U.S. patent application number 13/019530 was filed with the patent office on 2011-05-26 for novel anthranilamide pyridinureas as vascular endothelial growth factor (vegf) receptor kinase inhibitors.
Invention is credited to Rolf BOHLMANN, Martin Haberey, Holger Hess-Stumpp, Andreas Huth, Stuart James Ince, Martin Krueger, Andreas Reichel, Karl-Heinz Thierauch.
Application Number | 20110124680 13/019530 |
Document ID | / |
Family ID | 34928840 |
Filed Date | 2011-05-26 |
United States Patent
Application |
20110124680 |
Kind Code |
A1 |
BOHLMANN; Rolf ; et
al. |
May 26, 2011 |
NOVEL ANTHRANILAMIDE PYRIDINUREAS AS VASCULAR ENDOTHELIAL GROWTH
FACTOR (VEGF) RECEPTOR KINASE INHIBITORS
Abstract
The invention relates to novel anthranilamide pyridinureas as
VEGF receptor kinase inhibitors, their production and use as
pharmaceutical agents for preventing or treating diseases that are
triggered by persistent angiogenesis.
Inventors: |
BOHLMANN; Rolf; (Berlin,
DE) ; Haberey; Martin; (Berlin, DE) ; Huth;
Andreas; (Berlin, DE) ; Ince; Stuart James;
(Berlin, DE) ; Krueger; Martin; (Berlin, DE)
; Thierauch; Karl-Heinz; (Berlin, DE) ;
Hess-Stumpp; Holger; (Berlin, DE) ; Reichel;
Andreas; (Berlin, DE) |
Family ID: |
34928840 |
Appl. No.: |
13/019530 |
Filed: |
February 2, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11265517 |
Nov 3, 2005 |
7902229 |
|
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13019530 |
|
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60626918 |
Nov 12, 2004 |
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Current U.S.
Class: |
514/310 ;
514/312; 514/313; 514/338; 514/352 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
29/00 20180101; A61P 35/00 20180101; A61P 13/12 20180101; A61P
19/00 20180101; A61P 17/00 20180101; A61P 15/08 20180101; C07D
401/12 20130101; A61P 17/06 20180101; A61P 1/16 20180101; A61P
11/06 20180101; A61P 27/02 20180101; A61P 9/00 20180101; A61P 35/02
20180101; A61P 31/00 20180101; A61P 35/04 20180101; A61P 43/00
20180101; A61P 19/02 20180101 |
Class at
Publication: |
514/310 ;
514/338; 514/312; 514/313; 514/352 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 31/4725 20060101 A61K031/4725; A61K 31/4709
20060101 A61K031/4709; A61K 31/44 20060101 A61K031/44; A61P 35/00
20060101 A61P035/00; A61P 17/06 20060101 A61P017/06; A61P 27/02
20060101 A61P027/02; A61P 9/10 20060101 A61P009/10; A61P 11/06
20060101 A61P011/06; A61P 13/12 20060101 A61P013/12; A61P 1/16
20060101 A61P001/16; A61P 29/00 20060101 A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 3, 2004 |
EP |
04090419 |
Claims
1-46. (canceled)
47. A method for treating or preventing a disease associated with
persistent angiogenesis or a disease associated with excessive
lymphangiogenesis; for treating or preventing a tumor- or
metastases-growth; psoriasis; Karposi's sarcoma; restenosis;
stent-induced restenosis; Crohn's disease; Hodgkin's disease;
leukemia; arthritis; rheumatoid arthritis, hemangioma,
angiofibroma; endometriosis; an eye disease; diabetic retinopathy,
neovascular glaucoma; corneal transplants; a renal disease;
glomerulonephritis, diabetic nephropathy, malignant
nephrosclerosis, thrombotic microangiopathic syndrome, a transplant
rejections; glomerulopathy; a fibrotic disease; cirrhosis of the
liver; a mesangial cell proliferative disease; arteriosclerosis;
injuries to the nerve tissue, or for inhibiting the reocclusion of
vessels after balloon catheter treatment; in vascular prosthetics
or after a mechanical device is used to keep a vessel open, or for
supporting scar-free healing; senile keratosis; contact dermatitis;
or asthma; for inhibiting VEGF receptor kinase 3 of
lymphangiogenesis; for the prevention or treatment of a disease for
which an inhibition of angiogenesis and/or lymphangiogenesis and/or
the VEGF receptor kinases is beneficial; comprising administering
to a subject in need thereof an effective amount of a compound of
formula I ##STR00061## wherein: X is CH or N; W is hydrogen or
fluorine; A, E and Q, independently of one another, are CH or N,
wherein only a maximum of two nitrogen atoms are contained in the
ring; R.sup.1 is aryl or heteroaryl, which are optionally
substituted in one or more places in the same way or differently
with halogen, hydroxy, C.sub.1-C.sub.12-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.1-C.sub.12-alkoxy,
halo-C.sub.1-C.sub.6-alkyl, .dbd.O, --SO.sub.2R.sup.6, --OR.sup.5,
--SOR.sup.4, --COR.sup.6, --CO.sub.2R.sup.6 or --NR.sup.7R.sup.8,
wherein C.sub.1-C.sub.12-alkyl is optionally substituted with
--OR.sup.5 or --NR.sup.7R.sup.8, with the proviso that when R.sup.2
and R.sup.3 are both --CH.sub.3, R.sup.1 is not any one of the
following: ##STR00062## R.sup.2 and R.sup.3, independently of one
another, are C.sub.1-C.sub.12 alkyl optionally substituted with
--OR.sup.5; R.sup.4 is C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl, aryl or heteroaryl; R.sup.5 is
hydrogen, C.sub.1-C.sub.12-alkyl, C.sub.3-C.sub.8-cycloalkyl or
halo-C.sub.1-C.sub.6-alkyl; R.sup.6 is hydrogen,
C.sub.1-C.sub.12-alkyl, C.sub.3-C.sub.8-cycloalkyl,
halo-C.sub.1-C.sub.6-alkyl, aryl, or --NR.sup.7R.sup.8; and R.sup.7
and R.sup.8, independently of one another, are hydrogen,
--SO.sub.2R.sup.6, --COR.sup.6, aryl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.12-alkyl, halo-C.sub.1-C.sub.12-alkyl, or
C.sub.1-C.sub.12-alkoxy, wherein C.sub.1-C.sub.12-alkyl is
optionally substituted with --OR.sup.5 or --N(.sub.CH.sub.3).sub.2,
or R.sup.7 and R.sup.8 provide a 3-8 membered cycloalkyl ring,
which optionally contains one or more further heteroatoms, and is
optionally substituted in one or more places in the same way or
differently with halogen, cyano, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1 1-C.sub.6-alkyl, .dbd.O,
--OR.sup.5, COR.sup.6, --SR.sup.4, --SOR.sup.4 or
--SO.sub.2R.sup.6; or an isomer, diastereoisomer, enantiomer,
tautomer or salt thereof.
48. A method according to claim 47, which is for treating or
preventing a disease associated with persistent angiogenesis or a
disease associated with excessive lymphangiogenesis.
49. A method according to claim 47, which is for treating or
preventing a tumor- or metastases-growth; psoriasis; Karposi's
sarcoma; restenosis; stent-induced restenosis; Crohn's disease;
Hodgkin's disease; leukemia; arthritis; rheumatoid arthritis,
hemangioma, angiofibroma; endometriosis; an eye disease; diabetic
retinopathy, neovascular glaucoma; corneal transplants; a renal
disease; glomerulonephritis, diabetic nephropathy, malignant
nephrosclerosis, thrombotic microangiopathic syndrome, a transplant
rejections; glomerulopathy; a fibrotic disease; cirrhosis of the
liver; a mesangial cell proliferative disease; arteriosclerosis;
injuries to the nerve tissue, or for inhibiting the reocclusion of
vessels after balloon catheter treatment; in vascular prosthetics
or after a mechanical device is used to keep a vessel open, or for
supporting scar-free healing; senile keratosis; contact dermatitis;
or asthma.
50. A method according to claim 47, which is for inhibiting VEGF
receptor kinase 3 of lymphangiogenesis.
51. A method according to claim 47, which is for the prevention or
treatment of a disease for which an inhibition of angiogenesis
and/or lymphangiogenesis and/or the VEGF receptor kinases is
beneficial.
52. A method according to claim 51, which is for inhibiting the
tyrosine kinase VEGFR-1 or VEGFR-2.
53. A method according to claim 47, wherein the compound of formula
I is
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-ind-
azol-6-yl)-benzamide
2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-inda-
zol-6-yl)-benzamide
2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N--
(2-methyl-2H-indazol-6-yl)-benzamide
2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N--
(2-methyl-2H-indazol-6-yl)-benzamide
2-{[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-
-indazol-6-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(4-fluoro-2-meth-
yl-2H-indazol-6-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(7-methoxy-isoqu-
inolin-3-yl)-benzamide
6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-
-methyl-2H-indazole-3-carboxylic acid methyl ester
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-ben-
zotriazol-5-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-2-oxo--
1,2-dihydro-quinolin-6-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-ind-
azol-7-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-3a,7a--
dihydro-1H-indazol-4-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-2-meth-
yl-2H-indazol-4-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-meth-
yl-2H-indazol-7-yl)-benzamide
6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-
-methyl-1H-indazole-3-carboxylic acid methyl ester
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-hydroxymethyl-
-l-methyl-1H-indazol-6-yl)-benzamide
N-(3,6-difluoro-quinolin-2-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylme-
thyl]-amino}-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-sulfamoyl-phe-
nyl)-benzamide
N-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-yl-
methyl]-amino}-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-
-2-methyl-2H-indazol-6-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-
-1-methyl-1H-indazol-6-yl)-benzamide
6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-
-methyl-1H-indazole-3-carboxylic acid methylamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-l-meth-
yl-1H-indazol-5-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-meth-
yl-2H-indazol-5-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-l-meth-
yl-1H-indazol-4-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-quinolin-3-yl-be-
nzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-fluoro-
-6-methoxy-quinolin-2-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methyl-3H-ben-
zoimidazol-5-yl)-benzamide
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-1H-ben-
zoimidazol-5-yl)-benzamide
2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methanesulfon-
yl-phenyl)-benzamide or
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-meth-
yl-2H-indazol-6-yl)-benzamide or an isomer, diastereoisomer,
enantiomer, tautomer or salt thereof.
54. A method according to claim 47, wherein the compound of formula
I is ##STR00063## wherein: X is CH; W is hydrogen or fluorine; A, E
and Q, are CH; R.sup.1 is 2-methyl-2H-indazol-6-yl; R.sup.2 and
R.sup.3, independently of one another, are C.sub.1-C.sub.12 alkyl
optionally substituted with --OR.sup.5; and or an isomer,
diastereoisomer, enantiomer, tautomer or salt thereof.
