Note: Descriptions are shown in the official language in which they were submitted.
CA 02417042 2003-O1-22
r
73888fft
Boehringer Ingelheim Pharma KG Case 5/1301-FL
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
X ~
\ ~ . CI)
N C - D
the tautomers, the stereoisomers and the salts thereof,
particularly the physiologically acceptable salts thereof with
inorganic or organic acids or bases which have valuable
pharmacological properties, particularly an inhibitory effect
on signal transduction mediated by tyrosine kinases, the use
thereof for treating diseases, particularly tumoral diseases,
diseases of the lungs and respiratory tract, and the
preparation thereof.
In the above general formula I
Ra denotes a hydrogen atom or a methyl group,
Rb denotes a phenyl, benzyl or 1-phenylethyl group, wherein the
phenyl core is substituted in each case by the groups R1 to R3,
whilst
R1 and R2, which may be identical or different, each denote
a hydrogen, fluorine, chlorine, bromine or iodine atom,
CA 02417042 2003-O1-22
T t
- 2 -
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~ 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, each of which may be
substituted by one or two methyl groups or by a
trifluoromethyl group,
an ethynylene group, or
a 1,3-butadien-1,4-ylene group optionally substituted by a
methyl or trifluoromethyl group,
B denotes a hydrogen atom or a C,_4-alkyl group, a methyl group
substituted by 1 to 3 fluorine atoms, an ethyl group
substituted by 1 to 5 fluorine atoms, a C1_4-alkylcarbonyl,
carboxy, C1_4-alkoxycarbonyl, aminocarbonyl,
Cl_4-alkylaminocarbonyl, di- (C1_4-alkyl) -aminocarbonyl,
pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl or
a 4-(C1_4-alkyl)-piperazinocarbonyl group, or
a C1_4-alkyl group substituted by the group R4, whilst
CA 02417042 2003-O1-22
- 3 -
RQ denotes a Cl_4-alkoxy group,
an amino group substituted by two C1_4-alkyl groups, wherein
the alkyl groups may be identical or different and each
alkyl moiety may be substituted from position 2 by a
Cl_4-alkoxy- or di- (C1_4-alkyl) -amino group or by a 4- to
7-membered alkyleneimino group, whilst in the above-
mentioned 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, 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, by a sulphinyl, sulphonyl or
N- (C1_Z-alkyl) -imino group, or
an imidazolyl group optionally substituted by 1 to 3 methyl
groups,
C denotes a Cl_6-alkylene group, a -O-Cl_6-alkylene group, whilst
the alkylene moiety is linked to the group D, or an oxygen
atom, which may not be linked to a nitrogen atom of the group
D, and
D denotes a pyrrolidino group in which the two hydrogen atoms
are replaced in the 2-position by a group E, wherein
E denotes a -CH2-O-CO-CHZ-, -CHzCH2-O-CO-, -CHz-O-CO-CHzCH2-,
-CHZCH2-O-CO-CHZ- or -CHZCH2CHZ-O-CO- bridge optionally
substituted by one or two C1_2-alkyl groups,
CA 02417042 2003-O1-22
- 4 -
a pyrrolidino group in which the two hydrogen atoms are
replaced in the 3-position by a group F, wherein
F denotes a -O-CO-CHzCH2-, -CH2-O-CO-CHZ-, -CHZCHZ-O-CO-,
-O-CO-CHZCHZCHz-, -CHz-O-CO-CHZCHz-, -CHZCHZ-O-CO-CHZ-,
-CHzCHzCH2-O-CO-, -O-CO-CHZ-NRS-CHZ-, -CHZ-O-CO-CHZ-NRS-,
-O-CO-CHZ-O-CHZ- or -CHZ-O-CO-CH2-O- bridge optionally
substituted by one or two C1_2-alkyl groups, whilst
RS denotes a,hydrogen atom or a Cl_9-alkyl group,
a piperidino or hexahydroazepino group, wherein the two
hydrogen atoms are replaced in the 2-position by a group E,
where E is as hereinbefore defined,
a piperidino or hexahydroazepino group, wherein in each case
the two hydrogen atoms in the 3-position or in the 4-position
are replaced by a group F, where F is as hereinbefore defined,
a piperazino- or 4-(C1_9-alkyl)-piperazino group, wherein the
two hydrogen atoms in the 2-position or in the 3-position of
the piperazino ring are replaced by a group E, where E is as
hereinbefore defined,
a pyrrolidino or piperidino group, wherein two vicinal
hydrogen atoms are replaced by a -O-CO-CHZ-, -CHZ-O-CO-,
-O-CO-CHZCH2-, -CHZ-O-CO-CHZ-, -CH2CHz-O-CO-, -O-CO-CHz-NRS- or
-O-CO-CHZ-O- bridge optionally substituted by one or two
C1_z-alkyl groups, whilst RS is as hereinbefore defined and the
heteroatoms of the above-mentioned bridges are not bound to
the 2- or 5-position of the pyrrolidino ring and are not bound
to the 2- or 6-position of the piperidino ring,
a piperazino or 4-(C1_4-alkyl)-piperazino group, wherein a
hydrogen atom in the 2-position together with a hydrogen atom
in the 3-position of the piperazino ring are replaced by a
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-
-CH2-O-CO-CHZ- or -CHZCH2-O-CO- bridge optionally substituted by
one or two C1_2-alkyl groups,
a piperazino group in which a hydrogen atom in the 3-position
together with the hydrogen atom in the 4-position are replaced
by a -CO-O-CHzCH2- or -CHZ-O-CO-CHZ- bridge optionally
substituted by one or two C1_2-alkyl groups, whilst in each case
the left-hand end of the above-mentioned bridges is bound to
the 3-position of the piperazino ring,
a pyrrolidino, piperidino or hexahydroazepino group
substituted by the group R6, wherein
R6 denotes a 2-oxo-tetrahydrofuranyl, 2-oxo-tetra-
hydropyranyl, 2-oxo-1,4-dioxanyl or 2-oxo-4-(C1_4-alkyl)-
morpholinyl group optionally substituted by one or two
Cl_2-alkyl groups,
a pyrrolidino group substituted in the 3-position by a 2-oxo-
morpholino group, whilst the 2-oxo-morpholino group may be
substituted by one or two C1_2-alkyl groups,
a piperidino or hexahydroazepino group substituted in the 3-
or 4-position by a 2-oxo-morpholino group, whilst the 2-oxo-
morpholino group may be substituted by one or two C1_2-alkyl
groups,
a 4- (C1_4-alkyl) -piperazino or 4- (C1_4-alkyl) -homopiperazino
group substituted at a ring nitrogen atom by R6, wherein R6 is
as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4-
position by the group R." wherein
R., denotes a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-
tetrahydrofuran-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-
