U.S. patent number RE43,431 [Application Number 12/542,929] was granted by the patent office on 2012-05-29 for quinazoline derivatives and pharmaceutical compositions containing them.
This patent grant is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Anke Baum, Stefan Blech, Frank Himmelsbach, Birgit Jung, Elke Langkopf, Flavio Solca.
United States Patent |
RE43,431 |
Himmelsbach , et
al. |
May 29, 2012 |
Quinazoline derivatives and pharmaceutical compositions containing
them
Abstract
A compound of general formula I ##STR00001## wherein: R.sub.a is
a benzyl, 1-phenylethyl, or 3-chloro-4-fluorophenyl group; R.sub.b
is a dimethylamino, N-methyl-N-ethylamino, diethylamino,
N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino,
N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino,
bis(2-methoxyethyl)amino, morpholino,
N-methyl-N-(tetrahydrofuran-3-yl)amino,
N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino,
N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino,
N-methyl-N-(tetrahydropyran-4-yl)amino, or
N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group; and R.sub.c is
a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy,
tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy,
tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or
tetrahydropyran-4-ylmethoxy group, or a tautomer, stereoisomer, or
salt thereof, particularly the physiologically acceptable salts
thereof with inorganic or organic acids or bases which have
valuable pharmacological properties, in particular an inhibitory
effect on signal transduction mediated by tyrosine kinases, their
use in the treatment of diseases, especially tumoral diseases and
diseases of the lungs and airways, and the preparation thereof.
Inventors: |
Himmelsbach; Frank
(Mittelbiberach, DE), Langkopf; Elke (Biberach an der
Riss, DE), Blech; Stefan (Warthausen, DE),
Jung; Birgit (Laupheim, DE), Baum; Anke (Vienna,
AT), Solca; Flavio (Vienna, AT) |
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG (Ingelheim am Rhein, DE)
|
Family
ID: |
27214210 |
Appl.
No.: |
12/542,929 |
Filed: |
August 18, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60259201 |
Dec 28, 2000 |
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Reissue of: |
10023099 |
Dec 17, 2001 |
7019012 |
Mar 28, 2006 |
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Foreign Application Priority Data
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Dec 20, 2000 [DE] |
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100 63 435 |
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Current U.S.
Class: |
514/266.22;
514/266.24; 544/284; 514/217.06; 514/313; 514/266.4; 544/293;
544/122; 544/283; 514/314 |
Current CPC
Class: |
C07D
239/94 (20130101); C07D 405/12 (20130101); A61P
35/00 (20180101); A61P 17/06 (20180101); A61P
1/00 (20180101); A61P 11/00 (20180101) |
Current International
Class: |
A61K
31/517 (20060101); C07D 413/02 (20060101); C07D
239/94 (20060101) |
Field of
Search: |
;514/266.24,266.4
;544/293 |
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|
Primary Examiner: Wilson; James O
Assistant Examiner: Truong; Tamthom N
Attorney, Agent or Firm: Morris; Michael P. Bottino; Anthony
P.
Parent Case Text
RELATED APPLICATIONS
Benefit under 35 U.S.C. .sctn.119(e) of prior provisional
application Ser. No. 60/259,201, filed .[.Dec. 18, 2000.].
.Iadd.Dec. 28, 2000.Iaddend., is hereby claimed.Iadd.; benefit
under 35 U.S.C. .sctn.119 of German application 100 63 435.4 filed
Dec. 20, 2000 is also claimed.Iaddend..
Claims
We claim:
1. A compound of formula I ##STR00006## wherein R.sub.a is a
.[.benzyl, 1-phenylethyl, or.]. 3-chloro-4-fluorophenyl group;
R.sub.b is a dimethylamino.[., N-methyl-N-ethylamino,
N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino,
N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino,
bis(2-methoxyethyl)amino, morpholino,
N-methyl-N-(tetrahydrofuran-3-yl)amino,
N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino,
N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino,
N-methyl-N-(tetrahydropyran-4-yl)amino, or
N-methyl-N-(tetrahydropyran-4-ylmethyl)amino.]. group; and R.sub.c
is a .[.cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy,.].
tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy,
tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or
tetrahydropyran-4-ylmethoxy group, or a stereoisomer or
physiologically acceptable salt thereof.
.[.2. The compound of claim 1, wherein Rb is a dimethylamino or a
stereoisomer or physiologically acceptable salt thereof..].
.[.3. The compound of formula I according to claim 1, wherein:
R.sub.a is a 1-phenylethyl or 3-chloro-4-fluorophenyl group;
R.sub.b is a dimethylamino, N-methyl-N-ethylamino,
N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino,
N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino,
bis(2-methoxyethyl)amino, morpholino,
N-methyl-N-(tetrahydrofuran-3-yl)amino,
N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino,
N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino,
N-methyl-N-(tetrahydropyran-4-yl)amino, or
N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group; and R.sub.c is
a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy,
tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy,
tetradrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or
tetrahydropyran-4-ylmethoxy group, or a stereoisomer or
physiologically acceptable salt thereof..].
.[.4. The compounds of claim 3, wherein R.sub.b is a dimethylamino,
or a stereoisomer or physiologically acceptable salt
thereof..].
.[.5. The compounds of claim 3, wherein R.sub.a is a
3-chloro-4-fluorohenyl group and R.sub.b is a dimethylamino group,
or a stereoisomer or physiologically acceptable salt
thereof..].
.[.6. The compound of formula I according to claim 1, wherein:
R.sub.a is a 3-chloro-4-fluorophenyl group; R.sub.b is a
dimethylaminno group; and R.sub.c is a tetrahydrofuran-3-yloxy,
tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy,
tetrahydropyran-4-yloxy, or tetrahydropyran-4-ylmethoxy group, or a
steroisomer or physiologically acceptable salt thereof..].
.Iadd.7. The compound of claim 1, wherein: R.sub.c is a
tetrahydrofuran-3-yloxy, or a steroisomer or physiologically
acceptable salt thereof..Iaddend.
.Iadd.8.
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-o-
xo-2-buten-1-yl]amino}-7-((S)-(tetrahydrofuran-3-yl)oxy)quinazoline..Iadde-
nd.
.Iadd.9. A physiologically acceptable salt comprising the
combination of the compound according to claim 8 with an organic or
inorganic acid..Iaddend.
.Iadd.10. The salt according to claim 9 wherein the acid is
hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic
acid, phosphoric acid, fumaric acid, succinic acid, lactic acid,
citric acid, tartaric acid, or maleic acid..Iaddend.
.Iadd.11. The salt according to claim 10, wherein the acid is
maleic acid..Iaddend.
.Iadd.12.
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1--
oxo-2-buten-1-yl]amino}-7-((R)-(tetrahydrofuran-3-yl)oxy)quinazoline..Iadd-
end.
