U.S. patent application number 12/914003 was filed with the patent office on 2011-02-24 for methods of treating diseases using quinazoline derivatives and pharmaceutical compositions containing them.
This patent application 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.
Application Number | 20110046168 12/914003 |
Document ID | / |
Family ID | 27214210 |
Filed Date | 2011-02-24 |
United States Patent
Application |
20110046168 |
Kind Code |
A1 |
HIMMELSBACH; Frank ; et
al. |
February 24, 2011 |
METHODS OF TREATING DISEASES USING 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;
(Warthausen, DE) ; BLECH; Stefan; (Warthausen,
DE) ; JUNG; Birgit; (Laupheim, DE) ; BAUM;
Anke; (Vienna, AT) ; SOLCA; Flavio; (Vienna,
AT) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY ROAD, P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
BOEHRINGER INGELHEIM PHARMA GMBH
& CO. KG
Ingelheim am Rhein
DE
|
Family ID: |
27214210 |
Appl. No.: |
12/914003 |
Filed: |
October 28, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12563340 |
Sep 21, 2009 |
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12914003 |
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11313304 |
Dec 21, 2005 |
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12563340 |
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10023099 |
Dec 17, 2001 |
7019012 |
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11313304 |
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60259201 |
Dec 28, 2000 |
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Current U.S.
Class: |
514/266.24 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
35/00 20180101; C07D 239/94 20130101; A61P 11/00 20180101; C07D
405/12 20130101; A61P 17/06 20180101 |
Class at
Publication: |
514/266.24 |
International
Class: |
A61K 31/517 20060101
A61K031/517; A61P 35/00 20060101 A61P035/00; A61P 1/00 20060101
A61P001/00; A61P 11/00 20060101 A61P011/00; A61P 17/06 20060101
A61P017/06 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 2000 |
DE |
10063435 |
Claims
1. A method of treating benign or malignant tumors, diseases of the
airways and lungs, and diseases of the gastrointestinal tract, bile
duct, and gall bladder in a patient in need thereof, the method
comprising administering to the patient an effective amount of a
compound of formula I ##STR00006## wherein R.sub.a is a
3-chloro-4-fluorophenyl group; R.sub.b is a dimethylamino 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
stereoisomer or physiologically acceptable salt thereof.
2. The method according to claim 1, wherein: R.sub.c is a
tetrahydrofuran-3-yloxy, or a steroisomer or physiologically
acceptable salt thereof.
3. The method according to claim 1, wherein the compound is:
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-(tetrahydrofuran-3-yl)oxy)quinazoline or
physiologically acceptable salt thereof.
4. The method according to claim 1, wherein the compound is a
physiologically acceptable salt comprising the combination of the
compound
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
with an organic or inorganic acid.
5. The method according to claim 4, 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.
6. The method according to claim 5, wherein the acid is maleic
acid.
7. The method according to claim 1, wherein the compound is:
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((R)-(tetrahydrofuran-3-yl)oxy)quinazoline or
physiologically acceptable salt thereof.
8. The method according to claim 1, wherein the benign or malignant
tumors diseases is chosen from diseases involving tumours of
epithelial and neuroepithelial origin, metastasisation and the
abnormal proliferation of vascular endothelial cells
(neoangiogenesis).
9. The method according to claim 5, wherein the benign or malignant
tumors diseases is chosen from diseases involving tumours of
epithelial and neuroepithelial origin, metastasisation and the
abnormal proliferation of vascular endothelial cells
(neoangiogenesis).
10. The method according to claim 9, wherein the benign or
malignant tumors diseases is chosen from diseases involving tumours
of epithelial and neuroepithelial origin.
11. The method according to claim 1, wherein the diseases of the
airways and lungs is chosen from chronic bronchitis, chronic
obstructive bronchitis, asthma, bronchiectasis, allergic or
non-allergic rhinitis or sinusitis, cystic fibrosis,
.alpha.1-antitrypsin deficiency, pulmonary emphysema, pulmonary
fibrosis and hyperreactive airways.
12. The method according to claim 1, wherein the diseases of the
gastrointestinal tract, bile duct, and gall bladder is chosen from
cholecystitis, Crohn's disease, ulcerative colitis, ulcers in the
gastrointestinal tract, Menetrier's disease, secreting adenomas and
protein loss syndrome.
13. The method according to claim 1, wherein the disease is
psoriasis.
Description
SUMMARY OF THE INVENTION
[0001] 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.