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- 6 -
tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group
optionally substituted by one or two C1_2-alkyl groups,
a pyrrolidino group substituted in the 3-position by a
(RSNR.,) -, R.,O-, R,S-, R.,SO- or R.,S02- group, whilst RS and R., are
as hereinbefore defined,
a piperidino or hexahydroazepino group substituted in the 3-
or 4-position by a (RSNR.,) -, R.,O-, R.,S-, R.,SO- or R.,SOz- group,
wherein RS and R, are as hereinbefore defined,
a pyrrolidino, piperidino or hexahydroazepino group
t- substituted b a R -C -alk 1-, (R NR ) -C -alk 1 R O-C
y 6 1-4 y 5 7 1-4 y ~ 7 1-4
alkyl-, R,S-Cl_4-alkyl-, R.,SO-Cl_4-alkyl-, R~SOZ-Cl_4-alkyl- or
(RSNR.,) -CO- group, wherein RS to R~ are as hereinbefore defined,
a pyrrolidino group substituted in the 3-position by a
R6-CO-NR4, R6-Cl_4-alkylene-CONR4, (RSNR~) -Cl_4-alkylene-CONRS,
RIO-Cl_4-alkylene-CONRS, R.,S-Cl_4-alkylene-CONRS,
R.,SO-Cl_4-alkylene-CONRS, R,SOZ-Cl_4-alkylene-CONRS, 2-oxo-
morpholino-Cl_4-alkylene-CONRS, R6-Cl_4-alkylene-Y or CZ_4-alkyl-Y
group, whilst the CZ_4-alkyl moiety of the Cz_4-alkyl-Y group is
substituted in each case from position 2 by a (RSNR~) -, R,O-,
R.,S-, R,SO- or R,SOZ- group and the 2-oxo-morpholino moiety may
be substituted by one or two C1_z-alkyl groups, wherein
RS to R, are as hereinbefore defined and
Y denotes an oxygen or sulphur atom, an imino,
N-(C1_4-alkyl)-imino, sulphinyl or sulphonyl group,
a piperidino- or hexahydroazepino group substituted in the 3-
or 4-position by a R6-CO-NRS, R6-Cl_4-alkylene-CONRS,
(RSNR.,) -Cl_4-alkylene-CONRS, R.,O-Cl_4-alkylene-CONRS,
R.,S-C1_4-alkylene-CONRS, R.,SO-Cl_4-alkylene-CONRS,
R.,SOz-C1_4-alkylene-CONRS, 2-oxo-morpholino-Cl_4-alkylene-CONRS,
R6-C1_4-alkylene-Y or CZ_4-alkyl-Y group, wherein Y is as
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hereinbefore defined, the 2-oxo-morpholino moiety may be
substituted by one or two Cl_z-alkyl groups and the CZ_4-alkyl
moiety of the Cz_4-alkyl-Y group is substituted in each case
from position 2 by a (RSNR.,) -, R.,O-, RCS-, R.,SO- or R.,SOZ- group,
whilst RS to R~ are as hereinbefore defined,
a 4- (C1_4-alkyl) -piperazino or 4- (C1_4-alkyl) -homopiperazino
group substituted at a ring nitrogen atom by a R6-C,_4-alkyl-,
(RSNR~) -Cl_4-alkyl-, R.,O-C,_4-alkyl-, R.,S-Cl_4-alkyl-, R.,SO-Cl_4-
alkyl-, R.,SOZ-C1_4-alkyl- or RSNR.,-CO- group, wherein RS to R., are
as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4-
position by a R6-Cl_4-alkyl-, R6-CO-, R6-Cl_4-alkylene-CO-,
(RSNR.,) -Cl_4-alkylene-CO-, R.,O-C1_4-alkylene-CO-, RCS-Cl_9-alkylene-
CO-, R.,SO-Cl_4-alkylene-CO- or R~SOz-Cl_4-alkylene-CO- group,
wherein RS to R., are as hereinbefore defined,
a piperazino or homopiperazino group substituted in the 4-
position by a C2_4-alkyl group, wherein the Cz_4-alkyl group is
substituted in each case from position 2 by a (RSNR~) -, R.,O-,
R,S-, R.,SO- or R~SOZ- group, whilst RS and R., are as hereinbefore
defined,
a pyrrolidino, piperidino- or hexahydroazepino group
substituted by a 2-oxo-morpholino-C1_4-alkyl group, wherein the
2-oxo-morpholino moiety may be substituted by one or two
Cl_2-alkyl groups,
a pyrrolidino group substituted in the 3-position by a
CZ_q-alkyl-Y group, wherein Y is as hereinbefore defined and the
Cz_4-alkyl moiety of the CZ_4-alkyl-Y group is substituted in
each case from position 2 by a 2-oxo-morpholino group
optionally substituted by one or two C1_2-alkyl groups,
a piperidino or hexahydroazepino group substituted in the 3-
or 4-position by a C2_4-alkyl-Y group, wherein Y is as
CA 02417042 2003-O1-22
hereinbefore defined and the Cz_4-alkyl moiety of the
CZ_4-alkyl-Y group is substituted in each case from position 2
by a 2-oxo-morpholino group optionally substituted by one or
two Cl_z-alkyl groups,
a 4- (C1_4-alkyl) -piperazino- or 4- (Cl_4-alkyl) -homopiperazino
group substituted at a ring nitrogen atom by a 2-oxo-
morpholino-C1_4-alkyl group, wherein the 2-oxo-morpholino moiety
may be substituted by one or two C1_2-alkyl groups,
a piperazino or homopiperazino group substituted in the 4-
position by a 2-oxo-morpholino-C1_4-alkylene-CO group, wherein
the 2-oxo-morpholino moiety may be substituted by one or two
Cl_Z-alkyl groups,
a piperazino or homopiperazino group substituted in the 4-
position by a Cz_4-alkyl group, wherein the C2_4-alkyl moiety is
substituted in each case from position 2 by a 2-oxo-
morpholino group optionally substituted by one or two C1_Z-alkyl
groups,
a pyrrolidinyl or piperidinyl group substituted in the 1-
position by the group R." by a R6-Cl_4-alkyl-, R6-CO-, R6-Cl_4-
alkylene-CO-, (RSNR.,) -Cl_4-alkylene-CO-, RIO-Cl_4-alkylene-CO-,
RCS-Cl_4-alkylene-CO-, R,SO-Cl_4-alkylene-CO-, R.,SOZ-Cl_4-alkylene-
CO- or 2-oxo-morpholino-C,_4-alkylene-CO- group, wherein RS to R.,
are as hereinbefore defined and the 2-oxo-morpholino moiety
may be substituted by one or two C1_z-alkyl groups,
a pyrrolidinyl or piperidinyl group substituted in the 1-
position by a CZ_4-alkyl group, wherein the Cz_4-alkyl moiety is
substituted in each case from position 2 by a (RSNR~)-, R.,O-,
R.,S-, R,SO-, R.,SOz- or 2-oxo-morpholino group, whilst RS and R.,
are as hereinbefore defined and the 2-oxo-morpholino moiety
may be substituted by one or two C,_z-alkyl groups,
CA 02417042 2003-O1-22
_ g _
a pyrrolidin-3-yl-NRS, piperidin-3-yl-NRS or piperidin-4-yl-NRS
group substituted at the ring nitrogen atom in each case by
the group R." by a R6-Cl_4-alkyl-, R6-CO-, R6-Cl_4-alkylene-CO-,
(RSNR.,) -Cl_4-alkylene-CO-, RIO-Cl_4-alkylene-CO-, R.,S-Cl_4-alkylene-
CO-, R.,SO-C1_4-alkylene-CO-, R,SOZ-Cl_4-alkylene-CO- or 2-oxo-mor-
pholino-Cl_4-alkylene-CO- group, wherein RS to R., are as
hereinbefore defined and the 2-oxo-morpholino moiety may be
substituted by one or two C1_2-alkyl groups,
a pyrrolidin-3-yl-NRS, piperidin-3-yl-NRS or piperidin-4-yl-NRS
group substituted in each case at the ring nitrogen atom by a
C2-4 alkyl group, wherein the CZ_4-alkyl moiety is substituted in