55. A method according to claim 47, wherein the compound of formula
I is
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-ind-
azol-6-yl)-benzamide
2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-inda-
zol-6-yl)-benzamide
2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N--
(2-methyl-2H-indazol-6-yl)-benzamide
2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N--
(2-methyl-2H-indazol-6-yl)-benzamide
2-{[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-
-indazol-6-yl)-benzamide or
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-meth-
yl-2H-indazol-6-yl)-benzamide or an isomer, diastereoisomer,
enantiomer, tautomer or salt thereof.
56. A method according to claim 47, wherein a compound of formula I
or a pharmaceutically acceptable salt thereof is administered.
57. A method according to claim 53, wherein a compound of formula I
or a pharmaceutically acceptable salt thereof is administered.
58. A method according to claim 47, wherein in the compound of
formula I X is CH; W is hydrogen or fluorine; A, E and Q, are CH;
R.sup.1 is 2-methyl-2H-indazol-6-yl; R.sup.2 and R.sup.3,
independently of one another, are C.sub.1-C.sub.12 alkyl optionally
substituted with --OR.sup.5.
59. A method according to claim 47, wherein in the compound of
formula I W is fluorine.
60. A method according to claim 47, wherein in the compound of
formula I W is hydrogen.
61. A method according to claim 47, wherein in the compound of
formula I R.sup.2 and R.sup.3 independently of one another, are
C.sub.1-C.sub.12 alkyl optionally substituted with --OR.sup.5.
62. A method according to claim 47, wherein in the compound of
formula I R.sup.2 and R.sup.3 are both --CH.sub.3.
63. A method according to claim 47, wherein in the compound of
formula I R.sup.5 is --CH.sub.3 or hydrogen.
64. A method according to claim 47, wherein in the compound of
formula I R.sup.2 and R.sup.3 independently of one another are
unsubstituted C.sub.1-C.sub.2 alkyl.
Description
[0001] This application claims the benefit of the filing date of
U.S. Provisional Application Ser. No. 60/626,914 filed Nov. 12,
2004 which is incorporated by reference herein.
[0002] The invention relates to novel anthranilamide pyridinureas
as VEGF receptor kinase inhibitors, their production and use as
pharmaceutical agents for preventing or treating diseases that are
triggered by persistent angiogenesis.
[0003] Many diseases are known to be associated with persistent
angiogenesis, for example, diseases such as tumor- or
metastases-growth; psoriasis; arthritis, such as rheumatoid
arthritis, hemangioma, endometriosis, angiofibroma; eye diseases,
such as diabetic retinopathy, neovascular glaucoma; renal diseases,
such as glomerulonephritis, diabetic nephropathy, malignant
nephrosclerosis, thrombotic microangiopathic syndrome, transplant
rejections and glomerulopathy; fibrotic diseases, such as cirrhosis
of the Liver, mesangial cell proliferative diseases and
arteriosclerosis.
[0004] Lymphangiogenesis is a process accompanying tumor growth and
metastases. It is prominent in lymphedema, lymphangiectasia,
lymphangioma, and lymphangiosarcoma and in asthmatic disease, where
lymph vessels are chronically overexpressed in the lung.
[0005] Persistent angiogenesis is induced by the factor VEGF via
its receptors. In order for VEGF to exert this action, it is
necessary that VEGF bind to the receptor, and that a tyrosine
phosphorylation is induced.
[0006] Direct or indirect inhibition of the VEGF receptor can be
used for preventing or treating such diseases and other
VEGF-induced pathological angiogenesis and vascular permeable
conditions, such as tumor vascularization. For example, it is known
that the growth of tumors can be inhibited by soluble receptors and
antibodies against VEGF, an example for the latter being
Avastin.RTM. whose treatment paradigm has been introduced in human
cancer therapy.
[0007] Anthranilic acid amides effective in the treatment of
psoriasis; arthritis, such as rheumatoid arthritis, hemangioma,
angiofibroma; eye diseases, such as diabetic retinopathy,
neovascular glaucoma; renal diseases, such as glomerulonephritis,
diabetic nephropathy, malignant nephrosclerosis, thrombic
microangiopathic syndrome, transplant rejections and
glomerulopathy; fibrotic diseases, such as cirrhosis of the liver,
mesangial cell proliferative diseases, arteriosclerosis, injuries
to nerve tissue, and for inhibiting the reocclusion of vessels
after balloon catheter treatment, in vascular prosthetics or after
mechanical devices are used to keep vessels open, such as, e.g.,
stents, have is been reported in WO 00/27820.
[0008] Anthranilic acid amides that are effective in the treatment
of tumor or metastasis growth, psoriasis, Kaposi's sarcoma,
restenosis, such as, e.g., stent-induced restenosis, endometriosis,
Crohn's disease, Hodgkin's disease, leukemia; arthritis, such as
rheumatoid arthritis, hemangioma, angiofibroma;
[0009] eye diseases, such as diabetic retinopathy, neovascular
glaucoma; renal diseases, such as glomerulonephritis, diabetic
nephropathy, malignant nephrosclerosis, thrombic microangiopathic
syndrome, transplant rejections and glomerulopathy; fibrotic
diseases, such as cirrhosis of the liver, mesangial cell
proliferative diseases, arteriosclerosis, injuries to nerve tissue,
and for inhibiting the reocclusion of vessels after balloon
catheter treatment, in vascular prosthetics or after mechanical
devices are used to keep vessels open, such as, e.g., stents, as
immunosuppressive agents, as a support in scar-free healing, in
senile keratosis and in contact dermatitis have also been reported
in WO 04/13102.
[0010] There is, however, a desire to produce compounds that are as
efficaceous as possible in as broad a range of indications as
possible. A constant blockade of VEGF mediated signal transduction
is desirable in order to reduce persistant angiogenesis and
lymphangiogenesis. Suitable compounds for longer term treatment
should exhibit little or no drug-drug interaction potential. The
Cytochrome P450 isoenzymes play a pivotal role in the degradation
of pharmaceutical agents. The problem is also complicated by the
fact that patients may express different relative amounts of the
isoenzymes. An inhibition of these isoenzymes may result in
undesirable pharmaceutical agent interactions, especially in the
case of multimorbid patients (patients with multiple disease
conditions). For example, inhibition of the Cytochrome P450
isoenzymes responsible for metabolisation of the parent agent could
lead to toxic systemic concentrations. A further problem exists in
combination therapy with other medications, whereby inhibition of
the Cytochrome P450 isoenzymes responsible for metabolising the
co-medications could lead to toxic systemic concentrations of the
co-medication. This is especially the case for co-administered
cytostatics in the case of cancer therapy.
[0011] Thus, it has now surprisingly been found that compounds of
general formula (I), as described below, have more advantageous
physico-chemical and/or pharmacokinetic properties and prevent, for
example, tyrosine phosphorylation or stop persistent angiogenesis
and thus the growth and propagation of tumors, whereby they are
distinguished in particular by a potent inhibition of VEGF receptor
kinases and a reduced potential for drug-drug interactions,
specifically a reduced inhibition of cytochrome P450 isoenzymes 2C9
and 2C19.
[0012] The compounds of formula (I) are thus suitable, for example,
for the treatment or prevention of diseases for which an inhibition
of angiogenesis and/or the VEGF receptor kinases is beneficial.
[0013] In one aspect of the invention, there is provided an
anthranilamide pyridinurea compound of formula (I):
##STR00001##
wherein:
[0014] X is CH or N, preferably CH;
[0015] is hydrogen or fluorine; preferably hydrogen;
[0016] A, E and Q independently of one another, are CH or N,
whereby only a to maximum of two nitrogen atoms are contained in
the ring; preferably A, E, and Q are each CH;
[0017] R.sup.1 is aryl or heteroaryl, which may be optionally
substituted in one or more places in the same way or differently
with halogen, hydroxy, C.sub.1-C.sub.12-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.1-C.sub.12-atkoxy,
halo-C.sub.1-C.sub.6-alkyl, .dbd.O, --SO.sub.2R.sup.6, --OR.sup.5,
--SOR.sup.4, --COR.sup.6, --CO.sub.2R.sup.6 or --NR.sup.7R.sup.8,
whereby C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5
or --NR.sup.7R.sup.8, with the proviso that when R.sup.2 and
R.sup.3 are both --CH.sub.3, R.sup.1 is not any one of the
following:
##STR00002## [0018] preferably heteroaryl optionally substituted in
one or more places in the same way or differently with halogen,
hydroxy, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl, .dbd.O,
--SO.sub.2R.sup.6, --OR.sup.5, --SOR.sup.4, --COR.sup.6,
--CO.sub.2R.sup.6 or --NR.sup.7R.sup.8, whereby
C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5 or
--NR.sup.7R.sup.8, with the proviso that when R.sup.2 and R.sup.3
are both --CH.sub.3, R.sup.1 is not any one of the following:
[0018] ##STR00003## [0019] more preferably heteroaryl substituted
in one or more places in the same way or differently with halogen,
hydroxy, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl, .gradient.O,
--SO.sub.2R.sup.6, --OR.sup.5, --SOR.sup.4, --COR.sup.6,
--CO.sub.2R.sup.6 or --NR.sup.7R.sup.8, whereby
C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5 or
--NR.sup.7R.sup.8, with the proviso that when R.sup.2 and R.sup.3
are both --CH.sub.3, R.sup.1 is not any one of the following:
[0019] ##STR00004## [0020] even more preferably R.sup.1 is
[0020] ##STR00005## [0021] wherein R.sup.9 is hydrogen, halogen,
C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-alkoxy,
halo-C.sub.1-C.sub.6-alkyl, --COR.sup.6, --CO.sub.2R.sup.6 or
--NR.sup.7R.sup.8, whereby C.sub.1-C.sub.12-alkyl may be
substituted with --OR.sup.5 or --NR.sup.7R.sup.8 and R.sup.10 is
hydrogen or halogen; preferably R.sup.9 is hydrogen and R.sup.10 is
hydrogen or halogen, preferably fluorine; more particularly
preferably R.sup.9 and R.sup.10 are both hydrogen; [0022] more
particularly preferably R.sup.1 is
[0022] ##STR00006## [0023] wherein R.sup.9 is hydrogen, halogen,
C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-alkoxy,
halo-C.sub.1-C.sub.6-alkyl, --COR.sup.6, --CO.sub.2R.sup.6 or
--NR.sup.7R.sup.8, whereby C.sub.1-C.sub.12-alkyl may be
substituted with --OR.sup.5 or --NR.sup.7R.sup.8, more particularly
preferably R.sup.9 is hydrogen;
[0024] R.sup.2 and R.sup.3, independently of one another, are
C.sub.1-C.sub.12 alkyl optionally substituted with --OR.sup.5;
preferably C.sub.1-C.sub.2 alkyl optionally substituted with
--OR.sup.5; more preferably unsubstituted C.sub.1-C.sub.2 alkyl;
more particularly preferably are both --CH.sub.3;
[0025] R.sup.4 is C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl, aryl or heteroaryl; preferably
C.sub.1-C.sub.12-alkyl; more particularly preferably
--CH.sub.3;
[0026] R.sup.5 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl or halo-C.sub.1-C.sub.6-alkyl;
preferably --CH.sub.3 or hydrogen; more particularly preferably
hydrogen;
[0027] R.sup.6 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl, halo-C.sub.1-C.sub.6-alkyl, aryl, or
--NR.sup.7R.sup.8; preferably C.sub.1-C.sub.12-alkyl or
--NR.sup.7R.sup.8; more particularly preferably --CH.sub.3;
[0028] R.sup.7 and R.sup.8, independently of one another, are
hydrogen, --SO.sub.2R.sup.6, --COR.sup.6, aryl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.12-alkyl,
halo-C.sub.1-C.sub.12-alkyl, or C.sub.1-C.sub.12-alkoxY, whereby
C.sub.1-C.sub.12-alkyl may be optionally substituted with
--OR.sup.5 or --N(CH.sub.3).sub.2, or R.sup.7 and R.sup.8 may also
be chosen in such a way as to provide a 3-8 membered cycloalkyl
ring, preferably a 4-7 membered cycloalkyl ring, more preferably a
5 or 6 membered cycloalkyl ring, which may optionally contain
further heteroatoms, such as nitrogen, oxygen or sulphur, and may
be optionally substituted in one or more positions in the same way
or differently with halogen, cyano, C.sub.1-C.sub.12-alkyl, C.sub.1
-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl, .dbd.O, --OR.sup.5 ,
COR.sup.6, --SR.sup.4, --SOR.sup.4 or --SO.sub.2R.sup.6; preferably
R.sup.7 and R.sup.8 independently of one another, are hydrogen,
COR.sup.6, --SO.sub.2R.sup.6, alkyl; more preferably hydrogen or
C.sub.1-C.sub.12-alkyl; more particularly preferably hydrogen or
--CH.sub.3,
and as well as isomers, diastereoisomers, enantiomers, tautomers
and salts thereof.
