D, E and X are as hereinbefore defined and
C' denotes a correspondingly substituted N-(carboxymethyl)-N-
t2-hydroxyethyl)-amino or N-tCl_4-alkyloxycarbonymethyl)-N-

CA 02417907 2003-O1-30
- 13 -
(2-hydroxyethyl)-amino group which can be converted into a C
group by cyclisation.
The reaction is optionally carried out in a solvent or mixture
of solvents such as methylene chloride, acetonitrile,
dirnethylformamide, dimethylsulphoxide, sulpholane, benzene,
toluene, chlorobenzene, tetrahydrofran,
benzene/tetrahydrofuran or dioxane, 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'-dicyclohexyl carbodiimide, N,N'-dicyclohexyl
carbodiimidejN-hydroxysuccinimide or 1-hydroxy-benzotriazole,
N,N'-carbonyldiimidazole or triphenylphosphinejcarbon
tetrachloride, at temperatures between -20 and 200°C, but
preferably at temperatures between -10 and 160°C.
In the reactions described hereinbefore, any reactive groups
present such as hydroxy, carboxy or imino groups maybe
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,
a protecting group for a carboxyl group may be a
trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or
tetrahydropyranyl group and
protecting graups for an imino group may be a formyl, acetyl,
trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,
benzyloxycarbonyl, benzyl, rnethoxybenzyl or 2,4-diethoxybenzyl
group.

CA 02417907 2003-O1-30
- 14 -
Any protecting group used is optionally subsequently cleaved
for example by hydrolysis in an aqueous solvent, e.g. in
water, isopropanol/water, acetic acid/water,
tetrahydrofuran/water or dioxane/water, in the presence of an
acid such as trifluoroacetic acid, hydrochloric acid or
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,
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,
dioxane, methanol or diethylether.
A trifluoracetyl 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

CA 02417907 2003-O1-30
- 15 -
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 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 aryl group in amides, for
example, may be a (+)-or (-)-menthyloxycarbonyl.

CA 02417907 2003-O1-30
- 16 -
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,
phosphoric acid, fumaric acid, succinic acid, lactic acid,
citric acid, tartaric acid or malefic acid.
The compounds of general formulae II to IV used as starting
materials are knows from the literature in some cases or may be
obtained by methods known from the literature (see Examples I
to VII) .
As already mentioned hereinbefore, the compounds of general
formula I according to the invention and the physiologically
acceptable salts thereof have valuable pharmacological
properties, particularly an inhibiting effect on signal
transduction mediated by the Epidermal Growth Factor receptor
(EGF-R), whilst this may be achieved for example by inhibiting
ligand bonding, receptor 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 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
EMB4 J. 2, 2749-2756 (1988) and Pierce, J. H. et al. in
Science 2.~, 628-631 (1988)).

CA 02417907 2003-O1-30
- 17 -
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).
Alternatively, however, other growth-factor-dependent cells
may also be used (cf. for example Pierce, J. H. et al. in
Science 2~., 628-631 (1988), Shibuya, H. et al. in Cell 7~,
57-67 (1992) and Alexander, W. S. et al. in EMBO J. 1Q, 3683-
3691 (1991)). For expressing the human EGF-R cDNA (cf.
Ullrich, A. et al. in Nature 3~, 418-425 (1984)) recombinant
retroviruses were used as described by von Riiden, T. et al.,
EMBO J. 2, 2749-2756 (1988), except that the retroviral vector
LXSN (cf. Miller, A. D. et al. in BioTechniques 2, 980-990
(1989)) was used for the expression of the EGF-R cDNA and the
line GP+E88 (cf. Markowitz, D. et al. in J. Virol. ~, 1120-
1124 (1988)) was used as the packaging cell.
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% C02. 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), the cell proliferation being stimulated with
either EGF (20 ng/ml) or marine 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. Imcnunol. 1$, 97-104
(1988)). The compounds according to the invention were
dissolved in 100°s 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-

CA 02417907 2003-O1-30
- 18 -
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 500 (IC50) was derived therefrom. The following results
were obtained:
Compound Inhibition of the EGF-dependent
(Example No.) proliferation IC50 [nM]
1 .' 2
The compounds of general formula I according to the invention
thus inhibit the 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 increased or altered production of
mucus caused by stimulation of tyrosine kinases, e.g. in
inflammatory diseases of the airways such as chronic
bronchitis, chronic obstructive bronchitis, asthma,
bronchiectasias, 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