each case from position 2 by a (RSNR~) -, RIO-, RCS-, R~SO-,
R.,SOZ- or 2-oxo-morpholino group, whilst RS and R~ are as
hereinbefore defined and the 2-oxo-morpholino moiety may be
substituted by one or two C1_z-alkyl groups,
a R6-Cl_4-alkylene-NRS group in which RS and R6 are as
hereinbefore defined, or
a CZ_4-alkyl-NR4 group, wherein the Cz_4-alkyl moiety is
substituted in each case from position 2 by a (RSNR~) -, R.,O-,
R?S-, R~SO-, R.,SOZ- or 2-oxo-morpholino group, whilst RS and R.,
are as hereinbefore defined and the 2-oxo-morpholino moiety
may be substituted by one or two C1_2-alkyl groups,
a 2-oxo-morpholin-4-yl group substituted by the group Re or by
the group R8 and a Cl_4-alkyl group, whilst
R8 denotes a C3_4-alkyl, hydroxy-Cl_4-alkyl, Cl_4-alkoxy-Cl_4-
alkyl, di- (Cl_4-alkyl) -amino-Cl_4-alkyl, pyrrolidino-Cl_4-al-
kyl, piperidino-Cl_4-alkyl, morpholino-Cl_4-alkyl,
4- (C,_4-alkyl) -piperazino-Cl_4-alkyl, C1_4-alkylsulphanyl-
C1_4-alkyl, C1_4-alkylsulphinyl-C1_4-alkyl, Cl_4-alkylsulphonyl-
Cl_4-alkyl, cyan-Cl_4-alkyl, Cl_4-alkoxycarbonyl-C~_4-alkyl,
aminocarbonyl-Cl_4-alkyl, Cl_4-alkyl-aminocarbonyl-Cl_4-alkyl,
di- (Cl_4-alkyl) -aminocarbonyl-Cl_4-alkyl, pyrrolidino-
CA 02417042 2003-O1-22
- 1~ -
carbonyl-Cl_4-alkyl, piperidinocarbonyl-C1_4-alkyl,
morpholinocarbonyl-Cl_4-alkyl or a 4- (C1_4-alkyl) -piperazino-
carbonyl-C1_4-alkyl group,
a 2-oxo-morpholin-4-yl group substituted by two groups R8,
whilst RB is as hereinbefore defined and the two groups RB may
be identical or different,
a 2-oxo-morpholin-4-yl group in which the two hydrogen atoms
of a methylene growp are replaced by a - (CHZ)m-, -CHZ-Y-CHz-,
-CHZ-Y-CHZ-CHz-, -CHZCHZ-Y-CHZCHz- or -CHZCHZ-Y-CHZCHZCH2- bridge
optionally substituted by one or two C1_2-alkyl groups, whilst
s.
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 in which a hydrogen atom in the
5-position together with a hydrogen atom in the 6-position is
replaced by a - (CHz) n-, -CHZ-Y-CHz-, -CHZ-Y-CHZCHZ- or
-CHz-CHZ-Y-CHZ- bridge, whilst
Y is as hereinbefore defined and
n denotes the number 2, 3 or 4,
whilst, unless otherwise stated, the aryl moieties mentioned
in the definitions of the above-mentioned groups denote a
phenyl group which may be mono- or disubstituted by R9, whilst
the substituents may be identical or different and
R9 denotes a fluorine, chlorine, bromine or iodine atom, a
Cl_2-alkyl, trifluoromethyl or Cl_Z-alkoxy group, or
two groups R9, if they are bound to adjacent carbon atoms,
together denote a C3_4-alkylene, methylenedioxy or
1,3-butadien-1,4-ylene group.
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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 or ethynylene group,
B denotes a hydrogen atom,
C denotes an -O-CHZCHz-, -O-CH2CHZCHz- or -O-CH2CH2CHZCH2- group,
whilst the alkylene moiety in each case is linked to the group
D, and
D denotes a piperidino group in which the two hydrogen atoms
in the 4-position are replaced by a -CHZ-O-CO-CHZ-,
-CHZCHZ-O-CO-, -CHzCH2-O-CO-CHZ-, ,-O-CO-CHZ-NCH3-CHZ- or
-O-CO-CH2-O-CHZ- bridge,
a piperazino group in which a hydrogen atom in the 3-position
together with the hydrogen atom in the 4-position are replaced
by a -CO-O-CHZ-CHZ- or -CHZ-O-CO-CHz- bridge, whilst in each
case the left-hand ends of the above-mentioned bridges are
bound to the 3-position of the piperazino ring,
a piperidino group which is substituted in the 4-position by a
2-oxo-morpholino or 2-oxo-morpholinomethyl group, whilst the
2-oxo-morpholino moiety may be substituted in each case by one
or two methyl groups,
CA 02417042 2003-O1-22
- 12 -
a piperazino group which is substituted in the 4-position by a
2-oxo-tetrahydrofuran-3-yl- or 2-oxo-tetrahydrofuran-4-yl
group,
a piperidino group which is substituted in the 4-position by a
R6S group, whilst
R6 denotes a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetra-
hydrofuran-4-yl group,
a i erazino rout ~~which is substituted in the 4 osition b a
P P g P -P Y
2-oxo-tetrahydrofuranylmethyl or 2-oxo-tetrahydrofuranyl-
carbonyl group,
a piperazino group which is substituted in the 4-position by a
[2-(2-oxo-tetrahydrofuran-3-ylsulphenyl)ethyl] group,
a piperidin-4-yl group which is substituted in the 1-position
by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl
group,
a 2-oxo-morpholin-4-yl group which is substituted by a
methoxymethyl or methoxyethyl group,
a 2-oxo-morpholin-4-yl group in which the two hydrogen atoms
C_
of a methylene group are replaced by a -CHzCH2CH2CHz- ,
-CHzCHzCH2CHzCH2-, -CH2-O-CHZCHZ- or -CHZCHZ-0-CHZCHZ- bridge,
the tautomers, stereoisomers and the salts thereof.
Particularly preferred compounds of the above general formula
I are those wherein
Ra denotes a hydrogen atom,
Rb denotes a 1-phenylethyl or 3-chloro-4-fluorophenyl group,
CA 02417042 2003-O1-22
- 13 -
R~ denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a 1,2-vinylene group,
B denotes a hydrogen atom,
C denotes an -O-CHzCH2-, -O-CHZCHzCH2- or -O-CH2CHZCHZCH2- group,
whilst the alkylene moiety in each case is linked to the group
D, and
D denotes a piperazino group which is substituted in the 4-
(._
position by a 2-oxo-tetrahydrofuran-4-yl or 2-oxo-
tetrahydrofuran-5-ylcarbonyl group,
the tautomers, stereoisomers and the salts thereof.
The following particularly preferred compounds of the above
general formula I are mentioned by way of example:
(1) 4-[(3-chloro-4-fluorophenyl)amino]-7-{3-[4-(2-oxo-tetrahy-
drofuran-4-yl)-piperazin-1-yl]-propyloxy}-6-[(vinylcarbonyl)-
amino]-quinazoline,
(2) 4- ( (3-chloro-4-fluorophenyl) amino] -7- (2-{4- [ (S) - (2-oxo-te-
trahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-
6-[(vinylcarbonyl)amino]-quinazoline,
(3) 4- [ (R) - (1-phenylethyl) amino] -7-{2- [4- (2-oxo-tetra-
hydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-6-
[(vinylcarbonyl)amino]-quinazoline and
(4) 4- [ (3-chloro-4-fluorophenyl)amino] -7-{2- [4- (2-oxo-tetra-
hydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-6-[(vinylcarbonyl)-
amino]-quinazoline,
the tautomers, stereoisomers and the salts thereof.