[0029] In a second aspect of the present invention, there is
provided a pharmaceutical agent comprising at least one compound of
formula (I) or an isomer, diastereoisomer, enantiomer, tautomer or
salt thereof.
[0030] In a third aspect of the present invention, there is
provided a pharmaceutical agent comprising at least one compound of
formula (I) or an isomer, diastereoisomer, enantiomer, tautomer or
salt thereof and at least one pharmaceutically acceptable carrier,
diluent or excipient.
[0031] In a fourth aspect of the present invention, there is
provided a pharmaceutical agent comprising at least one compound of
formula (I) or an isomer, diastereoisomer, enantiomer, tautomer or
salt thereof for use in the prevention or treatment of diseases
associated with persistant angiogenesis and/or diseases associated
with excessive lymphangiogenesis.
[0032] In a fifth aspect of the present invention, there is
provided a pharmaceutical agent comprising at least one compound of
formula (I) or an isomer, diastereoisomer, enantiomer, tautomer or
salt thereof for use in the prevention or treatment of tumor- or
metastases-growth; psoriasis; Karposi's sarcoma; restenosis
including stent-induced restenosis; Crohn's disease; Hodgkin's
disease; leukemia; arthritis including rheumatoid arthritis,
hemangioma, angiofibroma; endometriosis; eye diseases including
diabetic retinopathy, neovascular glaucoma; corneal transplants;
renal diseases, including glomerulonephritis, diabetic nephropathy,
malignant nephrosclerosis, thrombotic microangiopathic syndrome,
transplant rejections and glomerulopathy; fibrotic diseases,
including cirrhosis of the liver; mesangial cell proliferative
diseases; arteriosclerosis; injuries to the nerve tissue, and for
inhibiting the reocclusion of vessels after balloon catheter
treatment; in vascular prosthetics or after mechanical devices are
used to keep vessels open, as immunosuppresive agent for supporting
scar-free healing; senile keratosis; contact dermatitis; and
asthma.
[0033] In a sixth aspect of the present invention, there is
provided a pharmaceutical agent comprising at least one compound of
formula (I) or an isomer, diastereoisomer, enantiomer, tautomer or
salt thereof for use as VEGF receptor kinase 3-inhibitors of
lymphangiogenesis.
[0034] In a seventh aspect of the present invention, there is
provided a pharmaceutical agent comprising at least one compound of
formula (I) or an isomer, diastereoisomer, enantiomer, tautomer or
salt thereof for use in a method for the treatment of the human or
animal body.
[0035] In an eighth aspect of the present invention, there is
provided a pharmaceutical agent comprising at least one compound of
formula (I) or an isomer, diastereoisomer, enantiomer, tautomer or
salt thereof for use in the preparation of a pharmaceutical product
for the prevention or treatment of a disease for which an
inhibition of angiogenesis and/or lymphangiogenesis and/or the VEGF
receptor kinases is beneficial.
[0036] In a ninth aspect of the present invention, there is
provided a pharmaceutical agent comprising at least one compound of
formula (I) or an isomer, diastereoisomer, enantiomer, tautomer or
salt thereof for use as an inhibitor of the tyrosine kinases
VEGFR-1 and VEGFR-2.
[0037] In a tenth aspect of the present invention, there is
provided a compound of general formula (III):
##STR00007##
in which A, E, Q, W, X, R.sup.2 and R.sup.3, are as defined for
formula (I) supra and R.sup.y is H or C.sub.1-C.sub.6-alkyl, as
intermediate for the preparation of a compound of formula (I).
Preferably W is H or C.sub.1-C.sub.2-alkyl, W is hydrogen and X is
CH; more preferably R.sup.y is H or --CH.sub.3, W is hydrogen and X
is CH.
[0038] In an eleventh aspect of the present invention, there is
provided the use of a compound of general formula (III), in which
A, E, Q, W, X, R.sup.2 and R.sup.3 are as defined for formula (I)
supra and R.sup.y is H or C.sub.1-C.sub.6-alkyl, as intermediate
for the preparation of a compound of formula (I).
[0039] In a twelfth aspect of the present invention, there is
provided a process for the preparation of a compound of formula
(I), wherein all substituents are as is described in claim 1, in
which a compound of formula (III), wherein A, E, Q, W, X, R.sup.2
and R.sup.3 are as defined in claim 1 and R.sup.y is H or
C.sub.1-C.sub.6-alkyl, is reacted with an amine of formula
R.sup.1NH.sub.2 in which R.sup.1 is as defined in claim 1.
[0040] In a thirteenth aspect of the present invention, there is
provided a process for the preparation of a compound of formula
(I), wherein all substituents are as described in claim 1, in which
a compound of formula (II):
##STR00008##
wherein A, E, Q, W, X, and R.sup.1 are as defined in claim 1 and M
stands for halogen, is:
[0041] (i) first converted to an amine and subsequently converted
to a compound of formula (I) by reaction with a carbamoyl chloride
of formula ClCONR.sup.2R.sup.3, wherein R.sup.2 and R.sup.3 are as
defined in claim 1; or alternatively,
[0042] (ii) reacted with a compound of formula
H.sub.2NCONR.sup.2R.sup.3, wherein R.sup.2 and R.sup.3 are as
defined in claim 1, or alternatively,
[0043] (iii) first converted to an amine and subsequently converted
to a compound of formula (I) by first reacting with a compound of
formula ClCO.sub.2Ph and then reacting with a compound of formula
HNR.sup.2R.sup.3, wherein R.sup.2 and R.sup.3 are as defined in
claim 1. Preferably a compound of formula (I) is prepared using the
(ii) process.
[0044] As used herein, the term "alkyl" is defined in each case as
a substituted or zo unsubstituted straight-chain or branched alkyl
group, such as, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl, heptyl,
octyt, nonyl, decyl, undecyl, or dodecyl.
[0045] As used herein, the term "alkoxy" is defined in each case as
a straight-chain or branched alkoxy group, such as, for example,
methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy,
isobutyloxy, tert-butyloxy, pentyloxy, isopentyloxy, hexyloxy,
heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy or
dodecyloxy.
[0046] As used herein, the term "cycloalkyl" is defined as a
monocyclic alkyl ring, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl, cyclooctyl, cyclononyt or
cyclodecyl, and also as bicyclic rings or tricyclic rings, such as,
for example, adamantanyl. The cycloalkyl group may also contain,
one or more heteroatoms, such as oxygen, sulphur and/or nitrogen,
such that a heterocycloalkyl ring is formed.
[0047] As used herein, the term "halogen" is defined in each case
as fluorine, chlorine, bromine or iodine, with fluorine being
preferred for compounds of formula (I ) and chlorine and bromine
being preferred as substituent M in compounds of formula (II).
[0048] As used herein, the term "halo-C.sub.1-C.sub.6-alkyl" is
defined as a C.sub.1-C.sub.6 alkyl group wherein some or all
hydrogen atoms are replaced by halogen atoms, preferably replaced
with fluoro atoms. Preferred is the group CF.sub.3.
[0049] As used herein, the term "alkenyl" is defined in each case
as a straight-chain or branched alkenyl group that contains 2-6,
preferably 2-4 carbon atoms. For example, the following groups can
be mentioned: vinyl, propen-1-yl, propen-2-yl, but-1-en-1 -yl,
but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl,
2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl,
but-3-en-1-yl, and allyl.
[0050] As used herein, the term "aryl" is defined in each case has
6-12 carbon atoms, such as, for example, cyclopropenyl,
cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl,
naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl etc, phenyl
being preferred.
[0051] As used herein, the term "C.sub.1-C.sub.12", as used
throughout this text e.g. in the context of the definitions of
"C.sub.1-C.sub.12-alkyl" and "C.sub.1-C.sub.12-alkoxy", is to be
understood as meaning an alkyl or alkoxy group having a finite
number of carbon atoms of 1 to 12, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11 or 12 carbon atoms. It is to be understood further that said
term "C.sub.1-C.sub.12" is to be interpreted as any subrange
comprised therein, e.g. C.sub.1-C.sub.12, C.sub.2-C.sub.11,
C.sub.3-C.sub.10, C.sub.4-C.sub.9, C.sub.5-C.sub.8,
C.sub.6-C.sub.7, C.sub.1-C.sub.2, C.sub.1-C.sub.3, C.sub.1-C.sub.4,
C.sub.1-C.sub.5, C.sub.1-C.sub.6, C.sub.1-C.sub.7, C.sub.1-C.sub.8,
C.sub.1-C.sub.9, C.sub.1-C.sub.10, C.sub.1-C.sub.11; preferably
C.sub.1-C.sub.2, C.sub.1-C.sub.3, C.sub.1-C.sub.4, C.sub.1-C.sub.5,
C.sub.1-C.sub.6; more preferably C.sub.1-C.sub.3.