Description
SUMMARY OF THE INVENTION
The present invention relates to quinazoline derivatives of general
formula
##STR00002## the tautomers, the stereoisomers and the salts
thereof, particularly the physiologically acceptable salts thereof
with inorganic or organic acids or bases which have valuable
pharmacological properties, particularly an inhibitory effect on
signal transduction mediated by tyrosine kinases, the use thereof
for treating diseases, particularly tumoral diseases, diseases of
the lungs and respiratory tract, and the preparation thereof.
In the above general formula I R.sub.a denotes a benzyl,
1-phenylethyl or 3-chloro-4-fluorophenyl group, R.sub.b denotes a
dimethylamino, N-methyl-N-ethylamino, diethylamino,
N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino,
N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino,
bis(2-methoxyethyl)amino, morpholino,
N-methyl-N-(tetrahydrofuran-3-yl)amino,
N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino,
N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino,
N-methyl-N-(tetrahydropyran-4-yl)amino or
N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group and R.sub.c
denotes a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy,
tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy,
tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy or
tetrahydropyran-4-ylmethoxy group, with the exception of the
compounds (1)
3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxyquinazoline, (2)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline, (3)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1--
yl]amino}-7-cyclopropylmethoxyquinazoline, (4)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclobutyloxyquinazoline, (5)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopentyloxyquinazoline, (6)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}7-cyclobutyloxyquinazoline, (7)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}7-cyclopentyloxyquinazoline, (8)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclobutyloxyquinazoline, (9)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopropylmethoxyquinazoline, (10)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopentyloxyquinazoline, (11)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclobutyloxyquinazoline, (12)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopentyloxyquinazoline, (13)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopropylmethoxyquinazoline, (14)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-
-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (15)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino-
]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (16)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-y-
l)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(17)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline, (18)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline, (19)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline, (20)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-2-y-
lmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
and (21)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-tetrahydrof-
uran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-
.
Preferred compounds of the above general formula I are those
wherein R.sub.a, R.sub.b, and R.sub.c are as hereinbefore defined,
but with the exception of the compounds (1)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxyquinazoline, (2)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline, (3)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1--
yl]amino}-7-cyclopropylmethoxyquinazoline, (4)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclobutyloxyquinazoline, (5)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopentyloxyquinazoline, (6)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-1-
-yl]amino}-7-cyclobutyloxyquinazoline, (7)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}7-cyclopentyloxyquinazoline, (8)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclobutyloxyquinazoline, (9)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopropylmethoxyquinazoline, (10)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopentyloxyquinazoline, (11)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclobutyloxyquinazoline, (12)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopentyloxyquinazoline, (13)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopropylmethoxyquinazoline, (14)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-
-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (15)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino-
]-1oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (16)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-y-
l)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(17)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline, (18)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline, (19)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-1-
yl]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline, (20)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-2-y-
lmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(21)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofura-
n-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(22)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methy-
lamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(23)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-
-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline, (24)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline, (25)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydrofuran-
-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
(26)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydrofuran-
-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
(27)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-y-
l)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline, (28)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydrofuran-
-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline,
(29)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydro-
furan-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazol-
ine, (30)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxye-
thyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-3-yloxy)quinazoli-
ne, (31)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyet-
hyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydropyran-4-yloxy)quinazolin-
e, (32)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyeth-
yl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-2-ylmethoxy)quinazo-
line and (33)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline, the
tautomers, the stereoisomers and the salts thereof.
Particularly preferred compounds of general formula I are those
wherein R.sub.a denotes a 1-phenylethyl or 3-chloro-4-fluorophenyl
group, R.sub.b denotes a dimethylamino, N-methyl-N-ethylamino,
diethylamino, N-methyl-N-isopropylamino,
N-methyl-N-cyclopropylamino, N-methyl-N-(2-methoxyethyl)amino,
N-ethyl-N-(2-methoxyethyl)amino, bis(2-methoxyethyl)amino,
morpholino, N-methyl-N-(tetrahydrofuran-3-yl)amino,
N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino,
N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino,
N-methyl-N-(tetrahydropyran-4-yl)amino or
N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group and R.sub.c
denotes a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy,
tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy,
tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy or
tetrahydropyran-4-ylmethoxy group, with the exception of the
compounds (1)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-b-
uten-1-yl]amino}-7-cyclopropylmethoxyquinazoline, (2)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline, (3)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1--
yl]amino}-7-cyclopropylmethoxyquinazoline, (4)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclobutyloxyquinazoline, (5)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopentyloxyquinazoline, (6)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}7-cyclobutyloxyquinazoline, (7)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-cyclopentyloxyquinazoline, (8)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclobutyloxyquinazoline, (9)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}7-cyclopropylmethoxyquinazoline, (10)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopentyloxyquinazoline, (11)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclobutyloxyquinazoline, (12)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopentyloxyquinazoline, (13)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopropylmethoxyquinazoline, (14)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-
-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (15)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino-
]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (16)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-y-
l)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(17)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline, (18)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline, (19)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline, (20)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-3-y-
l)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(21)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (22)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-
-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline, (23)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline, (24)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydrofuran-
-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
(25)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydrofuran-
-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
(26)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-y-
l)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline, (27)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amin-
o]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-3-yloxy)quinazoline,
(28)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amin-
o]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydropyran-4-yloxy)quinazoline,
(29)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amin-
o]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-2-ylmethoxy)quinazoline,
(30)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamin-
o)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline, (31)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-2-y-
lmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
(32)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydro-
furan-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazol-
ine and (33)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydrofuran-
-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline,
the tautomers, the stereoisomers and the salts thereof.
The following particularly preferred compounds of general formula I
may be mentioned by way of example: (a)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclobutyloxyquinazoline; (b)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentyloxyquinazoline, (c)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-bis(2-methoxyethyl)amino)-1-oxo-2-
-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline, (d)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-ethylamino]-1-ox-
o-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (e)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-o-
xo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (f)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methylamin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (g)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydrofuran-3-yl)-N-methylamin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, (h)
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tetrahydrofuran-3-yl)methyl-
]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline-
, (i)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-
-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)quinazoline, (j)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)quinazoline, (k)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-(tetrahydropyran-4-yloxy)quinazoline, (l)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline, (m)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]quinazoline, (o)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}7-[(tetrahydrofuran-3-yl)methoxy]quinazoline, (p)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl-
]amino}7-cyclopropylmethoxyquinazoline, (q)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-
-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,
(r)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline, (s)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline; and (t)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline, the
tautomers, the stereoisomers and the salts thereof.