CA 02417907 2003-O1-30
- 19 -
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,
also for treating nasal polyps and polyps of the
gastrointestinal tract of various origins, such as for example
villous or adenomatous polyps of the large bowel, but also
polyps in familial polyposis coli, intestinal polyps in
Gardner's syndrome, polyps throughout the entire
gastrointestinal tract in Peutz-Jeghers Syndrome, inflammatory
pseudopolyps, juvenile polyps, colitis cystica profunda and
pneumatosis cystoides intestinales.
Moreover, the compounds of general formula I and the
physiologically acceptable salts thereof may be used to treat
kidney diseases, particularly cystic changes as in cystic
kidneys, for treating renal cysts which may be idiopathic in
origin or which occur in syndromes such as e.g. tubercular
sclerosis, in von-Hippel-Lindau Syndrome, in nephronophthisis
and spongy kidney and other diseases caused by abnormal
functioning of tyrosine kinases such as e.g. epidermal hyper-
proliferation (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. inter-

CA 02417907 2003-O1-30
- 20 -
ferons?, antibodies, etc. For treating respiratory tract
diseases, these compounds may be used on their own or in
conjunction with other therapeutic agents for the airways, such
as substances with a secretolytic, broncholytic and/or anti-
inflammatory activity. Far 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 an motility or secretion or with 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, intrarectal, 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
0.1-35 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, polyvinylpyrralidone, 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 02417907 2003-O1-30
- 21 -
Preparation of the starting products:
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-[(ethoxy-
carbonyl)methyl]-N-((R)-2-hydroxy-3-methoxy-propyl)-amino}-1-
1.34 ml of oxalyl chloride are pipetted into 1.29 g of
bromocrotonic acid in 30 ml of methylene chloride, then
another 65 ~.1 of N,N-dimethylformamide are added. The reaction
mixture is stirred for about 45 minutes at ambient temperature
until the development of gas has ceased, and then evaporated
to dryness. The crude bromocrotonic acid chloride is taken up
in 15 ml of methylene chloride and, while being cooled in an
ice bath, added dropwise within five minutes to a solution of
2.00 g of 6-amino-4-[(3-chloro-4-fluoro-phenyl}amino]-7-
cyclopropylmethoxy-quinazoline and 2.91 ml of
diisopropylethylamine in 60 ml of tetrahydrofuran. The
reaction mixture is stirred for 45 minutes while cooling with
an ice bath, then stirred for two hours at ambient
temperature. Then a solution of 1.80 g of ethyl ((R)-2-
hydroxy-3-methoxy-propylamino)-acetate in 5 ml of tetra-
hydrofuran is added. The reaction mixture is heated to 60°C
for about 40 hours. To work it up, the reaction mixture is
evaporated down. The flask residue is dissolved in 200 ml of
ethyl acetate, washed with 5% citric acid solution and
saturated sodium chloride solution and evaporated down to
about 100 ml. The concentrate is chromatographed through a
silica gel column using ethyl acetate/methanol (100:0 to
70:30) as eluant. The title compound is obtained, contaminated
with some already cyclised product, as a brownish foam.
Yield: 1.10 g (32 0 of theory),
Rf value: 0.42 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI-) : mjz = 614, 616 [M-H]

CA 02417907 2003-O1-30
- 22 -
The following compound is obtained analogously to Example I:
(1) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [ (4-{N- [ (4-hydroxy-
tetrahydropyran-4-yl)methyl]-N-[(ethoxycarbonyl)methyl]-
amino)-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-
guinazoline
Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI-) : m/z = 640, 642 [M-H]
( 2 ) 4- [ ( 3 -chloro-4 -,f luoro-phenyl ) amino ] -6- [ ( 4- { N-
[(ethoxycarbonyl)methyl]-N-((S)-2-hydroxy-3-methoxy-propyl)-
amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-
quinazoline
Rf value: 0.30 (silica gel, methylene chloride/methanol = 20:1)
Mass spectrum (ESI+): m/z = 616, 618 [M+H]+
6-amino-4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropyl-
36.02 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-7-
cyclopropylmethoxy-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, whereupon the substance goes
into solution. 20.70 g of iron powder are then cautiously
added batchwise. After 30 minutes the reaction is complete and
the reaction mixture is evaporated to dryness. The residue is
taken up in 1200 m1 of methylene chloride/methanol (9:1) and
made alkaline with 33o ammonia solution. The iron slurry is
suction filtered through a high-speed filter and washed with
500 ml of methylene chloride/methanol (9:1). The brown
filtrate is filtered through a silica gel package, washed with
a total of 2000 ml of methylene chloride/methanol (9:1) and
evaparated down. The flask residue is suspended with 140 ml of
diethylether, suction filtered and and dried in the air.
-Yield: 29.70 g (89 % of theory),