[0052] Similarly, as used herein, the term "C.sub.2-C.sub.6", as
used throughout this text e.g. in the context of the definitions of
"C.sub.2-C.sub.6-alkenyl", is to be understood as meaning an
alkenyl group having a finite number of carbon atoms of 2 to 6,
i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further
that said term "C.sub.2-C.sub.6" is to be interpreted as any
subrange comprised therein, e.g. C.sub.2-C.sub.6, C.sub.3-C.sub.5,
C.sub.3-C.sub.4, C.sub.2-C.sub.3, C.sub.2-C.sub.4, C.sub.2-C.sub.5;
preferably C.sub.2-C.sub.3.
[0053] Further as used herein, the term "C.sub.1-C.sub.6", as used
throughout this text e.g. in the context of the definitions of
"halo-C.sub.1-C.sub.6-alkyl", is to be understood as meaning a
haloalkyl group having a finite number of carbon atoms of 1 to 6,
i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood
further that said term "C.sub.1-C.sub.6" is to be interpreted as
any subrange comprised therein, e.g. C.sub.1-C.sub.6,
C.sub.2-C.sub.5, C.sub.3-C.sub.4, C.sub.1-C.sub.2, C.sub.1-C.sub.3,
C.sub.1-C.sub.4, C.sub.1-C.sub.5, C.sub.1-C.sub.6; more preferably
C.sub.1-C.sub.3.
[0054] As used herein, the term "heteroaryl" as defined in each
case, is an aromatic ring system which contains, in the ring, at
least one heteroatom which may be identical or different, and which
comprises 3-16 ring atoms, preferably 5 or 6 atoms, more preferably
9 or 10 ring atoms, said heteroatom being such as oxygen, nitrogen
or sulphur, and can be monocyclic, bicyclic, or tricyclic, and in
addition in each case can be benzocondensed. Preferably heteroaryl
is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, etc., and benzo derivatives thereof, such
as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl,
benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyt,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo
derivatives thereof, such as, e.g., quinolinyl, isoquinotinyl,
etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo
derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthpyridinyt, pteridinyl, carbazolyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl,
etc. More preferably the heteroaryl is selected from indazolyl,
benzimidazolyl, quinolinyl, isoquinolinyl, benzotriazolyl.
Particularly preferably, the heteroaryl is indazolyl.
[0055] The aryl group and the heteroaryl group in each case can be
substituted in the same way or differently in one or more positions
with halogen, hydroxy, C.sub.1-C.sub.12-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.1-C.sub.12-alkoxy,
halo-C.sub.1-C.sub.6-alkyl, .dbd.O, --SO.sub.2R.sup.6, --OR.sup.5,
--SOR.sup.4, --COR.sup.6, --CO.sub.2R.sup.6 or --NR.sup.7R.sup.8,
whereby C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5
or --NR.sup.7R.sup.8. It is understood that the substitution on the
aryl group and the heteroaryl group may take place on any one of
the group's carbon atoms and/or on any one of the heteroatoms.
Preferably, the aryl group and the heteroaryl group is substituted
in one or two positions.
[0056] If an acid group is included, the physiologically compatible
salts of organic and inorganic bases are suitable as salts, such
as, for example, the readily soluble alkali salts and
alkaline-earth salts as well as N-methyl-glucamine,
dimethyl-glucamine, ethyl-glutamine, lysine, 1,6-hexadiamine,
ethanolamine, glucosamine, sarcosine, serinol,
tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base,
and 1-amino-2,3,4-butanetriol.
[0057] If a basic group is included, the physiologically compatible
salts of organic and inorganic acids are suitable, such as
hydrochloric acid, sulphuric acid, phosphoric acid, citric acid,
tartaric acid, succinic acid, fumaric acid, etc.
[0058] The compounds of general formula (I) according to the
invention also contain the possible tautomeric forms and comprise
the E-isomers or Z-isomers, or, if one or more stereogenic centers
are present, racemates and/or enantiomers and/or diastereoisomers.
Thus, a molecule with a single stereogenic center may be a mixture
of enantiomers (R,S), or may be a single (R) or (S) enantiomer. A
molecule with more than one stereogenic centre may be a mixture of
diastereoisomers, or may be a single diastereoisomer, whereby the
diastereoisomers may also exist as mixtures of enantiomers or
single enantiomers.
[0059] One embodiment of the present invention are compounds of
formula (I) wherein X is CH.
[0060] In one embodiment, W is hydrogen.
[0061] In one embodiment, A, E, and Q are each CH.
[0062] In one embodiment, X is CH, W is hydrogen, and A, E, and Q
each are CH.
[0063] In one embodiment, R.sup.1 is heteroaryl optionally
substituted in one or more places in the same way or differently
with halogen, hydroxy, C.sub.1-C.sub.12-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.1-C.sub.12-alkoxy,
halo-C.sub.1-C.sub.6-alkyl, .dbd.O, --SO.sub.2R.sup.6, --OR.sup.5,
--SOR.sup.4, --COR.sup.6, --CO.sub.2R.sup.6 or --NR.sup.7R.sup.8,
whereby C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5
or --NR.sup.7R.sup.8, with the proviso that when R.sup.2 and
R.sup.3 are both --CH.sub.3, R.sup.1 is not any one of the
following:
##STR00009##
[0064] In another embodiment, R.sup.1 is heteroaryl substituted in
one or more places in the same way or differently with halogen,
hydroxy, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl, .dbd.O,
--SO.sub.2R.sup.6, --OR.sup.5, --SOR.sup.4, --COR.sup.6,
--CO.sub.2R.sup.6 or --NR.sup.7R.sup.8, whereby
C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5 or
--NR.sup.7R.sup.8, with the proviso that when R.sup.2 and R.sup.3
are both --CH.sub.3, R.sup.1 is not any one of the following:
##STR00010##
[0065] In a preferred embodiment, R.sup.1 is
[0066] wherein R.sup.9 is hydrogen, halogen,
C.sub.1.sup.-C.sub.12.sup.-alkyl, C.sub.1-C.sub.12-alkoxy,
halo-C.sub.1-C.sub.6-alkyl, --COR.sup.6, --CO.sub.2R.sup.6 or
--NR.sup.7R.sup.8, whereby C.sub.1-C.sub.12-alkyl may be
substituted with --OR.sup.5 or --NR.sup.7R.sup.8 and R.sup.10 is
hydrogen or halogen.
[0067] In a more preferred embodiment, R.sup.1 is
##STR00011##
wherein R.sup.9 is hydrogen and R.sup.10 is hydrogen or
halogen.
[0068] In an even more preferred embodiment, R.sup.1 is
##STR00012##
wherein R.sup.9 is hydrogen, halogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl, --COR.sup.6,
--CO.sub.2R.sup.6 or --NR.sup.7R.sup.8, whereby
C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5 or
--NR.sup.7R.sup.8;
[0069] In a more particularly preferred embodiment, R.sup.1 is
##STR00013##
wherein R.sup.9 is hydrogen.
[0070] In one embodiment, R.sup.2 and R.sup.3, independently of one
another, are C.sub.1-C.sub.2 alkyl optionally substituted with
--OR.sup.5. In a preferred embodiment, R.sup.2 and R.sup.3,
independently of one another, are unsubstituted C.sub.1-C.sub.2
alkyl. In a more particularly preferred embodiment, R.sup.2 and
R.sup.3 are both --CH.sub.3.
[0071] In one embodiment, R.sup.4 is C.sub.1-C.sub.12-alkyl. In a
preferred embodiment, R.sup.4 is --CH.sub.3.
[0072] In one embodiment, R.sup.5 is --CH.sub.3 or hydrogen. In a
preferred embodiment, R.sup.5 is hydrogen.
[0073] In one embodiment, R.sup.6 is C.sub.1-C.sub.12-alkyl or
--NR.sup.7R.sup.8. In a preferred embodiment, R.sup.6 is
C.sub.1-C.sub.12-alkyl. In a more preferred embodiment, R.sup.6 is
--CH.sub.3.
[0074] In one embodiment, R.sup.7 and R.sup.8, independently of one
another, are hydrogen, COR.sup.6, SO.sub.2R.sup.6,
C.sub.1-C.sub.12-alkyl. In a preferred embodiment, R.sup.7 and
R.sup.8 independently of one another are hydrogen or
--CH.sub.3.
[0075] In one embodiment:
[0076] X is CH,
[0077] W is hydrogen,
[0078] A, E and Q each are CH,
[0079] R.sup.1 is heteroaryl optionally substituted in one or more
places in the same way or differently with halogen, hydroxy,
C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl, .dbd.O,
--SO.sub.2R.sup.6, --OR.sup.5, --SOR.sup.4, --COR.sup.6,
--CO.sub.2R.sup.6 or --NR.sup.7R.sup.8, whereby
C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5 or
--NR.sup.7R.sup.8, with the proviso that when R.sup.2 and R.sup.3
are both --CH.sub.3, R.sup.1 is not any one of the following:
##STR00014##
[0080] R.sup.2 and R.sup.3, independently of one another, are
C.sub.1-C.sub.2 alkyl optionally substituted with --OR.sup.5,
[0081] R.sup.4 is C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl, aryl or heteroaryl,
[0082] R.sup.5 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl or halo-C.sub.1-C.sub.6-alkyl,
[0083] R.sup.6 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl, halo-C.sub.1-C.sub.6-alkyl, aryl, or
--NR.sup.7R.sup.8,
[0084] R.sup.7 and R.sup.8, independently of one another, are
hydrogen, --SO.sub.2R.sup.6, --COR.sup.6, aryl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.12-alkyl,
halo-C.sub.1-C.sub.12-alkyl, or C.sub.1-C.sub.12-alkoxy, whereby
C.sub.1-C.sub.12-alkyl may be optionally substituted with
--OR.sup.5 or --N(CH.sub.3).sub.2, or R.sup.7 and R.sup.8 may also
be chosen in such a way as to provide a 3-8 membered cycloalkyl
ring, preferably a 4-7 membered cycloalkyl ring, more preferably a
5 or 6 membered cycloalkyl ring, which may optionally contain
further heteroatoms, such as nitrogen, oxygen or sulphur, and may
be optionally substituted in one or more places in the same way or
differently with halogen, cyano, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl, .dbd.O,
--OR.sup.5 , COR.sup.6, --SR.sup.4, --SOR.sup.4 or
--SO.sub.2R.sup.6, and
as well as isomers, diastereoisomers, enantiomers, tautomers and
salts thereof.