[0002] In the above general formula I
[0003] R.sub.a denotes a benzyl, 1-phenylethyl or
3-chloro-4-fluorophenyl group,
[0004] 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
[0005] 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 [0006] (1)
3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-cyclopropylmethoxyquinazoline, [0007] (2)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline, [0008] (3)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1--
yl]amino}-7-cyclopropylmethoxyquinazoline, [0009] (4)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclobutyloxyquinazoline, [0010] (5)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopentyloxyquinazoline, [0011] (6)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-cyclobutyloxyquinazoline, [0012] (7)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-cyclopentyloxyquinazoline, [0013] (8)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclobutyloxyquinazoline, [0014] (9)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopropylmethoxyquinazoline, [0015] (10)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopentyloxyquinazoline, [0016] (11)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclobutyloxyquinazoline, [0017] (12)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopentyloxyquinazoline, [0018] (13)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopropylmethoxyquinazoline, [0019] (14)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-
-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, [0020] (15)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino-
]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, [0021]
(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,
[0022] (17)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline, [0023]
(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, [0024] (19)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline, [0025] (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 [0026] (21)
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.
[0027] 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 [0028] (1)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxyquinazoline, [0029] (2)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline, [0030] (3)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1--
yl]amino}-7-cyclopropylmethoxyquinazoline, [0031] (4)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclobutyloxyquinazoline, [0032] (5)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopentyloxyquinazoline, [0033] (6)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-cyclobutyloxyquinazoline, [0034] (7)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-cyclopentyloxyquinazoline, [0035] (8)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclobutyloxyquinazoline, [0036] (9)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopropylmethoxyquinazoline, [0037] (10)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopentyloxyquinazoline, [0038] (11)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclobutyloxyquinazoline, [0039] (12)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopentyloxyquinazoline, [0040] (13)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopropylmethoxyquinazoline, [0041] (14)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-
-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, [0042] (15)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino-
]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, [0043]
(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,
[0044] (17)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline, [0045]
(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, [0046] (19)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline, [0047] (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,
[0048] (21)
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,
[0049] (22)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methy-
lamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
[0050] (23)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]--
1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline, [0051] (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, [0052]
(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,
[0053] (26)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydro-
furan-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
[0054] (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,
[0055] (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,
[0056] (29)
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,
[0057] (30)
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,
[0058] (31)
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,
[0059] (32)
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
and [0060] (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.
[0061] Particularly preferred compounds of general formula I are
those wherein
[0062] R.sub.a denotes a 1-phenylethyl or 3-chloro-4-fluorophenyl
group,
[0063] 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
[0064] 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 [0065] (1)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxyquinazoline, [0066] (2)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxyquinazoline, [0067] (3)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1--
yl]amino}-7-cyclopropylmethoxyquinazoline, [0068] (4)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclobutyloxyquinazoline, [0069] (5)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopentyloxyquinazoline, [0070] (6)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-cyclobutyloxyquinazoline, [0071] (7)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-cyclopentyloxyquinazoline, [0072] (8)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclobutyloxyquinazoline, [0073] (9)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopropylmethoxyquinazoline, [0074] (10)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]am-
ino}-7-cyclopentyloxyquinazoline, [0075] (11)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclobutyloxyquinazoline, [0076] (12)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopentyloxyquinazoline, [0077] (13)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amin-
o}-7-cyclopropylmethoxyquinazoline, [0078] (14)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-
-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, [0079] (15)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino-
]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, [0080]
(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,
[0081] (17)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline, [0082]
(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, [0083] (19)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-y-
l]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline, [0084] (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,
[0085] (21)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methy-
lamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
[0086] (22)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]--
1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline, [0087] (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, [0088]
(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,
[0089] (25)
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydro-
furan-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
[0090] (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,
[0091] (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,
[0092] (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,
[0093] (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,
[0094] (30)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline, [0095]
(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,
[0096] (32)
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
and [0097] (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.
[0098] The following particularly preferred compounds of general
formula I may be mentioned by way of example: [0099] (a)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclobutyloxyquinazoline; [0100] (b)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentyloxyquinazoline, [0101] (c)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-bis(2-methoxyethyl)amino)-1-oxo-2-
-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline, [0102] (d)
4-[(R)-(1-phenylethyl)amino]-6-({-4-[N-(2-methoxyethyl)-N-ethylamino]-1-o-
xo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, [0103] (e)
4-[(R)-(1-phenylethyl)amino]-6-({-4-[N-(2-methoxyethyl)-N-methylamino]-1--
oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline, [0104] (f)
4-[(R)-(1-phenylethyl)amino]-6-({-4-[N-(tetrahydropyran-4-yl)-N-methylami-
no]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
[0105] (g)
4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydrofuran-3-yl)-N-methylamin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
[0106] (h)
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-(4-{N-[(tetrahydrofuran-3-yl)met-
hyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazol-
ine, [0107] (i)
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, [0108]
(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, [0109]
(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, [0110] (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, [0111]
(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, [0112]
(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, [0113]
(p)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl-
]amino}-7-cyclopropylmethoxyquinazoline, [0114] (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,
[0115] (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, [0116] (s)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline; and [0117] (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.
[0118] The compounds of general formula I may be prepared by the
following methods, for example:
[0119] 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.
[0120] 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.
[0121] 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.
[0122] 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##
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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.
[0133] 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.
[0134] 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.
[0135] 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 allcoxide and
subsequently reducing the nitro compound thus obtained or
[0136] 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
[0137] a starting compound of general formula IV is obtained by
acylating a compound of general formula II with a suitable crotonic
acid derivative.