CA 02417907 2003-O1-30
- 23 -
Melting point: 208°C
Mass spectrum (ESI') : m/z = 359, 361 [M+H]'
4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-6-
29.36 g of cyclopropylmethanol are dissolved in 310 ml of N,N-
dirnethylformamide and cooled to about 10°C in an ice bath.
Then 41.58 g of potassium tert. butoxide are added batchwise,
while the temperature should remain below 15°C. The reaction
mixture is then stirred for another 30 minutes at 10°C, after
which time 31.19 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-7-
fluoro-6-nitro-quinazoline are added batchwise, while again
the temperature should not exceed 15°C. The deep 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 0 of theory),
Melting point: 204°C
Mass spectrum (ESI+) : m/z = 389, 391 [M+H]+
Eth~rl ( fR~~rdroxy-~-m _ -h~x~r-nropyl ami nnl -ar~At-arP
The crude product solution of ethyl [N-benzyl-N-((R)-2-
hydroxy-3-methoxy-prop-1-yl)-amino]-acetate in ethanol
obtained in Example ~l is combined with another 20 ml of
absolute ethanol and hydrogenated in the presence of 500 mg of
palladium (l00 on activated charcoal) as catalyst for about
another four hours at ambient temperature until the calculated
amount of hydrogen has been absorbed. For working up, the
catalyst is filtered off and the filtrate is evaporated down
in vacuo, leaving a colourless viscous oil.

CA 02417907 2003-O1-30
- 24 -
Yield: 1.90 g (88 % of theory),
Rf value: 0.48 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+) : mjz = 192 [M+H]
The following compounds are obtained analogously to Example
IV:
(1) (2-hydroxy-4-methoxy-butylamino)-acetic acid
(The hydrogenation is carried out in a mixture of
methanol/water = 10,:1. )
Rf value: 0.80 (Reversed phase ready-made TLC plate (E. Merck),
acetonitrile/water/trifluoroacetic acid = 50:50:1)
Mass spectrum (ESI-) : m/z = 176 [M-H]
(2) ethyl ((S)-2-Hydroxy-3-methoxy-propylamino)-acetate
Mass spectrum (EI): m/z = 191 [M]f
Ethyl [N-benzyl-N-((R)-2-hydroxy-3-methoxy-propyl)-amino]-
ar_et-.at-e
A mixture of 2.20 g of ethyl N-benzylamino-acetate and 1.00 g
of (R) (-) -2- (methoxymethyl) -oxirane (Fluka) in 10 ml of
absolute ethanol is left to stand over a weekend under an
argon atmosphere. The crude product solution obtained is
further reacted without any more purification.
Rf value: 0.57 (silica gel, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (ESI+) : m/z = 282 [M+H]
The following compounds are obtained analogously to Example V:
(1) [N-benzyl-N-(2-hydroxy-4-methoxy-butyl)-amino]-acetic acid
(the reaction is carried out with N-benzylglycine in 1N sodium
hydroxide solution.)
Rf value: 0.57 (Reversed phase ready-made TLC plate (E. Merck),
-acetonitrile/water/trifluoroacetic acid = 50:50:1)