[0085] In a preferred embodiment:
[0086] X is CH,
[0087] W is hydrogen,
[0088] A, E and Q each are CH,
[0089] R.sup.1 is heteroaryl substituted in one or more places in
the same way or differently with halogen, hydroxy,
C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl, .dbd.O,
--SO.sub.2R.sup.6, --OR.sup.5, --SOR.sup.4, --COR.sup.6,
--CO.sub.2R.sup.6 or --NR.sup.7R.sup.8, whereby
C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5 or
--NR.sup.7R.sup.8, with the proviso that when R.sup.2 and R.sup.3
are both --CH.sub.3, R.sup.1 is not any one of the following:
##STR00015##
[0090] R.sup.2 and R.sup.3 independently of one another, are
C.sub.1-C.sub.2 alkyl. optionally substituted with --OR.sup.5;
[0091] R.sup.4 is C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl, aryl or heteroaryl,
[0092] R.sup.5 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl or halo-C.sub.1-C.sub.6-alkyl,
[0093] R.sup.6 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl, halo-C.sub.1-C.sub.6-alkyl, aryl, or
--NR.sup.7R.sup.8,
[0094] R.sup.7 and R.sup.8, independently of one another, are
hydrogen, --SO.sub.2R.sup.6, --COR.sup.6, aryl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.12-alkyl,
halo-C.sub.1-C.sub.12-alkyl, or C.sub.1-C.sub.12-alkoxy, whereby
C.sub.1-C.sub.12-alkyl may be optionally substituted with
--OR.sup.5 or --N(CH.sub.3).sub.2, or R.sup.7 and R.sup.8 may also
be chosen in such a way as to provide a 3-8 membered cycloalkyl
ring, preferably a 4-7 membered cycloalkyl ring, more preferably a
5 or 6 membered cycloalkyl ring, which may optionally contain
further heteroatoms, to such as nitrogen, oxygen or sulphur, and
may be optionally substituted in one or more places in the same way
or differently with halogen, cyano, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl., .dbd.O,
--OR.sup.5 , COR.sup.6, --SR.sup.4, --SOR.sup.4 or
--SO.sub.2R.sup.6, and
as well as isomers, diastereoisomers, enantiomers, tautomers and
salts thereof.
[0095] In a further preferred embodiment:
[0096] X is CH,
[0097] W is hydrogen,
[0098] A, E and Q each are CH,
[0099] R.sup.1 is
##STR00016##
wherein R.sup.9 is hydrogen, halogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy, halo-C.sub.1-C.sub.6-alkyl, --COR.sup.6,
--CO.sub.2R.sup.6 or --NR.sup.7R.sup.8, whereby
C.sub.1-C.sub.12-alkyl may be substituted with --OR.sup.5 or
--NR.sup.7R.sup.8 and R.sup.10 is hydrogen or halogen;
[0100] R.sup.2 and R.sup.3 independently of one another, are
C.sub.1-C.sub.2 alkyl optionally substituted with --OR.sup.5;
[0101] R.sup.4 is C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl, aryl or heteroaryl,
[0102] R.sup.5 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl or halo-C.sub.1-C.sub.6-alkyl,
[0103] R.sup.6 is hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.3-C.sub.8-cycloalkyl, halo-C.sub.1-C.sub.6-alkyl, aryl, or
--NR.sup.7R.sup.8,
[0104] R.sup.7 and R.sup.8, independently of one another, are
hydrogen, --SO.sub.2R.sup.6, --COR.sup.6, aryl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.12-alkyl,
halo-C.sub.1-C.sub.12-alkyl, or C.sub.1-C.sub.12-alkoxy, whereby
C.sub.1-C.sub.12-alkyl may be optionally substituted with
--OR.sup.5 or --N(CH.sub.3).sub.2, or R.sup.7 and R.sup.8 may also
be chosen in such a way as to provide a 3-8 membered cycloalkyl
ring, preferably a 4-7 membered cycloalkyl ring, more preferably a
5 or 6 membered cycloalkyl ring, which may optionally contain
further heteroatoms, such as nitrogen, oxygen or sulphur, and may
be optionally substituted in one or more places in the same way or
differently with halogen, cyano, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-atkoxy, halo-C.sub.1-C.sub.6-alkyl, .dbd.O,
--OR.sup.5, COR.sup.6, --SR.sup.4, --SOR.sup.4 or --SO.sub.2R.sup.6
, and
as well as isomers, diastereoisomers, enantiomers, tautomers and
salts thereof.
[0105] In a more preferred embodiment:
[0106] X is CH,
[0107] W is hydrogen,
[0108] A, E and Q each are CH,
[0109] R.sup.1 is
##STR00017## [0110] wherein R.sup.9 is hydrogen and R.sup.10 is
hydrogen or halogen;
[0111] R.sup.2 and R.sup.3, independently of one another, are
C.sub.1-C.sub.2 alkyl optionally substituted with --OR.sup.5,
and
as well as isomers, diastereoisomers, enantiomers, tautomers and
salts thereof.
[0112] In an even more preferred embodiment:
[0113] X is CH,
[0114] W is hydrogen,
[0115] A, E and Q each are CH,
##STR00018##
[0116] R.sup.1 is [0117] wherein R.sup.9 is hydrogen, halogen,
C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-alkoxy,
halo-C.sub.1-C.sub.6-alkyl, --COR.sup.6, --CO.sub.2R.sup.6 or
--N.sup.7N.sup.8, whereby C.sub.1-C.sub.12-alkyl may be substituted
with --OR.sup.5 or --NR.sup.7R.sup.8,
[0118] R.sup.2 and R.sup.3, independently of one another are
unsubstituted C.sub.1-C.sub.2 alkyl, and
as well as isomers, diastereoisomers, enantiomers, tautomers and
salts thereof.
[0119] In a more particularly preferred embodiment:
[0120] X is CH,
[0121] W is hydrogen,
[0122] A, E and Q each are CH,
[0123] R.sup.1 is
##STR00019## [0124] wherein R.sup.9 is hydrogen,
[0125] R.sup.2 and R.sup.3 are both unsubstituted C.sub.1-C.sub.2
alkyl, and
as well as isomers, diastereoisomers, enantiomers, tautomers and
salts thereof.
[0126] It is understood that any combination of the definitions
given in the above-mentioned embodiments is possible within the
context of the present invention.
[0127] Some specific examples of compounds of the present invention
include the following:
[0128]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl--
2H-indazol-6-yl)-benzamide
[0129]
2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2-
H-indazol-6-yl)-benzamide
[0130]
2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-ami-
no)-N-(2-methyl-2H-indazol-6-yl)-benzamide
[0131]
2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-ami-
no)-N-(2-methyl-21-indazol-6-yl)-benzamide
[0132]
2-{[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-met-
hyl-2H-indazol-6-yl)-benzamide
[0133]
2-{([2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(4-fluoro-
-2-methyl-2H-indazol-6-yl)-benzamide
[0134]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(7-methoxy-
-isoquinolin-3-yl)-benzamide
[0135]
6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylam-
ino)-2-methyl-2H-indazole-3-carboxylic acid methyl ester
[0136]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl--
2H-benzotriazol-5-yl)-benzamide
[0137]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl--
2-oxo-1,2-dihydro-quinolin-6-yl)-benzamide
[0138]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl--
2H-indazol-7-yl)-benzamide
[0139]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl--
3a,7a-dihydro-1H-indazol-4-yl)-benzamide
[0140]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro--
2-methyl-2H-indazol-4-yl)-benzamide
[0141]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro--
2-methyl-2H-indazol-7-yl)-benzamide
[0142]
6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylam-
ino)-1-methyl-1H-indazole-3-carboxylic acid methyl ester
[0143] to
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-hydr-
oxymethyl-1-methyl-1H-indazol-6-yl)-benzamide
[0144]
N-(3,6-difluoro-quinolin-2-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin--
4-ylmethyl]-amino}-benzamide
[0145]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-sulfamo-
yl-phenyl)-benzamide
[0146]
N-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridi-
n-4-ylmethyl]-amino}-benzamide
[0147]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxy-
methyl-2-methyl-2H-indazol-6-yl)-benzamide
[0148]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxy-
methyl-1-methyl-1H-indazol-6-yl) -benzamide
[0149]
6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylam-
ino)-1-methyl-1H-indazole-3-carboxylic acid methylamide
[0150]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro--
1-methyl-1H-indazol-5-yl)-benzamide
[0151]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro--
2-methyl-2H-indazol-5-yl)-benzamide
[0152]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro--
1-methyl-1H-indazol-4-yl)-benzamide
[0153]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-quinolin-3-
-yl-benzamide
[0154]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-fluoro--
6-methoxy-quinolin-2-yl)-benzamide
[0155]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methyl--
3H-benzoimidazol-5-yl)-benzamide
[0156]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl--
1H-benzoimidazol-5-yl)-benzamide
[0157]
2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methane-
sulfonyl-phenyl)-benzamide
[0158]
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(-
2-methyl-2H-indazol-6-yl)-benzamide
[0159] The compounds of formula (I) can be used as pharmaceutical
agents based on their inhibitory activity relative to the
phosphorylation of VEGF receptors. Based on their profile of
action, the compounds according to the invention are suitable for
preventing or treating diseases that are caused or promoted by
persistent angiogenesis.
[0160] Since the compounds of formula (I) are identified as
inhibitors of the tyrosine kinases VEGFR-1 and VEGFR-2, they are
suitable in particular for preventing or treating those diseases
that are caused or promoted by persistent angiogenesis that is
triggered via the VEGF receptor or by an increase in vascular
permeability.
[0161] The present invention also provides the use of the compounds
of formula (I) as inhibitors of the tyrosine kinases VEGFR-1 and
VEGFR-2, or KDR and FLT.
[0162] The term "diseases that are caused or promoted by persistent
angiogenesis" relates especially to diseases such as tumor or
metastasis growth, psoriasis, Kaposi's sarcoma, restenosis, such
as, e.g., stent-induced restenosis, endometriosis, Crohn's disease,
Hodgkin's disease, leukemia; arthritis, such as rheumatoid
arthritis, hemangioma, angiofibroma; eye diseases, such as diabetic
retinopathy, neovascular glaucoma; corneal transplants; renal
diseases, such as glomerulonephritis, diabetic nephropathy,
malignant nephrosclerosis, thrombic microangiopathic syndrome,
transplant rejections and glomerulopathy; fibrotic diseases, such
as cirrhosis of the liver, mesangial cell proliferative diseases,
arteriosclerosis, injuries to nerve tissue, and for inhibiting the
reocclusion of vessels after balloon catheter treatment, in
vascular prosthetics or after mechanical devices are used to keep
vessels open, such as, e.g., stents, as immunosuppressive agents,
for supporting scar-free healing, in senile keratosis, in contact
dermatitis, and in asthma.