CA 02417042 2003-O1-22
- 14 -
The compounds of general formula I may be prepared by the
following methods, for example:
a. reacting a compound of general formula
Ra \ /Rb
N
NR~-H
X ~
\ ~ , (II)
N ~ C - D
wherein
Ra to R°, C, D and X are as hereinbefore defined, with a
compound of general formula
Z1 - CO - A - B , (III)
wherein
A and B 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.
The reaction is optionally carried out in a solvent or mixture
of solvents such as methylene chloride, dimethylformamide,
acetonitrile, toluene, chlorobenzene, tetrahydrofuran,
methylene chloride/tetrahydrofuran or dioxane, optionally in
the presence of an inorganic or organic base and optionally in
the presence of a dehydrating agent conveniently at
temperatures between -80 and 150°C, preferably at temperatures
between -60 and 80°C.
With a compound of general formula III wherein Z1 denotes a
leaving group, the reaction is optionally carried out in a
solvent or mixture of solvents such as methylene chloride,
dimethylformamide, acetonitrile, toluene, chlorobenzene,
tetrahydrofuran, methylene chloride/tetrahydrofuran or
dioxane, conveniently in the presence of a tertiary organic
CA 02417042 2003-O1-22
- 15 -
base such as triethylamine, pyridine, 2-dimethylaminopyridine
or N-ethyl-diisopropylamine (Hiznig's base), whilst these
organic bases may simultaneously serve as the solvent, or in
the presence of an inorganic base such as sodium carbonate,
potassium carbonate or sodium hydroxide solution, conveniently
at temperatures between -80 and 150°C, preferably at
temperatures between -60 and 80°C.
With a compound of general formula III wherein Z1 denotes a
hydroxy group, the reaction is preferably carried out in the
presence of a dehydrating agent, e.g. in the presence of
isobutyl chloroformate, thionyl chloride, trimethyl
chlorosilane, phosphorus trichloride, phosphorus pentoxide,
hexamethyldisilazane, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or
1-hydroxy-benzotriazole, and optionally additionally in the
presence of 4-dimethylaminopyridine, N,N'-carbonyldiimidazole
or triphenylphosphine/carbon tetrachloride, conveniently in a
solvent such as methylene chloride, tetrahydrofuran, dioxane,
toluene, chlorobenzene, dimethylsulphoxide, ethylene glycol
diethyl ether or sulpholane and optionally in the presence of
a reaction accelerator such as 4-dimethylaminopyridine at
temperatures between -80 and 150°C, but preferably at
temperatures between -60 and 80°C.
However, it is particularly advantageous to carry out the
reaction with acrylic acid and acrylic acid chloride in the
presence of triethylamine.
In the reactions described hereinbefore, any reactive groups
present such as hydroxy, carboxy or imino groups may be
protected during the reaction by conventional protecting groups
which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a
trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl,
trityl, benzyl or tetrahydropyranyl group,
CA 02417042 2003-O1-22
- 16 -
protecting groups for a carboxy group may be a trimethylsilyl,
methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group,
and
protecting groups for an imino group may be a formyl, acetyl,
trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl,
benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl
group.
Any protecting group used is optionally subsequently cleaved
for example by hydrolysis in an aqueous solvent, e.g. in water,
isopropanol/water, acetic acid/water, tetrahydrofuran/water or
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 room 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 diethyl ether.
CA 02417042 2003-O1-22
- 17 -
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 general formula I with at least 2 asymmetric
carbon atoms may be resolved into their diastereomers on the
basis of their different physical properties 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
CA 02417042 2003-O1-22
- 18 -
salts or derivatives by the action of suitable agents.
Optically active acids in common use are e.g. the D- and
L-forms of tartaric acid or dibenzoyltartaric acid, di-
o-tolyltartaric acid, malic acid, mandelic acid,
camphorsulphonic acid, glutamic acid, aspartic acid or quinic
acid. An optically active alcohol may be for example (+) or
(-)-menthol and an optically active acyl group in amides, for
example, may be a (+)- or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I obtained 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 malefic acid.
The compounds of general formulae II to III used as starting
materials are known from the literature in some cases or may
be obtained by methods known from the literature (cf. Examples
I to IX) .
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 downstream is blocked.
The biological properties of the new compounds were
investigated as follows:
CA 02417042 2003-O1-22
i
- 19 -
The inhibition of the EGF-R-mediated signal transmission can
be demonstrated e.g. with cells which express human EGF-R and
whose survival and proliferation depend on stimulation by EGF
or TGF-alpha. A cell line of murine origin dependent on
interleukin-3-(IL-3) which was genetically modified to express
functional human EGF-R was used here. The proliferation of
these cells known as F/L-HERc can therefore be stimulated
either by murine IL-3 or by EGF (cf. von Ruden, T. et al. in
EMBO J. Z, 2749-2756 (1988) and Pierce, J. H. et al. in
Science iiri.i, 628-631 (1988) ) .
The starting material used for the F/L-HERc cells was the cell
line FDC-P1~ the production of which has been described by
Dexter, T. M. et al. in J. Exp. Med. 152. 1036-1047 (1980).
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 2Q,
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,Q.~, 418-425 (1984)) recombinant
retroviruses were used as described by von Rizden, T. et al.,
EMBO J. .Z, 2749-2756 (1988), except that the retroviral vector
LXSN (cf. Miller, A. D. et al. in BioTechniques .Z, 980-990
(1989)) was used for the expression of the EGF-R cDNA and the
line GP+E86 (cf. Markowitz, D. et al. in J. Virol. .62, 1120-
1124 (1988)) was used as the packaging cell.
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
S% 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 ~.1), the cell proliferation being stimulated with
CA 02417042 2003-O1-22
r
- 20 -
either EGF (20 ng/ml) or murine IL-3. The IL-3 used was
obtained from culture supernatants of the cell line X63/0 mIL-
3 (cf. Karasuyama, H. et al. in Eur. J. Immunol. 1$, 97-104
(1988)). The compounds according to the invention were
dissolved in 100% dimethylsulphoxide (DMSO) and added to the
cultures in various dilutions, the maximum DMSO concentration
being 1%. The cultures were incubated for 48 hours at 37°C.