The compounds of general formula I may be prepared by the following
methods, for example:
a) reacting a compound of general formula
##STR00003## wherein: R.sub.a and R.sub.c are as hereinbefore
defined, with a compound of general formula
##STR00004## wherein: R.sub.b is as hereinbefore defined; and
Z.sub.1 denotes a leaving group such as a halogen atom, e.g., a
chlorine or bromine atom, or a hydroxy group.
The reaction is optionally carried out in a solvent or mixture of
solvents such as methylene chloride, dimethylformamide, benzene,
toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or
dioxane, optionally in the presence of an inorganic or organic base
and optionally in the presence of a dehydrating agent, expediently
at temperatures between -50.degree. C. and 150.degree. C.,
preferably at temperatures between -20.degree. C. and 80.degree.
C.
With a compound of general formula III wherein Z.sub.1 denotes a
leaving group, the reaction is optionally carried out in a solvent
or mixture of solvents such as methylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane, conveniently
in the presence of a tertiary organic base such as triethylamine,
pyridine or 4-dimethylaminopyridine, in the presence of
N-ethyldiisopropylamine (Hunig base), whilst these organic bases
may simultaneously also act as solvent, or in the presence of an
inorganic base such as sodium carbonate, potassium carbonate or
sodium hydroxide solution, expediently at temperatures between
-50.degree. C. and 150.degree. C., preferably at temperatures
between -20.degree. C. and 80.degree. C.
With a compound of general formula III wherein Z.sub.1 denotes a
hydroxy group, the reaction is preferably carried out in the
presence of a dehydrating agent, e.g., in the presence of isobutyl
chloroformate, thionyl chloride, trimethyl chlorosilane, phosphorus
trichloride, phosphorus pentoxide, hexamethyldisilazane,
N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,
1-hydroxybenzotriazole, N,N'-carbonyldiimidazole or
triphenylphosphine/carbon tetrachloride, expediently in a solvent
such as methylene chloride, tetrahydrofuran, dioxane, toluene,
chlorobenzene, dimethylformamide, dimethylsulfoxide, ethylene
glycol diethylether or sulfolane and optionally in the presence of
a reaction accelerator such as 4-dimethylaminopyridine at
temperatures between -50.degree. C. and 150.degree. C., but
preferably at temperatures between -20.degree. C. and 80.degree.
C.
b) Reacting a compound of general formula
##STR00005## wherein: R.sub.a and R.sub.c are as hereinbefore
defined; and Z.sub.2 denotes a leaving group such as a halogen
atom, a substituted hydroxy or sulfonyloxy group such as a chlorine
or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy
group, with a compound of general formula: H--R.sub.b (V) wherein
R.sub.b is as hereinbefore defined.
The reaction is expediently carried out in a solvent such as
isopropanol, butanol, tetrahydrofuran, dioxane, toluene,
chlorobenzene, dimethylformamide, dimethylsulfoxide, methylene
chloride, ethylene glycol monomethylether, ethylene glycol
diethylether or sulfolane or mixtures thereof, optionally in the
presence of an inorganic or tertiary organic base, e.g., sodium
carbonate or potassium hydroxide, a tertiary organic base, e.g.,
triethylamine or N-ethyldiisopropylamine (Hunig base), whilst these
organic bases may simultaneously also serve as solvent, and
optionally in the presence of a reaction accelerator such as an
alkali metal halide at temperatures between -20.degree. C. and
150.degree. C., but preferably at temperatures between -10.degree.
C. and 100.degree. C. The reaction may, however, also be carried
out without a solvent or in an excess of the compound of general
formula V used.
In the reactions described above, the secondary amino group bound
to the quinazoline of general formula II or IV may be protected
during the reaction by conventional protecting groups which are
cleaved again after the reaction. Examples of protecting groups
include the 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 sulfuric acid or in the presence of an
alkali metal base such as sodium hydroxide or potassium hydroxide
or aprotically, e.g., in the presence of iodotrimethylsilane, at
temperatures between 0.degree. C. and 120.degree. C., preferably at
temperatures between 10.degree. C. and 100.degree. C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is
cleaved, for example hydrogenolytically, e.g., with hydrogen in the
presence of a catalyst such as palladium/charcoal in a suitable
solvent such as methanol, ethanol, ethyl acetate or glacial acetic
acid, optionally with the addition of an acid such as hydrochloric
acid at temperatures between 0.degree. C. and 100.degree. C., but
preferably at ambient temperatures between 20.degree. C. and
60.degree. C., and at a hydrogen pressure of 1 to 7 bar, but
preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is
preferably cleaved in trifluoroacetic acid in the presence of
anisole.
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.
A trifluoroacetyl group is preferably cleaved by treating with an
acid such as hydrochloric acid, optionally in the presence of a
solvent such as acetic acid at temperatures between 50.degree. C.
and 120.degree. C. or by treating with sodium hydroxide solution
optionally in the presence of a solvent such as tetrahydrofuran at
temperatures between 0.degree. C. and 50.degree. C.
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 obtained may be resolved
by chromatography into the cis and trans isomers thereof, the
compounds of general formula I obtained which occur as racemates
may be separated by methods known per se (cf N. L. Allinger and E.
L. Eliel in "Topics in Stereochemistry", Vol. 6, Wiley
Interscience, 1971) into their optical antipodes and compounds of
general formula I with at least 2 asymmetric carbon atoms may be
resolved into their diastereomers on the basis of their
physical-chemical differences using methods known per se, e.g., by
chromatography and/or fractional crystallization, and, if these
compounds are obtained in racemic form, they may subsequently be
resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on
chiral phases or by recrystallization from an optically active
solvent or by reacting with an optically active substance which
forms salts or derivatives such as, e.g., esters or amides with the
racemic compound, particularly acids and the activated derivatives
or alcohols thereof, and separating the diastereomeric mixture of
salts or derivatives thus obtained, e.g., on the basis of their
differences in solubility, whilst the free antipodes may be
released from the pure diastereomeric salts or derivatives by the
action of suitable agents. Optically active acids in common use
are, e.g., the D- and L-forms of tartaric acid or dibenzoyltartaric
acid, di-o-tolyltartaric acid, malic acid, mandelic acid,
camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
An optically active alcohol may be for example (+) or (-)-menthol
and an optically active acyl group in amides, for example, may be a
(+)-or (-)-menthyloxycarbonyl.
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, sulfuric acid, methanesulfonic
acid, phosphoric acid, fumaric acid, succinic acid, lactic acid,
citric acid, tartaric acid, or maleic acid.
The compounds of general formulae II to V used as starting
materials are known from the literature in some cases or may be
obtained by methods known from the literature.
For example, a starting compound of general formula II is obtained
by reacting a 7-fluoro-6-nitro compound correspondingly substituted
in the 4 position with a corresponding alkoxide and subsequently
reducing the nitro compound thus obtained or a starting compound of
general formula III is obtained, for example, by reacting a
suitable bromocrotonic acid derivative with one of the amines of
general formula V known from the literature, or a starting compound
of general formula IV is obtained by acylating a compound of
general formula II with a suitable crotonic acid derivative.