[0163] In treating injuries to nerve tissue, quick scar formation
on the injury sites can be prevented with the compounds according
to the invention, i.e., scar formation is prevented from occurring
before the axons reconnect. A reconstruction of the nerve compounds
can thus be facilitated.
[0164] The formation of ascites in patients, especially patients
suffering from tumors caused by metastases, can also be suppressed
with the compounds according to the invention. VEGF-induced oedemas
can also be suppressed.
[0165] By a treatment with the compounds of formula (I), not only a
reduction of the size of metastases but also a reduction of the
number of metastases can be achieved.
[0166] Lymphangiogenesis plays an important role in lymphogenic
metastasis (Karpanen, T. et al., Cancer Res. 2001 Mar. 1, 61(5):
1786-90, Veikkola, T., et al., EMBO J. 2001, Mar. 15; 20 (6):
1223-31).
[0167] The compounds of formula (I) also show excellent action as
VEGFR kinase 3 inhibitors and are, therefore, also suitable as
effective inhibitors of lymphangiogenesis.
[0168] The compounds of formula (I) are thus effective in the
prevention or treatment of diseases that are associated with
excessive lymphangiogenesis, such as lymphedema, lymphangiectasia,
lymphangioma, and lymphangiosarcoma but also asthma. Lymphatic
growth around tumors may facilitate metastatic spread of malignant
cells that ultimately kill the patient. This process can be
effectively hindered by the compounds of this invention. Thus the
compounds are not only effective in inhibiting metastasis growth,
but can also be effective in reducing the number of metastases.
[0169] This invention also provides the use of the compounds of
formula (I) as inhibitors of the tyrosine kinase VEGFR-3
(FLT-4).
[0170] A further object of this invention is also a pharmaceutical
agent for preventing or treating diseases that are associated with
excessive lymphangiogenesis, such as metastasis growth, lymphedema,
lymphangiectasia, lymphangioma, and lymphangiosarcoma but also
asthma.
[0171] Furthermore, the invention relates to the use of the
compounds of general formula (I) for the preparation of a
pharmaceutical agent for use in or for the prevention or treatment
of tumor or metastasis growth, psoriasis, Kaposi's sarcoma,
restenosis, such as, e.g., stent-induced restenosis, endometriosis,
Crohn's disease, Hodgkin's disease, leukemia; arthritis, such as
rheumatoid arthritis, hemangioma, angiofibroma; eye diseases, such
as diabetic retinopathy, neovascular glaucoma; corneal transplants;
renal diseases, such as glomerulonephritis, diabetic nephropathy,
malignant nephrosclerosis, thrombic microangiopathic syndrome,
transplant rejections and glomerulopathy; fibrotic diseases, such
as cirrhosis of the liver, mesangial cell proliferative diseases,
arteriosclerosis, injuries to nerve tissue, and for inhibiting the
reocclusion of is vessels after balloon catheter treatment, in
vascular prosthetics or after mechanical devices are used to keep
vessels open, such as, e.g., stents, as immunosuppressive agents,
for supporting scar-free healing, in senile keratosis, in contact
dermatitis, and also in asthma.
[0172] To use the compounds of formula (I) as pharmaceutical
agents, the latter are brought into the form of a pharmaceutical
preparation, which in addition to the active ingredient for enteral
or parenteral administration contains suitable pharmaceutical,
organic or inorganic inert carrier materials, such as, for example,
water, gelatin, gum arabic, lactose, starch, magnesium stearate,
talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical
preparations can be present in solid form, for example as tablets,
coated tablets, suppositories, capsules or in liquid form, for
example as solutions, suspensions or emulsions. They also can
contain, moreover, adjuvants such as preservatives, stabilizers,
wetting agents or emulsifiers, salts for changing osmotic pressure
or buffers.
[0173] For parenteral administration, especially injection
solutions or suspensions, especially aqueous solutions of the
active compounds in polyhydroxyethoxylated castor oil, are
suitable.
[0174] As carrier systems, surface-active adjuvants such as salts
of bile acids or animal or plant phospholipids, but also mixtures
thereof as well as liposomes or components thereof can also be
used.
[0175] For oral administration, especially tablets, coated tablets
or capsules with talc and/or hydrocarbon vehicles or binders, such
as for example, lactose, corn starch or potato starch, are
suitable. The administration can also be carried out in liquid
form, such as, for example, as juice, to which optionally a
sweetener or, if necessary, one or more flavouring substances, is
added.
[0176] The dosage of the active ingredients can vary depending on
the method of administration, age and weight of the patient, type
and severity of the disease to be treated and similar factors. The
daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose
can be given as a single dose to be administered once or divided
into 2 or more daily doses.
[0177] A further object of this invention is therefore a
pharmaceutical agent comprising a compound of formula (I) in
combination with at least one pharmaceutically acceptable carrier
or excipient.
[0178] Compounds of formula (I) are obtained, in that a compound of
general formula (II):
##STR00020##
in which A, E, Q, W, X and R.sup.1 are defined supra as for general
formula (I) and M stands for halogen, is (i) first converted to an
amine and then, by reaction with a carbamoyl chloride of formula
ClCONR.sup.2R.sup.3 in which R.sup.2 and R.sup.3 are defined supra
as for general formula (I), is converted to a urea of general
formula (I), or (ii) reacted with a urea of general formula
H.sub.2NCONR.sup.2R.sup.3 in which R.sup.2 and R.sup.3 are defined
supra as for general formula (I), or (iii) first converted to an
amine, then converted to a compound of formula (I) by first
reacting with a compound of formula ClCO.sub.2Ph and then reacting
with a compound of formula HNR.sup.2R.sup.3, wherein R.sup.2 and
R.sup.3 are defined supra as for general formula (I); or a compound
of general formula (III) in which A, E, Q, W, X, R.sup.2, and
R.sup.3 are defined supra as for general formula (I) and R.sup.Y
stands for H or C.sub.1-C.sub.6-alkyl, is reacted with an amine of
general formula R.sup.1NH.sub.2 in which R.sup.1 is defined supra
as for general is formula (I),
##STR00021##
[0179] There are many methods known to the person skilled in the
art in the literature for amide formation. For example, it is
possible to start from the corresponding ester. The ester may be
reacted according to J. Org. Chem. 1995, 8414 with
trimethylaluminium and the corresponding amine in solvents such as
toluene or 1,2-dichloroethane, at temperatures of 0.degree. C. to
the boiling point of the solvent. If the molecule contains two
ester groups, both are converted into the same amide. Instead of
trimethylaluminium, sodium hexamethyldisilazide can also be
used.
[0180] For amide formation, however, all processes that are known
to the person skilled in the art from peptide chemistry are also
available. For example, the io corresponding acid, obtained from
the corresponding ester by saponification, can be reacted with the
amine in aprotic polar solvents, such as, for example,
dimethylformamide, via an activated acid derivative, obtainable,
for example, with hydroxybenzotriazote and a carbodiimide, such as,
for example, diisopropylcarbodiimide, at temperatures of between
0.degree. C. and the boiling point of the solvent, preferably at
80.degree. C., or else with preformed reagents, such as, for
example, HATU
(O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) (Chem. Comm. 1994, 201), at temperatures of
between 0.degree. C. and the boiling point of the solvent,
preferably at room temperature. The addition of a base such as
N-methylmorpholine, for example, is necessary. Amide formation, may
also be accomplished via the acid halide, mixed acid anhydride,
imidazolide or azide.
[0181] The ureas of aryl- or heteroaryl amines may be prepared by a
variety of literature known methods, known to the person skilled in
the art. For example, they may be prepared by the reaction of aryl-
or heteroaryl amines with isocyanates, the reaction of amines with
aryl- or heteroaryl-carbamates such as aryl- or
heteroaryl-phenoxycarbamates, or the reaction of aryl- or
heteroaryl amines with appropriately substituted carbamoyl
chlorides, or the reaction of an aryl- or heteroaryl-halide with
ureas under the influence of metal catalysis.
[0182] For example, the ureas of aminopyridines may be prepared by
reacting a urea with halopyridines, whereby chloro and
bromopyridines are preferred, under the catalytic influence of
metal complexes, for example, palladium- or copper complexes. In
the case of copper complexes the use of stoichiometric amounts of
the copper complexes may be advantageous for the reaction
outcome.
[0183] Suitable copper salts for the reaction are copper (I) or
copper (II) salts whereby copper (I) salts such as, for example,
copper (I) oxide or copper (I) iodide, are preferred. In the case
of copper (I) iodide the addition of an additive such as, for
example, ethylenediamine is necessary. Suitable solvents for this
copper promoted coupling are dioxane or dimethylformamide, at
temperatures upto the boiling point of the solvents, whereby
120.degree. C. is preferred. Addition of a base is also necessary,
such as potassium phosphate or caesium carbonate. In the case of
palladium catalysis, palladium complexes such as
tris-(dibenzylideneacetone)-dipalladium(0) maybe employed. Suitable
solvents for is the reaction are toluene, dioxane or
dimethylformamide, whereby mixtures of solvents may also be
advantageous for the reaction, at temperatures from room
temperature to the boiling points of the solvents, whereby
110.degree. C. is preferred. A co-ligand such as BINAP, DPPF or
xantphos is also employed. A base is also required, suitable bases
for the reaction are for example, cesium carbonate, potassium
phosphate or sodium tert-butoxide.
[0184] The required urea starting materials for the above copper or
palladium promoted coupling, may in turn be prepared from the
reaction of the corresponding amines with the corresponding
isocyanates. Solvents such as for example dichloromethane, or
isopropylalcohol may be employed at temperatures from 0.degree. C.
to the boiling points of the solvents, whereby room temperature is
preferred.
[0185] Methods for the preparation of substituted or unsubstituted
6-aminoindazoles are well known to the person skilled in the art,
in the literature. They may be obtained from the reduction of the
corresponding nitroindazoles via catalytic hydrogenation or other
well known reduction methods. N-alkylation of substituted
nitroindazoles may be accomplished with a variety of literature
known alkylating agents. For example, methylation of N-1 or N-2 of
a suitably functionalised 6-nitroindazole may be accomplished by
for example treatment with a base, preferably Cs.sub.2CO.sub.3 or
NaH, and a methyl halide, preferably methyl iodide in a suitable
solvent such as N,N-dimethylformamide, at temperatures ranging from
0.degree. C. to 50.degree. C., whereby 50.degree. C. is preferred.
3-Substituted-6-nitroindazoles may be prepared by a variety of
methods. For example alkyl substituents may be introduced in the
3-position by way of standard Suzuki reactions between an
appropriate 3-haloindazole, whereby the appropriate 3-iodoindazoles
are preferred, and an alkyl boronic acid, whereby the
trialkylboraxines may also be employed. N-protection of the
indazole may be advantageous for the reaction.