In order to determine the inhibitory activity of the compounds
according to the invention the relative cell number was
measured in O.D. units using the Cell Titer 96TM AQueous Non-
Radioactive Cell Proliferation Assay (Promega). The relative
cell number was calculated as a percentage of the control
(F/LHERc cells without inhibitor) and the concentration of
active substance which inhibits the proliferation of the cells
by 50% (IC50) was derived therefrom. The following results
were obtained:
Compound Inhibition of
(Example No.) EGF-dependent
proliferation
IC50 [nM]
1 (2) 12
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
CA 02417042 2003-O1-22
- 21 -
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
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
CA 02417042 2003-O1-22
- 22 -
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. vinblastin), 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-
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. For treating diseases in the region of
the gastrointestinal tract, these compounds may also be
administered on their own or in conjunction with substances
having an effect on motility or secretion or 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
0.1-15 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,
CA 02417042 2003-O1-22
- 23 -
magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric
acid, water, water/ethanol, water/glycerol, water/sorbitol,
water/polyethyleneglycol, propyleneglycol, stearylalcohol,
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 02417042 2003-O1-22
- 24 -
Preparation of the starting compounds:
6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-~3-[4-(2-oxo-
610 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-~3-[4-
(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-propyloxy}-
quinazoline and 268 mg iron powder are suspended in 22 ml of
ethanol and heated to boiling. Then 0.76 ml of glacial acetic
acid and 0.50 ml of water are added. Within a few minutes a
clear brown solution has formed and after one hour the
reduction is finished. For working up, the reaction mixture is
evaporated down. The residue is stirred with methylene
chloride, mixed with a few lumps of ice and made alkaline with
1 ml of 15N sodium hydroxide solution. The aqueous phase is
separated off and extracted with methylene chloride/methanol
(95:5). The combined organic phases are washed with water,
dried over magnesium sulphate and evaporated down. The resin-
like residue is crystallised by stirring with tert-butyl
methyl ether. The yellowish solid is suction filtered and
dried in vacuo.
Yield: 437 mg (76 % of theoretical),
Rf value: 0.30 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ESI+) : m/z = 515, 517 [M+H]
The following compounds are obtained analogously to Example I:
(1) 6-amino-4- [ (3-chloro-4-fluorophenyl) amino] -7- (2-{4- [ (S) -
(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-
quinazoline
Rf value: 0.38 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ESI+) : m/z = 529, 531 [M+H]'
CA 02417042 2003-O1-22
- 25 -
(2) 6-amino-4- [ (R) - (1-phenylethyl) amino] -7-{2- [4- (2-oxo-
tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy~-quinazoline
RE value: 0.36 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI+): m/z = 477 [M+H]'
(3) 6-amino-4- [ (3-chloro-4-fluorophenyl) amino] -7-{2- [4- (2-oxo-
tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-quinazoline
Rf value: 0.29 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI+) : m/z = 501, 503 [M+H]
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-{3-[4-(2-oxo-
1.10 g of 4-[(3-chloro-4-fluorophenyl)amino]-7-(3-
methanesulphonyloxy-propyloxy)-6-nitro-quinazoline and 2.33 g
of 4-piperazin-1-yl-dihydrofuran-2-one x 2 trifluoroacetic
acid in 25 ml of acetonitrile are combined with 360 mg of
sodium iodide and 1.63 g of potassium carbonate. The reaction
mixture is refluxed for about two hours. For working up, the
inorganic salts are filtered off and washed with ethyl acetate
and methylene chloride/methanol. The filtrate is evaporated
down and the evaporation residue is taken up in methylene
chloride/methanol. The solution is washed with water, dried
over magnesium sulphate and evaporated down. The yellow,
resin-like residue is chromatographed using a silica gel
column with methylene chloride/methanol/concentrated aqueous
ammonia solution (95:4:1). The title compound is obtained as a
yellow solid.
Yield: 625 mg (49 % of theoretical),
Rf value: 0.45 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
CA 02417042 2003-O1-22
- 26 -
Mass spectrum (ESI+) : m/z = 545, 547 [M+H]'
The following compounds are obtained analogously to Example
II:
(1) 4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[4-(tert-butyloxy-
carbonyl)-piperazin-1-yl]-ethoxy}-6-nitro-quinazoline
Rt value: 0.42 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
(2) 4- [ (R) - (1-phenylethyl)amino] -7-{2- [4- (tert-butyloxycar-
bonyl)-piperazin-1-yl]-ethoxy}-6-nitro-quinazoline
Rf value: 0.20 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 521 [M-H]
(3) 4- [ (3-chloro-4-fluorophenyl) amino] -7-{2- [4- (2-oxo-tetra-
hydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-6-nitro-quinazoline
Rf value: 0.43 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ESI-) : m/z = 529, 531 [M-H]
(4) 4-[(3-chloro-4-fluorophenyl)amino]-7-{3-[4-(tert.-
butyloxycarbonyl)-piperazin-1-yl]-propyloxy}-6-nitro-
quinazoline
Rf value: 0.55 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI') : m/z = 561, 563 [M+H]
(5) 4- [ (3- chloro-4-fluorophenyl) amino] -7-(4- [4- (tert.-
butyloxycarbonyl)-piperazin-1-yl]-butyloxy}-6-nitro-
quinazoline
Rf value: 0.49 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 597, 599 [M+Na]'
CA 02417042 2003-O1-22
- 27 -
Example III
4-[(3-chloro-4-fluorophenyl)amino]-7-(3-methanesulphonyloxy-
progyloxy)-6-nitro-quinazoline
0.96 ml of methanesulphonic acid chloride are added dropwise,
with stirring, to 4.60 g of 4-[(3-chloro-4-fluorophenyl)-
amino]-7-(3-hydroxy-propyloxy)-6-nitro-quinazoline and 4.29 ml
of diisopropylethylamine in 150 ml methylene chloride at
ambient temperature. The reaction mixture is stirred for about
30 minutes at ambient temperature, then another 0.1 ml of
methanesulphonic acid chloride are added. After about one hour
the reaction is complete and the cloudy reaction solution is
mixed with ice water. A thick, yellowish precipitate is formed
which is suction filtered, washed with a little methylene
chloride and water and dried in the desiccator.
Yield: 5.06 g (92 % of theoretical),
Rf value: 0.43 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 469, 471 [M-H]
The following compounds are obtained analogously to Example
III:
(1) 4- [ (3-chloro-4-fluorophenyl) amino] -7- (2-
methanesulphonyloxy-ethoxy)-6-nitro-quinazoline
Rf value: 0.53 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI-): m/z = 455, 457 [M-H]-
(2) 4-[(R)-(1-phenylethyl)amino]-7-(2-methanesulphonyloxy-eth-
oxy)-6-nitro-quinazoline
Rf value: 0.45 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 431 [M-H]
(3) 4- [ (3-chloro-4-fluorophenyl) amino] -7- (4-
methanesulphonyloxy-butyloxy)-6-nitro-quinazoline
Rf value: 0.42 (silica gel, methylene chloride/methanol = 95:5)
CA 02417042 2003-O1-22
- 28 -
Mass spectrum (ESI-) : m/z = 483, 485 [M-H]
Example IV
4-[(3-chloro-4-fluorophenyl)amino]-7-(3-hydroxy-propyloxy)-
6-nitro-quinazoline
3.00 ml of concentrated hydrochloric acid are added dropwise
to 21 .30 g of 4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (tetra-
hydropyran-2-yloxy)-propyloxy]-6-nitro-quinazoline (crude
product from Example V) in 200 ml methanol. A yellow
precipitate is formed. The suspension is stirred for another
3.5 hours at 50°C. For working up the methanol is distilled
off in vacuo using a rotary evaporator. The residue is
combined with ethyl acetate and some ice water and made
alkaline with sodium hydroxide solution. The organic phase is
washed with water and saturated sodium chloride solution and
left to stand overnight at ambient temperature, during which
time a yellow precipitate is formed. This is suction filtered,
washed with ethyl acetate and dried. The filtrate is
evaporated down and the evaporation residue is recrystallised
from ethyl acetate. The crystals thus obtained are combined
with the precipitate previously suction filtered and again
recrystallised from ethyl acetate. The desired product is
obtained in the form of slightly yellowish crystals.