As already mentioned hereinbefore, the compounds of general formula
I according to the invention and the physiologically acceptable
salts thereof have valuable pharmacological properties,
particularly an inhibiting effect on signal transduction mediated
by the Epidermal Growth Factor receptor (EGF-R), whilst this may be
achieved for example by inhibiting ligand bonding, receptor
dimerization or tyrosine kinase itself. It is also possible to
block the transmission of signals to components located further
down.
The biological properties of the new compounds were investigated as
follows:
The inhibition of human EGF-receptor kinase was determined using
the cytoplasmic tyrosine kinase domain (methionine 664 to alamine
1186, based on the sequence published in Nature 309 (1984), 418).
To do this, the protein was expressed in Sf9 insect cells as a GST
fusion protein using the Baculovirus expression system.
The enzyme activity was measured in the presence or absence of the
test compounds in serial dilutions. The polymer pEY (4:1) produced
by SIGMA was used as the substrate. Biotinylated pEY (bio-pEY) was
added as the tracer substrate. Every 100 .mu.l of reaction solution
contained 10 .mu.l of the inhibitor in 50% DMSO, 20 .mu.l of the
substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate,
2.5 mg/ml poly(EY), 5 .mu.g/ml bio-pEY) and 20 .mu.l of enzyme
preparation. The enzyme reaction was started by the addition of 50
.mu.l of a 100 .mu.M ATP solution in 10 mM magnesium chloride. The
dilution of the enzyme preparation was adjusted so that the
incorporation of phosphate into the bio-pEY was linear in terms of
time and quantity of enzyme. The enzyme preparation was diluted in
20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% Triton
X-100, 1 mM DTT and 10% glycerol.
The enzyme assays were carried out at ambient temperature over a
period of 30 minutes and were ended by the addition of 50 .mu.l of
a stopping solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 .mu.l
were placed on a streptavidin-coated microtiter plate and incubated
for 60 minutes at ambient temperature. Then the plate was washed
with 200 .mu.l of a washing solution (50 mM Tris, 0.05% Tween 20).
After the addition of 100 .mu.l of a HRPO-labelled anti-PY antibody
(PY20H Anti-PTyr:HRP produced by Transduction Laboratories, 250
ng/ml), it was incubated for 60 minutes. Then the microtiter plate
was washed three times with 200 .mu.l of washing solution. The
samples were then combined with 100 .mu.l of a TMB-peroxidase
solution (A:B=1:1, Kirkegaard Perry Laboratories). After 10
minutes, the reaction was stopped. The extinction was measured at
OD.sub.450 nm with an ELISA reader. All data points were measured
three times.
The data were matched by means of an iterative calculation using an
analytical program for sigmoidal curves (Graph Pad Prism Version
3.0) with variable Hill pitch. All the iteration data released
showed a correlation coefficient of more 0.9 and the upper and
lower values of the curves showed a spread of at least a factor of
5. The concentration of active substance which inhibits the
activity of EGF-receptor kinase by 50% (IC.sub.50) was derived from
the curves.
The following results were obtained:
TABLE-US-00001 Compound Inhibition of EGF-Receptor (Example No.)
Kinase IC.sub.50 [nM] 1 .sup. 0.7 1(2) 0.6 1(3) 4.0 1(5) 3.0 1(10)
0.5 1(22) 1.0 1(32) 0.3 1(33) 0.5 1(34) 0.4
The compounds of general formula I according to the invention thus
inhibit signal transduction by tyrosine kinases, as demonstrated by
the example of the human EGF receptor, and are therefore useful for
treating pathophysiological processes caused by hyperfunction of
tyrosine kinases. These are, e.g., benign or malignant tumors,
particularly tumors of epithelial and neuroepithelial origin,
metastasization and the abnormal proliferation of vascular
endothelial cells (neoangiogenesis).
The compounds according to the invention are also useful for
preventing and treating diseases of the airways and lungs which are
accompanied by increased or altered production of mucus caused by
stimulation by tyrosine kinases, e.g., in inflammatory diseases of
the airways such as chronic bronchitis, chronic obstructive
bronchitis, asthma, bronchiectasis, allergic or non-allergic
rhinitis or sinusitis, cystic fibrosis, .alpha.1-antitrypsin
deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and
hyperreactive airways.
The compounds are also suitable for treating diseases of the
gastrointestinal tract and bile duct and gall bladder which are
associated with disrupted activity of the tyrosine kinases, such as
may be found, e.g., in chronic inflammatory changes such as
cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in
the gastrointestinal tract or such as may occur in diseases of the
gastrointestinal tract which are associated with increased
secretions, such as Menetrier's disease, secreting adenomas and
protein loss syndrome.
In addition, the compounds of general formula I and the
physiologically acceptable salts thereof may be used to treat other
diseases caused by abnormal function of tyrosine kinases, such as,
e.g., epidermal hyperproliferation (psoriasis), inflammatory
processes, diseases of the immune system, hyperproliferation of
hematopoietic cells, etc.
By reason of their biological properties the compounds according to
the invention may be used on their own or in conjunction with other
pharmacologically active compounds, for example in tumour therapy,
in monotherapy or in conjunction with other anti-tumour therapeutic
agents, for example in combination with topoisomerase inhibitors
(e.g., etoposide), mitosis inhibitors (e.g., vinblastine),
compounds which interact with nucleic acids (e.g., cis-platin,
cyclophosphamide, adriamycin), hormone antagonists (e.g.,
tamoxifen), inhibitors of metabolic processes (e.g., 5-FU etc.),
cytokines (e.g., interferons), antibodies, etc. For treating
respiratory tract diseases, these compounds may be used on their
own or in conjunction with other therapeutic agents for the
airways, such 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. These combinations may be
administered either simultaneously or sequentially.
These compounds may be administered either on their own or in
conjunction with other active substances by intravenous,
subcutaneous, intramuscular, intraperitoneal or intranasal route,
by inhalation or transdermally or orally, whilst aerosol
formulations are particularly suitable for inhalation.
For pharmaceutical use the compounds according to the invention are
generally used for warm-blooded vertebrates, particularly humans,
in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg.
For administration they are formulated with one or more
conventional inert carriers and/or diluents, e.g., with corn
starch, lactose, glucose, microcrystalline cellulose, magnesium
stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water,
water/ethanol, water/glycerol, water/sorbitol, water/polyethylene
glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose
or fatty substances such as hard fat or suitable mixtures thereof
in conventional galenic preparations such as plain or coated
tablets, capsules, powders, suspensions, solutions, sprays or
suppositories.