6-Nitroindazole-3-carboxylic acid provides a suitable starting
material for ester, amide, hydroxymethyl and alkoxymethyl
substitution in the 3-position of 6-nitroindazole, via well known
transformations such as transesterification, amide coupling,
reduction, or reduction followed by alkylation.
6-Nitroindazole-3-carbaldehyde (prepared by the reaction of
commercial 6-nitroindole with NaNO.sub.2 in the presence of dilute
aqueous hydrochloric acid according to J. Med. Chem. 2001, 44, 7,
1021) provides a useful precursor to 6-nitroindazole-3-carboxylic
acid via well known oxidation methods. In turn
6-nitroindazote-3-carbaldehyde may also be converted to
3-hydroxymethyl-6-nitroindazole, 3-alkoxymethyl-6-nitroindazole, or
3-aminomethyl-6-nitroindazole derivatives by equally standard
transformations such as reduction, reduction followed by
alkylation, or reductive amination. Such standard transformations
may also be applied to the synthesis of other substituted
aminoindazoles. A variety of substituted nitroindazoles are
commercially available, however they may be readily synthesised via
the reaction of a suitable 2-amino-nitrotoluene derivative with,
for example, NaNO.sub.2 and aqueous hydrochloric acid. if required,
the nitro group may be introduced after the cyclisation reaction of
a suitable 2-aminotoluene derivative by standard nitration
chemistry.
[0186] The preparation of N-alkylated-aminobenzimidazoles may be
accomplished from the corresponding N-alkylated-nitrobenzimidazotes
via standard reduction chemistry. Alkylation of a suitable
functionalised nitrobenzimidazole, for example with an alkyl halide
and a base, furnishes N1- and N3-alkylated-nitrobenzimidazoles,
which may be separated and isolated in pure form by standard
purification techniques. For example,
6-amino-1-methyl-benzimidazole may be produced by the reaction of
commercial 5-nitrobenzimidazole with Mel and Cs.sub.2CO.sub.3 in
DMF followed by purification (of the resulting mixture of 5- and
6-nitro-1-methyl-benzimidazoles) and hydrogenation in the presence
of 10% Pd on charcoal. Similarly, the preparation of
N-alkylated-aminobenzotriazoles may also be accomplished from the
corresponding nitrobenzotriazoles. Alkylation of a suitable
functionalised nitrobenzotriazole, for example with an alkyl halide
and a base, furnishes N1-, N2- and
N3-alkylated-nitrobenzotriazoles, which may be separated and
isolated in pure form by standard purification techniques. Standard
reduction chemistry furnishes the corresponding
aminobenzotriazoles. For example, 5-amino-2-methyl-benzotriazole
may be prepared according to a literature procedure (Eur. J. Med.
Chem. 1992, 27, 161-166).
[0187] The preparation of 3-aminoisoquinolines which are
substituted in the 7-position, may be accomplished via the
corresponding 3-amino-1-bromo-7-substituted isoquinoline by way of
reductive dehalogenation. 3-amino-1-bromo-7-substituted
isoquinolines may in turn be prepared by the reaction of a suitable
2-cyano-4-substituted-benzeneacetonitrile with HBr in acetic acid.
For example, 3-amino-7-methoxyisoquinoline may be prepared in two
steps (HBr mediated cyclisation followed by reductive
dehalogenation) from 2-cyano-4-methoxy-benzeneacetonitrile, which
may be prepared according to a literature procedure (Bull. Chem.
Soc. Jpn. 1980, 53, 10, 2885-2890).
[0188] 1-Alkyl-6-amino-quinolin-2-ones may be prepared by known
methods. For example, 6-amino-2-methyl-quinolin-2-one may be
prepared according to a literature procedure (J. Chem. Research,
Synopses, 1997, 310-311).
[0189] 2-Amino-3,6-disubstituted quinolines may be prepared by a
number of procedures. For example, the reaction of the lithium salt
(generated with a base such as lithium diisopropylamide) of a
suitably substituted cyanomethyl-dialkylphosphonate with a suitably
substituted 2-nitrobenzaldehyde derivative in a suitable solvent,
such as THF, furnishes a suitable acrylonitrile derivative which
may be cyclised to the desired 2-amino-3,6-disubstituted quinoline
by treating with a suitable reducing agent, such as iron in acetic
acid.
[0190] The compounds of the general formulae II and III:
##STR00022##
in which A, E, Q, W, R.sup.1, R.sup.2 and R.sup.3, are defined in
the same way as for the general formula (I), M is halogen and
R.sup.y is H or C.sub.1-C.sub.6-alkyl, provide valuable
intermediates for the preparation of the inventive compounds of
general formula (I) and, are therefore also objects of the
invention. The use of compounds of formula (II) and (III) in the
production of a compound of formula (I), as well as the process
described above using these compounds in the production of a
compound of formula (I) are also objects of the invention.
EXAMPLES
Production of the Compounds According to the Invention
[0191] The following examples explain the production of the
compounds according to the invention without the scope of the
claimed compounds being limited to these examples.
Abbreviations
[0192] The following abbreviations used in the invention have the
following meanings:
[0193] Brine saturated aqueous sodium chloride solution
[0194] Cl+ chemical ionisation (NH.sub.3)
[0195] DCE 1,2-dichloroethane
[0196] DMF N,N-dimethyl formamide
[0197] d.sub.6-DMSO d.sub.6-dimethylsulfoxide
[0198] d doublet
[0199] dd doublet of doublets
[0200] ES+ positive mode electrospray ionisation
[0201] EtOAc ethyl acetate
[0202] EtOH ethanol
[0203] 1H-NMR proton nuclear magnetic resonance spectroscopy:
chemical shifts (.quadrature.) are given in ppm.
[0204] Hex n-hexane
[0205] LC-ES+ liquid chromatography/positive mode electrospray
ionisation
[0206] LDA Lithium diisopropylamide
[0207] MeOH methanol
[0208] m multiplet
[0209] Mp. melting point
[0210] MS mass spectrometry
[0211] m/z mass/charge ratio
[0212] Pd.sub.2dba.sub.3
tris-(dibenzylideneacetone)-dipalladium(0)-chloroform complex
[0213] rt room temperature
[0214] RT retention time (LC)
[0215] s singlet
[0216] THF tetrahydrofuran
[0217] t triplet
[0218] Xantphos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene
Example 1.0
Preparation of
2{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-i
ndazol-6-yl)-benzamide
##STR00023##
[0220]
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-
-benzamide (110 mg, 0.25 mmol, prepared as detailed infra in
Example 4A) and 1,1-dimethylurea (114 mg, 1.3 mmol) were suspended
in dioxane (3 mL) under a nitrogen atmosphere and treated
consecutively with DMF (1 mL), cesium carbonate (98 mg, 0.3 mmol),
Pd.sub.2dba.sub.3 (5 mg, 0.005 mmol) and Xantphos (9 mg, 0.015
mmol). The reaction mixture was flushed with nitrogen and heated
for 5 hours at 110.degree. C. (bath temperature). On cooling the
reaction was concentrated in vacua. The residue was partitioned
between CH.sub.2Cl.sub.2 and water. The organic phase was washed
with brine, dried, filtered and concentrated in vacuo. The residue
was purified by chromatography on Isolute.RTM. flash silica gel
(Separtis)
[0221] (Gradient elution: 100% CH.sub.2Cl.sub.2 to
CH.sub.2Cl.sub.2/EtOH 95:5) to give
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-ind-
azol-6-yl)-benzamide (79 mg, 71%) as a solid; 1H-NMR (300 MHz,
d.sub.6-DMSO) 10.15 (1H, s), 8.80 (1H, s), 8.25 (1H, s), 8.13 (1H,
d), 8.10 (1H, s), 7.95 (1H, t), 7.82 (1H, s), 7.72 (1H, d), 7.63
(1H, d), 7.22-7.32 (2H, m), 6.95 (1H, d), 6.68 (1H, t), 6.54 (1H,
d), 4.45 (2H, d), 4.13 (3H, s), 2.91 (6H, s); m/z (ES+) 444
[M+H].sup.+, 223; Mp. 184.degree. C.
[0222] The following compounds were prepared in analogy from
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benza-
mide and the corresponding urea:
TABLE-US-00001 ##STR00024## Example Nr. R.sup.2 R.sup.3 MW Mp.
[.degree. C.] or MS (m/z) 1.1 --CH.sub.2CH.sub.3 --CH.sub.2CH.sub.3
471.57 Foam (ES+) 472 [M + H].sup.+, 237 1.2 --CH.sub.3
--CH.sub.2CH.sub.2OH 473.54 Foam (ES+) 474 [M + H].sup.+ 1.3
--CH.sub.3 --CH.sub.2CH.sub.2OCH.sub.3 487.57 Mp. 174 1.4
--CH.sub.3 --CH.sub.2CH.sub.3 457.54 Foam (ES+) 458 [M + H].sup.+,
230
[0223] The following compounds were prepared in analogy from the
corresponding 2-bromopyridine intermediate and
1,1-dimethylurea.
TABLE-US-00002 ##STR00025## Example Mp. [.degree. C.] or Nr.
R.sup.1 MW MS (m/z) 1.5 ##STR00026## 461.48 Foam (ES+) 462 [M +
H].sup.+, 227, 222 1.6 ##STR00027## 470.54 Foam (ES+) 471 [M +
H].sup.+, 236
Example 2.0
Preparation of
6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-
-methyl-2H-indazole-3-carboxylic acid methyl ester
##STR00028##
[0225]
2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoic acid
(112 mg, 0.35 mmol), 6-amino-2-methyl-2H-indazole-3-carboxylic acid
methyl ester (62 mg, 0.3 mmol), N-methylmorpholine (0.09 mL, 0.82
mmol) and HATU (152 mg, 0.4 mmol) were suspended in dry DMF (3 mL)
and stirred at rt overnight. The reaction mixture was concentrated
in vacuo and the residue partitioned between dichloromethane.The
organic phase was washed consecutively with saturated aqueous
sodium hydrogencarbonate solution, water and brine, dried and
concentrated in vacuo. The residue was purified by chromatography
on Isolute.RTM. flash silica get (Separtis) (Gradient elution: 100%
CH.sub.2Cl.sub.2 to CH.sub.2Cl.sub.2/EtOH 9:1) to give
6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylami-
no)-2-methyl-2H-indazole-3-carboxylic acid methyl ester (53 mg,
35%) as a solid; 1H-NMR (300 MHz, d.sub.6-DMSO) 10.30 (1H, s), 8.79
(1H, s), 8.30 (1H, m), 8.15 (1H, d), 7.92-7.99 (2H, m), 7.82 (1H,
s), 7.75 (1H, dd), 7.62 (1H, o dd), 7.25-7.29 (1H, m), 6.93-6.96
(1H, m), 6.68 (1H, t), 6.55 (1H, d), 4.45(2H, d), 4.41 (3H, s),
3.99 (3H, s), 2.92 (6H, s); m/z (ES+) 502 [M+H].sup.+.