Yield: 4.60 g (40 % of theoretical),
Melting point: 224-227°C
Mass spectrum (ESI-) : m/z = 391, 393 [M-H]
The following compounds are obtained analogously to Example
IV:
(1) 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-hydroxy-ethoxy)-
6-nitro-quinazoline
Rf value: 0.46 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI-) : m/z = 377, 379 [M-H]
CA 02417042 2003-O1-22
29 -
(2) 4- ( (R) - (1-phenyl-ethyl) amino] -7- (2-hydroxy-ethoxy) -
6-nitro-quinazoline
Melting point: 192-194°C
Mass spectrum (ESI-) : m/z = 353 [M-H]
(3) 4-((3-chloro-4-fluorophenyl)amino]-7-(4-hydroxy-butyloxy)-
6-nitro-quinazoline
Rf value: 0.25 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI-) : m/z = 405, 407 [M-H]
4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (tetrahydropyran-
2.40 g of sodium hydride (60o in mineral oil) are added
batchwise to 14.50 g of 3-(tetrahydropyran-2-yloxy)-propan-1-
ol in 120 ml tetrahydrofuran. The reaction mixture is stirred
for about 15 minutes at ambient temperature, then 10.10 g of
4-[(3-chloro-4-fluorophenyl)amino]-7-fluoro-6-nitro-
quinazoline are added while cooling with an ice bath and
rinsed with 20 ml of tetrahydrofuran. The reaction mixture
suddenly turns dark red and the ice bath is removed. After
about 2.5 hours a total of 500 mg of sodium hydride are added
in two batches and the reaction mixture is stirred overnight
at ambient temperature. For working up, the dark reaction
solution is poured onto about 400 ml of ice water, mixed with
tent-butyl methyl ether and ethyl acetate and neutralised with
citric acid. The organic phase is separated off and evaporated
down. 21.30 g of a brown oil are obtained, which is subjected
to cleavage of the protecting groups without any further
purification (cf . Example IV) .
Rf value: 0.37 (silica gel, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (ESI-) : m/z = 475, 477 [M-H]
The following compounds are obtained analogously to Example V:
CA 02417042 2003-O1-22
- 30 -
(1) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(tetrahydropyran-
2-yloxy)-ethoxy]-6-nitro-quinazoline
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate =
1:2)
Mass spectrum (ESI-) : m/z = 461, 463 [M-H]
(2) 4-[(R)-(1-phenyl-ethyl)amino]-7-[2-(tetrahydropyran-2-yl-
oxy)-ethoxy]-6-nitro-quinazoline
Rf value: 0.12 (silica gel, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (ESI-,) : m/z = 437 [M-H]
(3) 4- [ (3-chloro-4-fluorophenyl) amino] -7- [4- (tetrahydropyran-
2-yloxy)-butyloxy]-6-nitro-quinazoline
Rf value: 0.31 (silica gel, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (ESI-) : m/z = 489, 491 [M-H]
Example VI
4- [ (3-chloro-4-fluorophenyl) amino] -7- (2- {4- [ (S) - (2-oxo-tetra-
hydrofuran-5-yl)carbonyl]-piperazin-1-yl)-ethoxy)-6-nitro-
quinazoline
93 mg of (S)-(+)-5-oxo-tetrahydrofuran-2-carboxylic acid and
176 ~.1 of triethylamine are added to 320 mg of 4-[(3-chloro-4-
fluorophenyl)amino]-7-[2-(piperazin-1-yl)-ethoxy]-6-nitro-
quinazoline in 4 ml of N,N-dimethylformamide. Then the
reaction mixture is combined with 230 mg of (benzotriazol-1-
yl)-N,N,N',N'-tetramethyl-uronium-tetrafluoroborate and
stirred for four hours at ambient temperature. For working up,
about 20 ml of ice water are added. The precipitate formed is
suction filtered, washed with water and tert-butyl methyl
ether and dried in the desiccator. The ochre-coloured solid
crude product is further reacted without further purification.
Yield: 330 mg (82 % of theoretical),
Rf value: 0.40 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
CA 02417042 2003-O1-22
- 31 -
The following compounds are obtained analogously to Example
VI:
(1) 4- [ (3-chloro-4-fluorophenyl) amino] -7- (3-~4- [ (S) - (2-oxo-
tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl~-propyloxy)-6-
nitro-quinazoline
Rf value: 0.48 (silica gel, methylene chloride/methanol/conc.
aqueous ammonia solution = 90:10:0.1)
Mass spectrum (ESI') : m/z = 573, 575 [M+H]+
(2) 4- [ (3-chloro-4-fluorophenyl)amino] -7- (4-{4- [ (S) - (2-oxo-
tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl?-butyloxy)-6-
nitro-quinazoline
Rf value: 0.47 (silica gel, methylene chloride/methanol/conc.
aqueous ammonia solution = 90:10:0.1)
Mass spectrum (ESI-) : m/z = 585, 587 [M-H] -
4- [ (3-chloro-4-fluorophenyl) amino] -7- [2- (piperazin-1-yl) -
780 mg of 4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[4-(tert-
butyloxycarbonyl)-piperazin-1-yl]-ethoxy~-6-nitro-quinazoline
in 10 ml of methylene chloride are combined with 2.00 ml of
trifluoroacetic acid. The yellow reaction solution is stirred
for one hour at ambient temperature and then left to stand
overnight. The next morning, the reaction mixture is
evaporated down, mixed with about 20 ml of water and made
alkaline with concentrated ammonia solution. The precipitate
formed is suction filtered and washed with water and tert-
butyl methyl ether. The yellowish solid is taken up in
methylene chloride/methanol (5:1). The solution is washed with
2 N sodium hydroxide solution. The aqueous phase is extracted
with a total of 400 ml of methylene chloride/methanol (5:1).
The combined organic phases are washed with saturated sodium
chloride solution, dried over magnesium sulphate and
evaporated down. The flask residue is triturated with tert-
CA 02417042 2003-O1-22
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butyl methyl ether, suction filtered and dried in a
desiccator.
Yield: 680 mg (5 % of theoretical),
Rf value: 0.15 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI-) : m/z = 445, 447 [M-H]
The following compounds are obtained analogously to Example
VII:
(1) 4- [ (R) - (1-phenyl-ethyl) amino] -7- (2- (piperazin-1-yl) -
ethoxy]-6-nitro-quinazoline
Rf value: 0.12 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI-) : m/z = 421 [M-H]
(2) 4-(piperazin-1-yl)-dihydrofuran-2-one x 2 trifluoroacetic
acid (The reaction solution is evaporated down without any
aqueous working up.)
Rf value: 0.09 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI') : m/z = 171 [M+H]
(3) 4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (piperazin-1-yl) -
propyloxy]-6-nitro-quinazoline
Rf value: 0.18 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI+) : m/z = 461, 463 [M+H]
(4) 4- ( (3-chloro-4-fluorophenyl) amino] -7- [4- (piperazin-1-yl) -
butyloxy]-6-nitro-quinazoline
CA 02417042 2003-O1-22
- 33 -
Rf value: 0.20 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI') : m/z = 475, 477 [M+H]'
4- [ (R) - (1-phenylethyl) amino] -7-{2- [4- (2-oxo-tetrahydrofuran-.4-
y,~~i p ,ra~i n-~ -girl ] - hoxy~ -6-ni _rc~-qui na .cal ' ne
1 . 99 g of 4- [ (R) - (1-phenyl-ethyl) amino] -7- [2- (piperazin-1-yl) -
ethoxy]-6-nitro-quinazoline are dissolved in 10 ml of methanol
and combined with 376 ~.1 of (5H)-furan-2-one. The reaction
mixture is stirred overnight at ambient temperature, then
another 35 ~,1 of (5H)-furan-2-one are added. After another 1.5
hours' stirring at ambient temperature the reaction is
complete. The brown reaction solution is evaporated down and
chromatographed using a silica gel column, with methylene
chloride/methanol (95:5 to 93:7) as eluant. The title compound
is obtained as a yellowish solid.