The following Examples are intended to illustrate the present
invention without restricting it.
Preparation of the Starting Compounds
EXAMPLE I
3-methylaminotetrahydrofuran
3.43 g of lithium aluminium hydride are added batchwise to 50 ml of
tetrahydrofuran while cooling with an ice bath. Then a solution of
5.00 g of 3-[(benzyloxycarbonyl)-amino]tetrahydrofuran in 20 ml
tetrahydrofuran is added dropwise, while the temperature remains
below 10.degree. C. After 10 minutes, the cooling bath is removed
and the reaction mixture is refluxed for about three hours. For
working up, 3.7 ml of water, 3.7 ml of 15% sodium hydroxide
solution, and another 3 ml of water are carefully added dropwise to
the reaction mixture while cooling with an ice bath. Then some
tetrahydrofuran is added and the mixture is stirred for another 15
minutes. The aluminium hydroxide slurry precipitated is suction
filtered and washed with a total of 150 ml of tetrahydrofuran. The
filtrate is evaporated down using the rotary evaporator. A
colorless oil remains, which is reacted without any further
purification. Mass spectrum (ESI.sup.+): m/z=102 [M+H].sup.+;
R.sub.f value: 0.20 (silica gel, methylene
chloride/methanol=9:1).
EXAMPLE II
3-[(benzyloxycarbonyl)amino]tetrahydrofuran
12.36 ml of tetrahydrofuran-3-carboxylic acid and 27.84 ml of
diphenylphosphorylazide in 500 ml of dioxane are combined with
41.91 g of benzyl alcohol and 35.81 ml of triethylamine. The
reaction mixture is heated to 100.degree. C. for about seven hours.
After cooling to ambient temperature, the reaction mixture is
evaporated down using the rotary evaporator. The residue is taken
up in 500 ml of methylene chloride and washed twice with 100 ml of
1 N sodium hydroxide solution. The organic phase is dried over
magnesium sulfate and evaporated down. The crude product is
purified by chromatography over a silica gel column with
cyclohexane/ethyl acetate (3:1 to 1:2) as eluant. Yield: 15.60 g
(55% of theory); mass spectrum (ESI.sup.-): m/z=220 [M-H].sup.-;
R.sub.f value: 0.78 (silica gel, methylene
chloride/methanol=9:1).
EXAMPLE III
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((R)-tetrahydrofuran-3-yloxy-
)quinazoline
A mixture of 12.80 g of
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((R)-tetrahydrofuran-3-yloxy-
)quinazoline, 200 ml of ethanol, 100 ml of water, and 17.20 ml of
glacial acetic acid is heated to reflux temperature. Then a total
of 7.00 g of iron powder is added in batches. The reaction mixture
is refluxed for about four hours and then cooled to ambient
temperature overnight. For working up, the reaction mixture is
evaporated using the rotary evaporator. The residue is taken up in
methylene chloride/methanol (9:1), mixed with 20 ml of concentrated
ammonia solution and filtered through a layer of silica gel. It is
washed with copious amounts of methylene chloride/methanol (9:1)
and the combined filtrates are evaporated down. The residue is
stirred with diethylether and suction filtered. Yield: 8.59 g (73%
of theory); mass spectrum (ESI.sup.-): m/z=373, 375 [M-H].sup.-;
R.sub.f value: 0.27 (silica gel, ethyl acetate/methanol=9:1).
The following compounds are obtained analogously to Example III:
(1)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((S)-tetrahydrofuran-3-yloxy-
)quinazoline
Mass spectrum (ESI.sup.-): m/z=373, 375 [M-H].sup.-; R.sub.f value:
0.27 (silica gel, ethyl acetate/methanol=9:1). (2)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-(tetrahydropyran-4-yloxy)qui-
nazoline
Mass spectrum (ESI.sup.-): m/z=387, 389 [M-H].sup.-; R.sub.f value:
0.20 (silica gel, ethyl acetate). (3)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydrofuran-2-yl)metho-
xy]quinazoline
Mass spectrum (ESI.sup.-): m/z=387, 389 [M-H].sup.-; R.sub.f value:
0.55 (silica gel, ethyl acetate/methanol=9:1). (4)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydrofuran-3-yl)metho-
xy]quinazoline
Mass spectrum (ESI.sup.-): m/z=387, 389 [M-H].sup.-; R.sub.f value:
0.40 (silica gel, ethyl acetate/methanol=9:1).
EXAMPLE IV
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((R)-tetrahydrofuran-3-yloxy-
)quinazoline
13.80 g of potassium tert-butoxide are added batchwise to a
solution of 10.80 g of (R)-3-hydroxytetrahydrofuran in 100 ml of
N,N-dimethylformamide while cooling with an ice bath. The reaction
mixture is stirred for about one hour, then 10.40 g of
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-fluoroquinazoline are
added batchwise. The cooling bath is then removed and the deep red
reaction mixture is stirred for two hours at ambient temperature.
For working up the reaction mixture is poured onto about 500 ml of
water and neutralized with 2 N hydrochloric acid. The yellowish
precipitate formed is suction filtered and dried at 70.degree. C.
in a circulating air drier. Yield: 12.80 g; melting point:
244.degree. C.; mass spectrum (ESI.sup.-): m/z=403, 405
[M-H].sup.-.
The following compounds are obtained analogously to Example IV: (1)
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy-
)quinazoline
Mass spectrum (ESI.sup.-): m/z=403, 405 [M-H].sup.-; R.sub.f value:
0.45 (silica gel, ethyl acetate). (2)
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-(tetrahydropyran-4-yloxy)qui-
nazoline
Mass spectrum (ESI.sup.-): m/z=417, 419 [M-H].sup.-; R.sub.f value:
0.42 (silica gel, ethyl acetate). (3)
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydrofuran-2-yl)metho-
xy]quinazoline
Mass spectrum (ESI.sup.-): m/z=417, 419 [M-H].sup.-; R.sub.f value:
0.47 (silica gel, ethyl acetate). (4)
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydrofuran-3-yl)metho-
xy]quinazoline
Mass spectrum (ESI.sup.-): m/z=417, 419 [M-H].sup.-; R.sub.f value:
0.41 (silica gel, ethyl acetate). (5)
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydropyran-4-yl)metho-
xy]quinazoline
Mass spectrum (ESI.sup.+): m/z=433, 435 [M+H].sup.+; R.sub.f value:
0.79 (silica gel, ethyl acetate/methanol=9:1). (6)
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(R)-(tetrahydrofuran-2-yl)m-
ethoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=419, 421 [M+H].sup.+; R.sub.f value:
0.44 (silica gel, ethyl acetate). (7)
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(S)-(tetrahydrofuran-2-yl)m-
ethoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=419, 421 [M+H].sup.+; R.sub.f value:
0.44 (silica gel, ethyl acetate).