CA 02417907 2003-O1-30
- 25
Mass spectrum (ESI-) : m/z = 266 [M-H]
(2) ethyl [N-benzyl-N-((S)-2-hydroxy-3-methoxy-propyl)-amino)-
acetate
Rf value: 0.5? (silica gel, cyclohexane/ethyl acetate = 1:l)
Mass spectrum (ESI+): m/z = 282 [M+HJ+
5.30 g of glycine ethyl ester hydrochloride are dissolved in
ml of saturated potassium carbonate solution. Then 10 g of
solid potassium carbonate are added while cooling with an ice
bath. The mass formed is extracted thoroughly several times
with diethylether. The combined ether extracts are dried over
sodium sulphate and evaporated down. The glycine ethyl ester
is dissolved together with 4.20 g 1,6-dioxa-spiro[2.5]octane
in 20 ml of absolute ethanol and and heated to 90°C for about
six hours in a Rath bomb. After cooling to ambient temperature
the reaction mixture is evaporated down. The yellowish oily
crude product is further reacted without any more
purification.
Mass spectrum (ESI+) : m/z = 240 [M+Na]
11.94 ml of thionylchloride are added dropwise, within 20
minutes, to a suspension of 5.80 g of (2-hydroxy-4-methoxy-
butylamino)-acetic acid in 200 ml methanol while cooling with
an ice bath. The reaction mixture is allowed to come up to
ambient temperature overnight. For working up, the cloudy
solution is evaporated to dryness. The residue is stirred
several times with 100 ml aliquots of methanol, which is then
distilled off in vacuo using the rotary evaporator. The

CA 02417907 2003-O1-30
- 26 -
viscous crude product is reacted further without any
additional purification. '
Yield: 8.70 g,
Mass spectrum (ESI') : m/z = 192 [M+H]'
Preparation of the final compounds:
Example 1
4- [ (3-chloro-4-fluoro-phenyl) amino] -6-{ [4- ( (R) -2-
methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-
7-cycloprooylmethoxy-quinazoline
950 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-
[(ethoxycarbonyl)methyl]-N-((R)-2-hydroxy-3-methoxy-propyl)-
amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-
quinazoline and 195 ~l of methanesulphonic acid in 10 ml
acetonitrile are refluxed for about four hours. For working
up, the reaction mixture is cooled in a bath of ice water,
mixed with 75 ml of ethyl acetate and 25 ml of saturated
sodium hydrogen carbonate solution and vigorously stirred for
minutes. The organic phase is separated off, washed with
saturated sodium hydrogen carbonate solution and saturated
sodium chloride solution and dried over magnesium sulphate.
The solvent is distilled off in vacuo, leaving a brownish
foam.
Yield: 610 mg (69 % of theory),
Rf value: 0.55 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 570, 572 [M+H]+
The following compounds are obtained analogously to Example 1:
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(2-oxo-1,9-
dioxa-4-aza-spiro[5.5]under-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxy-quinazoline
Rf value: 0.53 (silica gel, methylene chloride/methanol = 15:1)
-Mass spectrum (ESI-) : m/z = 594, 596 [M-H]

CA 02417907 2003-O1-30
- 27 -
(2) 4-[{3-chloro-4-fluoro-phenyl)amino]-6-{[4-((S)-2-
methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino)-
7-cyclopropylmethoxy-quinazoline
Rf value: 0.53 {silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI-): m/z = 568, 570 [M-H]-
4- [ (3-chloro-4-fluoro-phenyl) amino] -6- ( {4- [2- (2-methoxy-
ethyl)-6-oxo-morpholin-4-yl]-1-oxo-2-buten-1-yl}amino)-7-
~,yc~ l oz rp~~~lmet_h_~x~r~ ~ ; na .01 inn -
1.68 ml of oxalyl chloride are pipetted into 1.61 g of
bromocrotonic acid in 50 ml methylene chloride, then one more
drop of N,N-dimethylformamide is added. The reaction mixture
is stirred for about one hour at ambient temperature until the
development of gas has ceased, and then evaporated to dryness.
The crude bromocrotonic acid chloride is taken up in 20 ml of
methylene chloride and while cooling with an ice bath added
dropwise, within five minutes, to a solution of 2.50 g of 6-
amino-4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropyl-
methoxy-quinazoline and 12.14 ml of diisopropylethylamine in
75 ml of tetrahydrofuran. The reaction mixture is stirred for
one hour while cooling with an ice bath, then for another two
hours at ambient temperature. A solution of 8.20 g of methyl
(2-hydroxy-4-methoxy-butylamino)-acetate hydrochloride in 15
ml N,N-dimethylformamide is added in one go. The reaction
mixture is stirred for 24 hours at 75°C. For working up, the
reaction mixture is evaporated to dryness and the flask
residue is partitioned between 250 ml of ethyl acetate and 200
ml of 5% citric acid solution. The organic phase is washed
with saturated sodium chloride solution, dried over magnesium
sulphate and evaporated down. The crude product is purified by
chromatography through a silica gel column using ethyl acetate
as eluant. The cyclised product is obtained as a beige solid.
Yield: 825 mg (20 % of theory),
Rf value: 0.38 (silica gel, ethyl acetate)