Yield: 1.71 g (72 % of theoretical),
Rf value: 0.45 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI-): m/z = 505 IM-H]-
The following compound is obtained analogously to Example
VIII:
(1) 4-(4-tert-butyloxy-piperazin-1-yl)-dihydrofuran-2-one (The
reaction is carried out in methylene chloride.)
Rf value: 0.54 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI') : m/z = 293 [M+Na]
CA 02417042 2003-O1-22
- 34 -
(2) 4- [ (3-chloro-4-fluorophenyl) amino] -7-{4- [4- (2-oxo-
tetrahydrofuran-4-yl)-piperazin-1-yl]-butyloxy}-6-nitro-
quinazoline
Rf value: 0.50 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ESI+): m/z = 559, 561 [M+H]'
Example IX
4-[(R)-(1-phenyl-ethyl)amino -6-nitro-7-fluoro-quinazoline
A solution of 74 ml of (R)-1-phenyl-ethylamine in 100 ml of
dioxane is added dropwise, while cooling with an ice bath, to
108.8 g of 4-chloro-6-nitro-7-fluoro-quinazoline in 800 ml
methylene chloride. The reaction mixture is stirred overnight
at ambient temperature. For working up it is extracted with
water. The organic phase is dried over magnesium sulphate and
evaporated down. The residue is purified by chromatography
using a silica gel column with petroleum ether/ethyl acetate
(1:1) as eluant.
Yield 52.90 g (35 % of theoretical),
Melting point: 203°C
Mass spectrum (ESI') : m/z = 313 [M+H]
Example X
6-Amino-4- [ (3-chloro-4-fluorophenyl) amino] -7- (3-{4- [ (S) - (2-
oxo-tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl)-propyloxy)-
auinazoline
The substance is obtained in a 75 % yield by hydrogenation of
4- [ (3-chloro-4-fluorophenyl) amino] -7- (3- {4- [ (S) - (2-oxo-
tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-propyloxy)-6-
nitro-quinazoline in tetrahydrofuran in the presence of Raney
nickel in a Parr apparatus at a partial hydrogen pressure of
50 psi.
CA 02417042 2003-O1-22
- 35 -
Rfvalue: 0.44 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ESI-) : m/z = 541, 543 [M-H]
The following compounds are obtained analogously to Example X:
(1) 6-Amino-4- [ (3-chloro-4-fluorophenyl) amino] -7- (4- [4- (2-oxo-
tetrahydrofuran-4-yl)-piperazin-1-yl]-butyloxy}-quinazoline
Rf value: 0.24 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ESI+) : m/z = 529, 531 [M+H]+
(2) 6-Amino-4- [ (3-chloro-4-fluorophenyl) amino] -7- (4-(4- [ (S) -
(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-
butyloxy)- quinazoline
Rf value: 0.35 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ES I') : m/z = 579, 581 [M+Na]
CA 02417042 2003-O1-22
- 36 -
Preparation of the final compounds:
4-[(3-chloro-4-fluorophenyl)amino]-7-~3-[4-(2-oxo-tetrahydro-
furan-4-yl)-piperazin-1-yl]-propyloxy~-6-[(vinylcarbonyl)-
] cam i nazol i ne
A mixture of 166 mg of acrylic acid and 0.77 ml of
triethylamine in 10 ml of tetrahydrofuran is cooled to -50°C
in a dry ice/aceton~ cooling bath and mixed with a solution of
175 ~,1 of acrylic acid chloride in 4 ml of tetrahydrofuran.
The reaction mixture is stirred for 45 minutes at this
temperature. Then a solution of 427 mg of 6-amino-4-[(3-
chloro-4-fluorophenyl)amino]-7-{3-[4-(2-oxo-tetrahydrofuran-4-
yl)-piperazin-1-yl]-propyloxy}-quinazoline in 10 ml of
tetrahydrofuran is added within 20 minutes. The reaction
mixture is then left to come up slowly to 0°C and stirred at
this temperature until the reaction is complete. Ice water is
then added, whereupon a viscous precipitate is formed. This is
thoroughly extracted several times with ethyl
acetate/methanol. The combined organic phases are washed with
saturated sodium chloride solution, dried over magnesium
sulphate and evaporated down. The yellowish, resin-like crude
product is purified by chromatography using a silica gel
column with methylene chloride/methanol (95:5) as eluant.
Yield: 148 mg (31 % of theoretical),
Rf value: 0.45 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ESI-) : m/z = 567, 569 [M-H]
The following compounds are obtained analogously to Example 1:
(1) 4- [ (3-chloro-4-fluorophenyl) amino] -7- (2-{4- [ (S) - (2-oxo-te-
trahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-6-[(vi-
nylcarbonyl)amino]-quinazoline
CA 02417042 2003-O1-22
a
37 -
Rf value: 0.46 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ESI-) : m/z = 581, 583 [M-H]
(2) 4- [ (R) - (1-phenylethyl) amino] -7-~2- [4- (2-oxo-tetrahydrofu-
ran-4-yl)-piperazin-1-yl]-ethoxy~-6-[(vinylcarbonyl)amino]-
quinazoline (The reaction is carried out only with acrylic
acid chloride in methylene chloride in the presence of
triethylamine.)
Rf value: 0.42 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI~) : m/z = 529 [M-H]
(3) 4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[4-(2-oxo-tetra-
hydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-6-[(vinylcarbonyl)-
amino]-quinazoline (The reaction is carried out with acrylic
acid and isobutyl chloroformate in the presence of
triethylamine in tetrahydrofuran.)