EXAMPLE V
(R)-N-[(tetrahydrofuran-2-yl)methyl]-N-methylamine
21.10 g of
(R)-N-[(tetrahydrofuran-2-yl)methyl]-N-benzyl-N-methylamine (crude
product from Example VI) are dissolved in 200 ml of methanol and
hydrogenated in the presence of 4.00 g of palladium on activated
charcoal (10% Pd) at ambient temperature until the uptake of
hydrogen has ended. For working up the catalyst is filtered off and
the filtrate is evaporated using the rotary evaporator. A thin
yellow oil is left, which is further reacted without any more
purification. Yield: 8.60 g (73% of theory); mass spectrum
(ESI.sup.+): m/z=116 [M+H].sup.+.
The following compounds are obtained analogously to Example V: (1)
(S)-N-[(tetrahydrofuran-2-yl)methyl]-N-methylamine
Mass spectrum (ESI.sup.+): m/z=116 [M+H].sup.+. (2)
N-[(tetrahydropyran-4-yl)methyl]-N-methylamine
Mass spectrum (ESI.sup.+): m/z=130 [M+H].sup.+.
EXAMPLE VI
(R)-N-[(tetrahydrofuran-2-yl)methyl]-N-benzyl-N-methylamine
A solution of 24.60 g of (R)-tetrahydrofuran-2-carboxylic
acid-N-benzyl-N-methylamide in 90 ml tetrahydrofuran is added
dropwise to 17.00 g of lithium aluminium hydride in 150 ml of
tetrahydrofuran. The reaction mixture is refluxed for two hours.
For working up it is cooled to 0.degree. C. in an ice bath, mixed
with 20 ml of water and 10 ml of 15 N sodium hydroxide solution and
stirred for another 20 minutes. Then it is filtered through a layer
of magnesium sulfate and washed with a total of about 500 ml of
tetrahydrofuran. The filtrate is evaporated down in vacuo, leaving
a yellowish oil which is further reacted without any more
purification. Yield: 21.10 g (92% of theory); mass spectrum
(ESI.sup.+): m/z=206 [M+H].sup.+.
The following compounds are obtained analogously to Example VI: (1)
(S)-N-[(tetrahydrofuran-2-yl)methyl]-N-benzyl-N-methylamine
R.sub.f value: 0.20 (silica gel, ethyl acetate/methanol=9:1). (2)
N-[(tetrahydropyran-4-yl)methyl]-N-benzyl-N-methylamine
Mass spectrum (ESI.sup.+): m/z=220 [M+H].sup.+.
EXAMPLE VII
(R)-tetrahydrofuran-2-carboxylic acid-N-benzyl-N-methylamide
25.30 g of N-benzyl-N-methylamine are added to a solution of 20.00
ml of (R)-tetrahydrofuran-2-carboxylic acid in 200 ml
tetrahydrofuran. Then a total of 67.10 g of
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate are added batchwise while cooling with an ice
bath and the reaction mixture is then stirred for about 48 hours at
ambient temperature. The precipitate formed is suction filtered,
the filtrate is evaporated, mixed with water and filtered again.
The filtrate obtained is made alkaline with sodium hydrogen
carbonate solution and extracted with ethyl acetate. The combined
ethyl acetate extracts are washed with water and saturated sodium
chloride solution, dried over magnesium sulfate, and evaporated
down. A yellowish oil remains, which is further reacted without any
further purification. Yield: 24.60 g (54% of theory); mass spectrum
(ESI.sup.+): m/z=220 [M+H].sup.+; R.sub.f value: 0.62 (silica gel,
ethyl acetate).
The following compounds are obtained analogously to Example VII:
(1) (S)-tetrahydrofuran-2-carboxylic
acid-N-benzyl-N-methylamide
Mass spectrum (ESI.sup.+): m/z=242 [M+Na].sup.+; R.sub.f value:
0.62 (silica gel, ethyl acetate). (2) tetrahydropyran-4-carboxylic
acid-N-benzyl-N-methylamide
The amide coupling is carried out with 1,1'-carbonyldiimidazole in
tetrahydrofuran. Mass spectrum (ESI.sup.+): m/z=256 [M+Na].sup.+;
R.sub.f value: 0.45 (silica gel, ethyl acetate).
EXAMPLE VIII
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydropyran-4-yl)metho-
xy]quinazoline
22.80 g of
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydropyran-4-yl)metho-
xy]quinazoline are hydrogenated in 300 ml of tetrahydrofuran in the
presence of 3.50 g of platinum dioxide at ambient temperature until
the calculated amount of hydrogen has been taken up. The catalyst
is filtered off and the filtrate is evaporated to dryness using the
rotary evaporator. The residue is stirred with diethylether,
suction filtered, washed with diethylether and dried at ambient
temperature. Yield: 19.95 g (93% of theory); mass spectrum
(ESI.sup.+): m/z=403, 405 [M+H].sup.+; melting point: 221.degree.
C.
The following compounds are obtained analogously to Example VIII:
(1)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(R)-(tetrahydrofuran-2-yl)m-
ethoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=389, 391 [M+H].sup.+; R.sub.f value:
0.11 (silica gel, ethyl acetate). (2)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-2-yl)m-
ethoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=389, 391 [M+H].sup.+; R.sub.f value:
0.33 (silica gel, ethyl acetate/methanol=9:1).
Preparation of the Final Compounds
EXAMPLE 1
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
4.70 ml of oxalyl chloride are added dropwise to a solution of 4.50
g of bromocrotonic acid in 60 ml of methylene chloride. Then one
drop of N,N-dimethylformamide is added. After about 30 minutes, the
development of gas has ended and the reaction mixture is evaporated
using the rotary evaporator. The crude bromocrotonic acid chloride
is taken up in 30 ml of methylene chloride and, while cooling with
an ice bath, added dropwise to a solution of 7.00 g of
4-[(3-chloro-4-fluorophenyl)amino]-6-amino-7-cyclopropylmethoxyquinazolin-
e and 10.20 ml of Hunig base in 150 ml of tetrahydrofuran. The
reaction mixture is stirred for about 1.5 hours while cooling with
an ice bath and then for another two hours at ambient temperature.
Then 5.20 g of N-(2-methoxyethyl)-N-methylamine are added and the
reaction mixture is stirred overnight at ambient temperature. For
working up, it is diluted with methylene chloride and washed
thoroughly with water. The organic phase is dried over magnesium
sulfate and evaporated down. The crude product is purified by
chromatography over a silica gel column with ethyl acetate followed
by ethyl acetate/methanol (19:1) as eluant. Yield: 5.07 g (51% of
theory); mass spectrum (ESI.sup.-): m/z=512, 514 [H-H].sup.-;
R.sub.f value: 0.25 (silica gel, ethyl acetate/methanol=9:1).