[0138] 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.
[0139] The biological properties of the new compounds were
investigated as follows:
[0140] The inhibition of human EGF-receptor kinase was determined
using the cytoplasmic tyrosine kinase domain (methionine 664 to
alanine 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.
[0141] 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.
[0142] 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.450nm with an ELISA reader. All data points were
measured three times.
[0143] 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.
[0144] The following results were obtained:
TABLE-US-00001 Compound Inhibition of EGF-Receptor (Example No.)
Kinase IC.sub.50 [nM] 1 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
[0145] 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).
[0146] 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.
[0147] 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.
[0148] 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.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] The following Examples are intended to illustrate the
present invention without restricting it.
Preparation of the Starting Compounds
Example I
3-methylaminotetrahydrofuran
[0153] 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
[0154] 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
[0155] 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).
[0156] The following compounds are obtained analogously to Example
III:
(1)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((S)-tetrahydrofuran-3-y-
loxy)quinazoline Mass spectrum (ESL): 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
[0157] 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.-.
[0158] The following compounds are obtained analogously to Example
IV:
(1)
4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-y-
loxy)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
[0159] 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.+.
[0160] 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
[0161] 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.+.
[0162] 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
[0163] 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
0-(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).
[0164] 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)methox-
y]quinazoline
[0165] 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.
[0166] The following compounds are obtained analogously to Example
VIII:
(1)
6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(R)-(tetrahydrofuran-2--
yl)methoxy]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-methylamino-
]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
[0167] 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 [M-H].sup.-;
R.sub.f value: 0.25 (silica gel, ethyl acetate/methanol=9:1).
[0168] The following compounds are obtained analogously to Example
1:
(1)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2--
buten-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 (ESL):
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-o-
xo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline Mass
spectrum (ESL): 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--
oxo-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-methylami-
no]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline Mass
spectrum (ESI.sup.-): m/z=514 [M-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-(4-{N-[(tetrahydrofuran-3-yl)meth-
yl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoli-
ne 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-methylami-
no]-1-oxo-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-cyclopropylmethoxyquinazo-
line 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. [0169] (23)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
[0170] 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)m-
ethyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinaz-
oline 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)me-
thyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopentyloxyquinazoline
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-oxo-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-buten-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).
[0171] The following compounds may also be prepared analogously to
the foregoing Examples and other methods known from the literature:
[0172] (1)
4-benzylamino-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cy-
clopropylmethoxyquinazoline [0173] (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
[0174] (3)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(tetrahydropyran-4-yl)methoxy]quinazoline [0175]
(4)
4-[(R)-(1-phenylethyl)amino]-6-[(4-(4-{N-[(tetrahydrofuran-2-yl)methyl]-N-
-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
[0176] (5)
4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl-
]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline [0177] (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
[0178] (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
Coated Tablets Containing 75 Mg Of Active Substance
1 Tablet Core Contains:
TABLE-US-00002 [0179] 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:
[0180] 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
Tablets Containing 100 Mg of Active Substance
Composition:
1 Tablet Contains:
TABLE-US-00003 [0181] 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:
[0182] 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
Tablets Containing 150 Mg of Active Substance
Composition:
1 Tablet Contains:
TABLE-US-00004 [0183] 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:
[0184] 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
Hard Gelatine Capsules Containing 150 Mg of Active Substance
1 Capsule Contains:
TABLE-US-00005 [0185] 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:
[0186] 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
Suppositories Containing 150 Mg of Active Substance
1 Suppository Contains:
TABLE-US-00006 [0187] 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:
[0188] After the suppository mass has been melted, the active
substance is homogeneously distributed therein and the melt is
poured into chilled molds.
Example 7
Suspension Containing 50 Mg of Active Substance
100 ml of Suspension Contains:
TABLE-US-00007 [0189] 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:
[0190] 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
Ampoules Containing 10 Mg Active Substance
Composition:
TABLE-US-00008 [0191] active substance 10.0 mg 0.01 N hydrochloric
acid q.s. double-distilled water ad 2.0 ml
Preparation:
[0192] 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
Ampoules Containing 50 Mg of Active Substance
Composition:
TABLE-US-00009 [0193] active substance 50.0 mg 0.01 N hydrochloric
acid q.s. double-distilled water ad 10.0 ml
Preparation:
[0194] 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
Capsules for Powder Inhalation Containing 5 Mg of Active
Substance
1 Capsule Contains:
TABLE-US-00010 [0195] active substance 5.0 mg lactose for
inhalation 15.0 mg 20.0 mg
Preparation:
[0196] 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 Nebulizers Containing 2.5 Mg
Active Substance
1 Spray Contains:
TABLE-US-00011 [0197] active substance 2.500 mg benzalkonium
chloride 0.001 mg 1N hydrochloric acid q.s. ethanol/water (50/50)
ad 15.000 mg
Preparation:
[0198] 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.
* * * * *