CA 02417907 2003-O1-30
- 28 -
Mass spectrum (ESI-) : m/z = 582, 584 [M-H]
The following compounds may be prepared analogously to the
foregoing Examples and other methods known from the
literature:
(1) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-{ [4- ( (S) -2-
methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-
7-methoxy-quinazoline
(2) 4- [ (3-chloro-4-fluoro-phenyl) amino -6- { [4- ( (S) -2-methoxy-
methyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-
quinazoline
(3) 4- ( (R) - (1-phenyl-ethyl) amino] -6- ( {4- [2- (2-methoxy-ethyl) -
6-oxo-morphalin-4-yl]-1-oxo-2-buten-1-yl}amino)-quinazoline
(4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-({4-[3-(2-methoxy-
ethyl)-2-oxo-morpholin-4-yl]-1-oxo-2-buten-1-yl}amino)-
7-cyclopropylmethoxy-quinazoline
(5) 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(2-oxo-1,9-dioxa-
4-aza-spiro[5.5]under-4-yl?-1-oxo-2-buten-1-yl]amino}-
7-methoxy-quinazoline
(&) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(2-oxo-perhydro-
cyclopenta[1,4]oxazin-4-y1)-1-oxo-2-buten-1-yl]amino}-
7-methoxy-quinazoline
(7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(5-oxo-perhydro-
2,4-dioxa-7-aza-inden-7-yl)-1-oxo-2-buten-1-yl]amino}-
7-methoxy-quinazoline

CA 02417907 2003-O1-30
- 29 -
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 't.5 ma
230.0 mg
Pre= arat i on
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 apparatus and mixed with the rest of the
magnesium stearate. This granulate is campressed 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.

CA 02417907 2003-O1-30
- 30 -
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 ma
220.0 mg
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.

CA 02417907 2003-O1-30
- 31 -
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
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
1 capsule contains:
active substance 50.0 mg
corn starch tdried) approx. 80.0 mg
lactose (powdered) approx. 87.0 mg
magnesium stearate 3.0 ~g
approx. 420.0 mg

CA 02417907 2003-O1-30
- 32 -
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.
F, x m
1 suppository contains:
active substance 150.0 mg
polyethyleneglycol 1500 550.0 mg
polyethyleneglycol 6000 460.0 mg
polyoxyethylene sorbitan monostearate ~~o.o mg
2,000.0 mg
After the suppository mass has been melted the active substance
r is homogeneously distributed therein and the melt is poured
into chilled moulds.

CA 02417907 2003-O1-30
- 33 -
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 ad 100 ml
The distilled water is heated to 70°C. The methyl and propyl
p-hydroxybenzoates together with the glycerol and carboxy-
methylcellulose sodium salt 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.
ml of suspension contain 50 mg of active substance.
Composition:
active substance 10.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml

CA 02417907 2003-O1-30
- 34
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.
~po~ 1 P~ ron'r~ai ; nor 5(l-Iriy o - a . _i v . ~ ~b~ _an~
Composition:
active substance 50.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml
The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile
and transferred into 10 ml ampoules.
1 capsule contains:
active substance 5.0 mg
lactose fox inhalation ~5_o ma
20.0 mg

CA 02417907 2003-O1-30
- 35 -
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
1 spray contains:
active substance 2.500 mg
benzalkonium chloride 0.001 mg
1N hydrochloric acid q.s.
ethanol/water (50/50) ad 15.000 mg
The active substance and benzalkonium chloride are dissolved
in ethanol/water (50/50). The pH of the solution is adjusted
with 1N hydrochloric acid. The resulting solution is filtered
and transferred into suitable containers for use in hand-held
nebulisers (cartridges).
Contents of the container: 4.5 g