The following compounds are obtained analogously to Example 1: (1)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclobutyloxyquinazoline
Mass spectrum (ESI.sup.-): m/z=468, 470 [M-H].sup.-; R.sub.f value:
0.09 (silica gel, ethyl acetate/methanol=9:1). (2)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentyloxyquinazoline
Mass spectrum (ESI.sup.-): m/z=482, 484 [M-H].sup.-; R.sub.f value:
0.11 (silica gel, ethyl acetate/methanol=9:1). (3)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-bis(2-methoxyethyl)amino)-1-oxo-2-
-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.-): m/z=532 [M-H].sup.-; R.sub.f value: 0.40
(silica gel, ethyl acetate/methanol=9:1). (4)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-ethylamino]-1-ox-
o-2-buten-1yl}amino)-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.-): m/z=502 [M-H].sup.-; R.sub.f value: 0.20
(silica gel, ethyl acetate/methanol=9:1). (5)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-o-
xo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.-): m/z=488 [M-H].sup.-; R.sub.f value: 0.25
(silica gel, ethyl acetate/methanol=9:1). (6)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methylamin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.-): m/z=514 [H-H].sup.-; R.sub.f value: 0.15
(silica gel, ethyl acetate/methanol=9:1). (7)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydrofuran-3-yl)-N-methylamin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.-): m/z=500 [M-H].sup.-; R.sub.f value: 0.18
(silica gel, ethyl acetate/methanol=9:1). (8)
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tetrahydrofuran-3-yl)methyl-
]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.-): m/z=538, 540 [M-H].sup.-; R.sub.f value:
0.27 (silica gel, ethyl acetate/methanol=9:1). (9)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)quinazoline; mass
spectrum (ESI.sup.+): m/z=486, 488 [M+H].sup.+. (10)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)quinazoline
Mass spectrum (ESI.sup.+): m/z=486, 488 [M+H].sup.+; R.sub.f value:
0.45 (silica gel, methylene chloride/methanol=5:1). (11)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-(tetrahydropyran-4-yloxy)quinazoline
Mass spectrum (ESI.sup.+): m/z=500, 502 [M+H].sup.+; R.sub.f value:
0.55 (silica gel, methylene chloride/methanol=5:1). (12)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=500, 502 [M+H].sup.+; R.sub.f value:
0.60 (silica gel, methylene chloride/methanol=5:1). (13)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=500, 502 [M+H].sup.+; R.sub.f value:
0.50 (silica gel, methylene chloride/methanol=5:1). (14)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=528, 530 [M+H].sup.+; R.sub.f value:
0.31 (silica gel, ethyl acetate/methanol=9:1). (15)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl-
]amino}-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.+): m/z=446 [M+H].sup.+; R.sub.f value: 0.11
(silica gel, ethyl acetate/methanol=9:1). (16)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-
-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=588, 590 [M+H].sup.+; R.sub.f value:
0.55 (silica gel, methylene chloride/methanol=9:1). (17)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=542, 544 [M+H].sup.+; R.sub.f value:
0.55 (silica gel, methylene chloride/methanol=9:1). (18)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamin-
o]-1oxo-2-buten-1-yl}amino)-7-cyclopentyloxyquinazoline
Mass spectrum (ESI.sup.+): m/z=528, 530 [M+H].sup.+; R.sub.f value:
0.25 (silica gel, ethyl acetate/methanol=9:1). (19)
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{(R)-N-[(tetrahydrofuran-2-yl)me-
thyl]-N-methylamino}1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazol-
ine
Mass spectrum (ESI.sup.+): m/z=540, 542 [M+H].sup.+; melting point:
149.degree. C.-153.degree. C. (20)
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{(S)-N-[(tetrahydrofuran-2-yl)me-
thyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazo-
line
Mass spectrum (ESI.sup.+): m/z=540, 542 [M+H].sup.+; R.sub.f value:
0.29 (silica gel, ethyl acetate/methanol=9:1). (21)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl-
]amino}-7-cyclopentyloxyquinazoline
Mass spectrum (ESI.sup.+): m/z=560 [M+H].sup.+; R.sub.f value: 0.17
(silica gel, ethyl acetate/methanol=9:1). (22)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline
Mass spectrum (ESI.sup.-): m/z=508, 510 [M-H].sup.-; melting point:
140.degree. C. (23)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.+): m/z=496, 498 [M+H].sup.+; R.sub.f value:
0.42 (silica gel, ethyl acetate/methanol=9:1). (24)
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tetrahydropyran-4-yl)methyl-
]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.+): m/z=554, 556 [M+H].sup.+; melting point:
141.degree. C. (25)
4-[(R)-(1-phenylethyl)amino]-6-[(4-{N-[(tetrahydropyran-4-yl)methyl]-N-me-
thylamino}1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
Mass spectrum (ESI.sup.+): m/z=530 [M+H].sup.+; R.sub.f value: 0.32
(silica gel, ethyl acetate/methanol/conc. aqueous
ammonia=90:10:0.5). (26)
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{(R)-N-[(tetrahydrofuran-2--
yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopentyloxyquinaz-
oline
Mass spectrum (ESI.sup.+): m/z=554, 556 [M+H].sup.+; melting point:
117.degree. C.-121.degree. C. (27)
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{(S)-N-[(tetrahydrofuran-2-yl)me-
thyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopentyloxyquinazoline
Mass spectrum (ESI.sup.+): m/z=554, 556 [M+H].sup.+; R.sub.f value:
0.32 (silica gel, ethyl acetate/methanol/conc. aqueous
ammonia=90:10:0.5). (28)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-
-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=514, 516 [M+H].sup.+; R.sub.f value:
0.19 (silica gel, methylene chloride/methanol/conc. aqueous
ammonia=95:5:0.05). (29)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}7-[(tetrahydropyran-4-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.-): m/z=554, 556 [M-H].sup.-; melting point:
174.degree. C. (30)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-
-oxo-2-buten-1-yl}amino)-7-[(tetrahydropyran-4-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=602, 604 [M+H].sup.+; melting point:
100.degree. C.-102.degree. C. (31)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=500, 502 [M+H].sup.+; melting point:
110.degree. C.-112.degree. C. (32)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=500, 502 [M+H].sup.+; R.sub.f value:
0.23 (silica gel, ethyl acetate/methanol/conc. aqueous
ammonia=90:10:0.1). (33)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-ethyl-N-methylamino)-1-o-
xo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=500, 502 [M+H].sup.+; melting point:
154.degree. C.-157.degree. C. (34)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-isopropyl-N-methylamino)-1-ox-
o-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=514, 516 [M+H].sup.+; R.sub.f value:
0.34 (silica gel, ethyl acetate/methanol/conc. aqueous
ammonia=90:10:1). (35)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=528, 530 [M+H].sup.+; melting point:
184.degree. C.-185.degree. C. (36)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-isopropyl-N-methylamino)-1-ox-
o-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline
Mass spectrum (ESI.sup.+): m/z=512, 514 [M+H].sup.+; R.sub.f value:
0.53 (silica gel, ethyl acetate/methanol/conc. aqueous
ammonia=90:10:0.5). (37)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-ethyl-N-methylamino)-1-o-
xo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.-): m/z=512, 514 [M-H].sup.-; R.sub.f value:
0.15 (silica gel, ethyl acetate/methanol/conc. aqueous
ammonia=90:10:1). (38)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.-): m/z=526, 528 [M-H].sup.-; R.sub.f value:
0.27 (silica gel, methylene chloride/methanol=9:1). (39)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-isopropyl-N-methylamino)-1-ox-
o-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline
Mass spectrum (ESI.sup.+): m/z=528, 530 [M+H].sup.+; R.sub.f value:
0.31 (silica gel, methylene chloride/methanol=9:1).