Rf value: 0.40 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:1)
Mass spectrum (ESI-) : m/z = 553 , 555 [M-H]
(4) 4- [ (3-chloro-4-fluorophenyl) amino] -7- (3-~4- [ (S) - (2-oxo-
tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-propyloxy)-6-
[(vinylcarbonyl)amino]-quinazoline
Rf value: 0.26 (silica gel, methylene chloride/ methanol = 9:1)
Mass spectrum (ESI+) : m/z = 597, 599 [M+H]'
(5) 4- [ (3-chloro-4-fluorophenyl) amino] -7-~4- [4- (2-oxo-
tetrahydrofuran-4-yl)-piperazin-1-yl]-butyloxy~-6-
[(vinylcarbonyl)amino]-quinazoline
Rf value: 0.28 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
CA 02417042 2003-O1-22
- 38 -
Mass spectrum (ESI+) : m/z = 583, 585 [M+H]+
(6) 4- [ (3-chloro-4-fluorophenyl)amino] -7- (4-~4- [ (S) - (2-oxo-
tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-butyloxy)-6-
[(vinylcarbonyl)amino]-quinazoline
Rf value: 0.45 (silica gel, methylene
chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.1)
Mass spectrum (ESI+) : m/z = 611, 613 [M+H]
The following compounds can be prepared analogously to the
foregoing Examples and other methods known from the
literature:
(1) 4-[(3-chloro-4-fluorophenyl)amino]-7-(3-{4-[(2-oxo-tetra-
hydrofuran-5-yl)methyl]-piperazin-1-yl~-propyloxy)-6-[(vinyl-
carbonyl)amino]-quinazoline
(2) 4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (4-{2- [ (2-oxo-
tetrahydrofuran-3-yl)sulphanyl]-ethyl}-piperazin-1-yl)-propyl-
oxy] -6- [ (vinylcarbonyl) amino] -quinazoline
(3) 4- [ (3-chloro-4-fluorophenyl) amino] -7-{3- [1- (2-oxo-tetrahy-
drofuran-4-yl)-piperidin-4-yl]-propyloxy~-6-[(vinylcarbonyl)-
amino]-quinazoline
(4) 4- [ (3-bromophenyl) amino] -7-{3- [1- (2-oxo-tetrahydrofuran-
4-yl)-piperidin-4-yl]-propyloxy}-6-[(vinylcarbonyl)amino]-
quinazoline
(5) 4- [ (3-methylphenyl) amino] -7- f 3- [1- (2-oxo-tetrahydrofuran-
4-yl)-piperidin-4-yl]-propyloxy}-6-[(vinylcarbonyl)amino]-
quinazoline
(6) 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(3-oxo-perhydro-
pyrazino[2,1-c][1,4]oxazin-8-yl)-propyloxy]-6-[(vinylcarbo-
nyl)amino]-quinazoline
CA 02417042 2003-O1-22
- 39 -
(7) 4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (1-oxo-perhydro-
pyrazino [2, 1-c] [1, 4] oxazin-8-yl) -propyloxy] -6- [ (vinylcarbo-
nyl) amino] -quinazoline
(8) 4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (2-oxa-3-oxo-
8-aza-spiro [4, 5] dec-8-yl) -propyloxy] -6- [ (vinylcarbonyl) amino] -
quinazoline
(9) 4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (3-oxa-2-oxo-
9-aza-spiro (5.5] undecan-9-yl) -propyloxy]'-6-
[(vinylcarbonyl)amino]-quinazoline
(10) 4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (1, 4-dioxa-2-oxo-
9-aza-spiro [5. 5] undecan-9-yl) -propyloxy] -6- [ (vinylcarbonyl) -
amino]-quinazoline
(11) 4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (4-methyl-1-oxa-
2-oxo-4,9-diaza-spiro[5.5]undecan-9-yl)-propyloxy]-6-[(vinyl-
carbonyl)amino]-quinazoline
(12) 4-[(3-chloro-4-fluorophenyl)amino]-7-{3-[4-(2-oxo-morpho-
lin-4-yl)-piperidin-1-yl]-propyloxy}-6-[(vinylcarbonyl)amino]-
quinazoline
(13) 4- [ (3-chloro-4-fluorophenyl)amino] -7-~3- [4- (6-methyl-
2-oxo-morpholin-4-yl)-piperidin-1-yl]-propyloxy}-6-[(vinyl-
carbonyl)amino]-quinazoline
(14) 4- [ (3-chloro-4-fluorophenyl) amino] -7- (3-{4- [ (6-methyl-
2-oxo-morpholin-4-yl)methyl]-piperidin-1-yl)-propyloxy)-
6-[(vinylcarbonyl)amino]-quinazoline
(15) 4- [ (3-chloro-4-fluorophenyl) amino] -7- (3- f 4- [ (2-oxo-tetra-
hydrofuran-3-yl)sulphanyl]-piperidin-1-yl}-propyloxy)-6-[(vi-
nylcarbonyl)amino]-quinazoline
CA 02417042 2003-O1-22
- 40 -
(16) 4- [ (3-chloro-4-fluorophenyl) amino] -7- [3- (6-methoxymethyl-
2-oxo-morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-
quinazoline
(17) 4- [ (3-chloro-4-fluorophenyl) amino] -7-{3- [6- (2-methoxy-
ethyl)-2-oxo-morpholin-4-yl]-propyloxy}-6-[(vinylcarbonyl)-
amino]-quinazoline
(18) 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(1,9-dioxa-2-oxo-
4-aza-spiro [5. 5] und~can-4-yl) -propyloxy] -6- [ (vinylcarbonyl) -
amino] -quinazoline ~~
One 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
230.0 mg
prP~ arafi ~ can
The active substance is mixed with calcium phosphate, corn
starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and
half the specified amount of magnesium stearate. Blanks, 13 mm
in diameter, are produced in a tablet-making machine and these
are then rubbed through a screen with a mesh size of 1.5 mm
using a suitable machine and mixed with the rest of the
magnesium stearate. This granulate is compressed in a tablet-
making machine to form tablets of the desired shape.
Weight of core: 230 mg
die: 9 mm, convex
CA 02417042 2003-O1-22
- 41 -
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.
Composition:
One tablet contains:
active substance 100.0 mg
lactose 80.0 mg
corn starch 34.0 mg
polyvinylpyrrolidone 4.0 mg
magnesium stearate x-
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.
Composition:
One tablet contains:
active substance 50.0 mg
CA 02417042 2003-O1-22
- 42 -
powdered lactose 89.0 mg
corn starch 40.0 mg
colloidal silica 10.0 mg
polyvinylpyrrolidone 10.0 mg
magnesium stearate 1.0 ma
300.0 mg
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 are mixed with the specified amount of magnesium
stearate. Tablets are pressed from the mixture.
Weight of tablet: 300 mg
die: 10 mm, flat
Example 5
Hard gelatine capsules containing 150 mg of active substance
One capsule contains:
active substance 50.0 mg
corn starch (dried) approx. 80.0 mg
lactose (powdered) approx. 87.0 mg
magnesium stearate 3.0 ma
approx. 420.0 mg
Preparation:
The active substance is mixed with the excipients, passed
through a screen with a mesh size of 0.75 mm and mixed until
homogeneous 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.
CA 02417042 2003-O1-22
- 43 -
Example 6
Suppositories containing 150 ma of active substance
One suppository contains:
active substance 150.0 mg
polyethyleneglycol 1500 550.0 mg
polyethyleneglycol 6000 460.0 mg
polyoxyethylene sorbitan monostearate 840.0 ma
2,000.0 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 7
Suspension containing 50 ma 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 ad 100 ml
Preparation:
The distilled water is heated to 70°C. The methyl and propyl
p-hydroxybenzoates together with the glycerol and the sodium
CA 02417042 2003-O1-22
- 44 -
salt of carboxymethylcellulose are dissolved therein with
stirring. The solution is cooled to ambient temperature and the
active substance is added and homogeneously dispersed therein
by 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.
Example 8
Ampoules containing 10 mg active substance
Composition:
active substance 10.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml
Preparation:
The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterilely
and transferred into 2 ml ampoules.
Example 9
Ampoules containing' 50 mQ of active substance
Composition:
active substance 50.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml
CA 02417042 2003-O1-22
- 45 -
Pre aration:
The active substance is dissolved in the necessary amount of
0.01 N HC1, made isotonic with common salt, filtered sterilely
and transferred into 10 ml ampoules.
Example 10
Capsules for powder inhalation containina 5 ma of active
substance
One capsule contains:
active substance 5.0 mg
lactose for inhalation 15.0 ma
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 11
Solution for inhalation for hand-held nebulisers containina
2.5 ma active substance
One 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
CA 02417042 2003-O1-22
- 46 -
Preparation:
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