The following compounds may also be prepared analogously to the
foregoing Examples and other methods known from the literature: (1)
4-benzylamino-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclop-
ropylmethoxyquinazoline (2)
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tetrahydropyran-4-yl)methyl-
]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
(3)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2--
buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)methoxy]quinazoline (4)
4-[(R)-(1-phenylethyl)amino]-6-[(4-{N-[(tetrahydrofuran-2-yl)methyl]-N-me-
thylamino}1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
(5)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl-
]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline (6)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-oxo-2-
-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline (7)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
EXAMPLE 2
TABLE-US-00002 Coated tablets containing 75 mg of active substance
1 tablet core contains: active substance 75.0 mg calcium phosphate
93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg
hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg
230.0 mg
Preparation
The active substance is mixed with calcium phosphate, corn starch,
polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the
specified amount of magnesium stearate. Blanks 13 mm in diameter
are produced in a tablet-making machine and these are then rubbed
through a screen with a mesh size of 1.5 mm using a suitable
machine and mixed with the rest of the magnesium stearate. This
granulate is compressed in a tablet-making machine to form tablets
of the desired shape. Weight of core: 230 mg; die: 9 mm, convex.
The tablet cores thus produced are coated with a film consisting
essentially of hydroxypropylmethylcellulose. The finished
film-coated tablets are polished with beeswax. Weight of coated
tablet: 245 mg.
EXAMPLE 3
TABLE-US-00003 Tablets containing 100 mg of active substance
Composition: 1 tablet contains: active substance 100.0 mg lactose
80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium
stearate 2.0 mg 220.0 mg
Preparation
The active substance, lactose and starch are mixed together and
uniformly moistened with an aqueous solution of the
polyvinylpyrrolidone. After the moist composition has been screened
(2.0 mm mesh size) and dried in a rack-type drier at 50.degree. C.,
it is screened again (1.5 mm mesh size) and the lubricant is added.
The finished mixture is compressed to form tablets. Weight of
tablet: 220 mg; diameter: 10 mm, biplanar, facetted on both sides
and notched on one side.
EXAMPLE 4
TABLE-US-00004 Tablets containing 150 mg of active substance
Composition: 1 tablet contains: active substance 150.0 mg powdered
lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg
polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg
Preparation
The active substance mixed with lactose, corn starch and silica is
moistened with a 20% aqueous polyvinylpyrrolidone solution and
passed through a screen with a mesh size of 1.5 mm. The granules,
dried at 45.degree. C., are passed through the same screen again
and mixed with the specified amount of magnesium stearate. Tablets
are pressed from the mixture. Weight of tablet: 300 mg; die: 10 mm,
flat.
EXAMPLE 5
TABLE-US-00005 Hard gelatine capsules containing 150 mg of active
substance 1 capsule contains: active substance 50.0 mg corn starch
(dried) approx. 80.0 mg lactose (powdered) approx. 87.0 mg
magnesium stearate 3.0 mg approx. 420.0 mg
Preparation
The active substance is mixed with the excipients, passed through a
screen with a mesh size of 0.75 mm and homogeneously mixed using a
suitable apparatus. The finished mixture is packed into size 1 hard
gelatine capsules. Capsule filling: approx. 320 mg; capsule shell:
size 1 hard gelatine capsule.
EXAMPLE 6
TABLE-US-00006 Suppositories containing 150 mg of active substance
1 suppository contains: active substance 150.0 mg
polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg
polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg
Preparation
After the suppository mass has been melted, the active substance is
homogeneously distributed therein and the melt is poured into
chilled molds.
EXAMPLE 7
TABLE-US-00007 Suspension containing 50 mg of active substance 100
ml of suspension contains: active substance 1.00 g
carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05
g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g
70% sorbitol solution 20.00 g flavoring 0.30 g dist. water ad 100
ml
Preparation
The distilled water is heated to 70.degree. C. The methyl and
propyl p-hydroxybenzoates together with the glycerol and sodium
salt of carboxymethylcellulose are dissolved therein with stirring.
The solution is cooled to ambient temperature and the active
substance is added and homogeneously dispersed therein with
stirring. After the sugar, the sorbitol solution, and the flavoring
have been added and dissolved, the suspension is evacuated with
stirring to eliminate air. 5 ml of suspension contains 50 mg of
active substance.
EXAMPLE 8
TABLE-US-00008 Ampoules containing 10 mg active substance
Composition: active substance 10.0 mg 0.01N hydrochloric acid q.s.
double-distilled water ad 2.0 ml
Preparation
The active substance is dissolved in the requisite amount of 0.01 N
HCl, made isotonic with common salt, filtered sterile and
transferred into 2 ml ampoules.
EXAMPLE 9
TABLE-US-00009 Ampoules containing 50 mg of active substance
Composition: active substance 50.0 mg 0.01N hydrochloric acid q.s.
double-distilled water ad 10.0 ml
Preparation
The active substance is dissolved in the necessary amount of 0.01 N
HCl, made isotonic with common salt, filtered sterile and
transferred into 10 ml ampoules.
EXAMPLE 10
TABLE-US-00010 Capsules for powder inhalation containing 5 mg of
active substance 1 capsule contains: active substance 5.0 mg
lactose for inhalation 15.0 mg 20.0 mg
Preparation
The active substance is mixed with lactose for inhalation. The
mixture is packed into capsules in a capsule-making machine (weight
of the empty capsule approx. 50 mg). Weight of capsule: 70.0 mg;
size of capsule: 3.
EXAMPLE 11
TABLE-US-00011 Solution for inhalation for hand-held nebulizers
containing 2.5 mg active substance 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
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
nebulizers (cartridges). Contents of the container: 4.5 g.
* * * * *
References