[0226] The following compounds were prepared in analogy from
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ytmethyl]-amino}-benzoic acid
and the corresponding amine:
TABLE-US-00003 ##STR00029## Example Mp. [.degree. C.] or Nr.
R.sup.1 MW MS (m/z) 2.1 ##STR00030## 444.50 Mp. 190.6 2.2
##STR00031## 470.54 (ES+) 471 [M + H].sup.+, 236 2.3 ##STR00032##
443.51 Foam (ES+) 444 [M + H].sup.+, 223 2.4 ##STR00033## 443.51
Foam (ES+) 444 [M + H].sup.+ 2.5 ##STR00034## 461.50 Foam (ES+) 462
[M + H].sup.+, 343, 252 2.6 ##STR00035## 461.50 Foam (ES+) 462 [M +
H].sup.+, 232 2.7 ##STR00036## 501.54 Foam (ES+) 502 [M + H].sup.+
2.8 ##STR00037## 473.53 Foam (ES+) 474 [M + H].sup.+ 2.9
##STR00038## 476.48 Mp. 208 2.10 ##STR00039## 468.54 Resin (ES+)
469 [M + H].sup.+, 342
Example 3.0
Preparation of
N-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-yl-
methyl]-amino}-benzamide
##STR00040##
[0228] To a stirred solution of 2,3-dimethyl-2H-indazol-6-ylamine
(60 mg, 0.34 mmol) in DCE (1.5 mL) at 0.degree. C., under nitrogen,
was added trimethylaluminium (2M in toluene, 0.35 mL, 0.7 mmol),
followed by a solution of
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethy]-amino}-benzoic acid
methyl ester (111 mg, 0.34 mmol) in DCE (1.5 mL). The reaction was
heated at 100.degree. C. (bath temperature) for 5 hours. On cooling
the reaction was poured onto saturated aqueous sodium
hydrogencarbonate solution and diluted with dichloromethane. The
mixture was stirred for 15 minutes before filtering through
Celite.RTM.. The organic phase was washed with water and brine,
dried, and concentrated in vacuo. The residue was purified by
repeated chromatography on Isolute.RTM. flash silica gel (Separtis)
(Gradient elution: 100% CH.sub.2CL.sub.2 to CH.sub.2Cl.sub.2/EtOH
95:5) to give
N-(2,3-dimethyl-2H-indazol-6-yl)-{[2-(3,3-dimethyl-ureido)-
pyridin-4-ylmethyl]-amino}-benzamide (23 mg, 15%) as a solid;
1H-NMR (300 MHz, d.sub.6-DMSO) 10.10 (1H, s), 8.79 (1H, s), 8.15
(1H, d), 8.00 (1H, s), 7.95 (1H, t), 7.82 (1H, s), 7.70-7.73 (1H,
m), 7.60 (1H, d), 7.22-7.29 (2H, m), 6.93-6.95 (1H, m), 6.67 (1H,
t), 6.53 (1H, d), 4.45 (2H, d), 4.01 (3H, s), 2.91 (6H, s), 2.59
(3H, s); m/z (ES+) 458 [M+H].sup.+, 230.
[0229] The following compounds were prepared in analogy from
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyt]-amino}-benzoic acid
methyl ester and the corresponding amine:
TABLE-US-00004 ##STR00041## Example Mp. [C.] or Nr. R.sup.1 MW MS
(m/z) 3.1 ##STR00042## 487.56 Foam (ES+) 488 [M + H].sup.+, 245 3.2
##STR00043## 487.56 Foam (ES+) 488 [M + H].sup.+, 383, 247 3.3
##STR00044## 500.56 Foam (ES+) 501 [M + H].sup.+ 3.4 ##STR00045##
461.50 Foam (ES+) 462 [M + H].sup.+ 3.5 ##STR00046## 461.50 Foam
(ES+) 462 [M + H].sup.+, 417 3.6 ##STR00047## 461.50 Foam (ES+) 462
[M + H].sup.+ 3.7 ##STR00048## 440.51 Foam (ES+) 441 [M +H].sup.+,
396, 221, 219 3.8 ##STR00049## 488.52 Mp. 211.6 3.9 ##STR00050##
443.51 Foam (ES+) 444 [M + H].sup.+, 399, 222 3.10 ##STR00051##
443.51 Foam (ES+) 444 [M + H].sup.+, 399, 223, 221 3.11
##STR00052## 467.55 Foam (ES+) 468 [M + H].sup.+
Example 4.0
Preparation of
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-meth-
yl-2H-indazol-6-yl)-benzamide
##STR00053##
[0231]
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-inda-
zol-6-yl)-benzamide (227 mg, 0.5 mmol) was suspended in dioxane (4
mL) and treated io consecutively with DMF (1.6 mL),
Pd.sub.2dba.sub.3 (13 mg, 0.013 mmol), Xantphos (18 mg, 0.031
mmol), cesium carbonate (193 mg, 0.59 mmol) and 1,1-dimethylurea
(232 mg, 2.63 mmol). The reaction mixture was placed under an argon
atmosphere and heated for 3 hours at 110.degree. C. (bath
temperature). On cooling the reaction was partitioned between EtOAc
and water. The organic phase was dried and concentrated in vacuo.
The residue was purified by chromatography on Isolute.RTM. Flash
silica gel (Separtis) (Gradient elution: 100% CH.sub.2Cl.sub.2 to
CH.sub.2Cl.sub.2/EtOH 9:1) to give
2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-meth-
yl-2H-indazol-6-yl)-benzamide (93 mg, 40%) as a resin. Further
purification was accomplished by preparative reverse phase HPLC
[Column: Kromasil C8 5.mu., 125.times.20 mm. Eluant: 38% CH.sub.3CN
in H.sub.2O (containing 0.2% NH.sub.3) to 95% CH.sub.3CN in
H.sub.2O (containing 0.2% NH.sub.3)]; 1H-NMR (300 MHz,
d.sub.6-DMSO) 10.43 (1H, s), 8.77 (1H, s), 8.26 (1H, s), 8.23 (1H,
s), 8.13 (1H, d), 7.80 (1H, s), 7.64 (1H, d), 7.13-7.25 (2H, m),
6.93 (1H, d), 6.73 (1H, t), 6.48 (1H, t), 6.29 (1H, d), 4.40 (2H,
d), 4.14 (3H, s), 2.92 (6H, s); m/z (ES+) 462 [M+H].sup.+.
Production of Starting and Intermediate Compounds
[0232] If the production of the intermediate compounds is not
described, the latter are known, commerically available, or can be
produced analogously to known compounds or processes that are
described here or in WO2004/013102. Particularly, the intermediate
compound
2-[(2-bromopyridin-4-yl-methyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benza-
mide is prepared as is published in WO 2004/013102, which is
reiterated herein as Example 4a:
Example 4A
Step 1: Production of
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-benzoic Acid Methyl
Ester
##STR00054##
[0234] 6.04 g (40 mmol) of anthranilic acid methyl ester in 600 ml
of methanol is mixed with 3.2 ml of acetic acid and 7.4 g (40 mmol)
of 2-bromopyridine-4-carbaldehyde and stirred overnight at
40.degree. C. 3.8 g (60 mmol) of sodium cyanoborohydride is added
thereto and stirred overnight at 40.degree. C. 3.8 g (60 mmol) of
sodium cyanoborohydride is added again and stirred over the weekend
at 40.degree. C. It is mixed with water and largely concentrated by
evaporation. The aqueous phase is extracted with ethyl acetate, and
the combined organic phases are dried, filtered and concentrated by
evaporation. The crude product is chromatographed on silica gel
with a gradient that consists of hexane and hexane/ethyl acetate
1:3 and hexane/ethyl acetate 1:1 as an eluant. 10.0 g (78% of
theory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid
methyl ester is obtained as a colorless oil.
Step 2
Production of 2-[(2-Bromo-pyridin-4-ylmethyl)-amino]benzoic
Acid
##STR00055##
[0236] 10.0 g (31.2 mmol) of
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester is
dissolved in 290 ml of ethanol and mixed with 31.2 ml of 2 M sodium
hydroxide solution. After having been stirred overnight at room
temperature, the ethanol is drawn off, and the aqueous phase is
shaken out with ethyl acetate. The aqueous phase is acidified with
concentrated hydrochloric acid. The precipitate that is formed is
suctioned off and dried. 5.93 g (62%) of
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid accumulates in
the form of a white solid.
Step 3: Production of
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benza-
mide
##STR00056##
[0238] 0.500 g (1.6 mmol) of
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid, 0.471 g (3.2
mmol) of 2-methyl-2H-indazol-6-ylamine, 0.4 ml (3.68 mmol) of
N-methylmorpholine and 0.729 g (1.92 mmol) of
O-(7-azabenzotriazol-1-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphat-
e (HATU) in 25 ml of dimethylformamide are stirred for 16 hours at
room temperature. The dimethylformamide is drawn off in an oil pump
vacuum. The remaining residue is drawn off in saturated sodium
bicarbonate solution. It is extracted three times with ethyl
acetate, and the combined organic phases are dried, filtered and
concentrated by evaporation. The residue is chromatographed on
silica gel with a gradient that consists of hexane:acetone=100:0 to
50:50 as an eluant. 0.669 g (96% of theory) of
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benza-
mide is obtained in the form of a beige foam.
Example 5.0
Preparation of
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-(4-fluoro-2-methyl-2H-indazol-7-yl-
)-benzamide
##STR00057##
[0240]
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(4-fluoro-2-methyl-2H-inda-
zol-7-yl)-benzamide was prepared from
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester
and 7-amino-4-fluoro-2-methyl-2H-indazote in analogy to the
procedures detailed in Example 4A; 1H-NMR (300 MHz, d.sub.6-DMSO)
9.86 (1H, s), 8.60 (1H, s), 8.32 (1H, d), 8.13 (1H, t), 7.83 (1H,
d), 7.58-7.61 (2H, m), 7.42 (1H, d), 7.30 (1H, t), 6.82 (1H, dd),
6.72 (1H, t), 6.59 (1H, d), 4.52 (2H, d), 4.22 (3H, s); m/z (ES+)
454, 456 [M+H, Br isotopes].sup.+.
Example 6.0
Preparation of
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(7-methoxy-isoquinolin-3-yl)-ben-
zamide
##STR00058##
[0242]
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(7-methoxy-isoquinolin-3-y-
l)benzamide was prepared from
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester
and 3-amino-7-methoxyisoquinoline in analogy to the procedures
detailed in Example 4A ; 1H-NMR (300 MHz, d.sub.6-DMSO) 10.62 (1H,
s), 9.10 (1H, s), 8.51 (1H, s), 8.32 (1H, d), 8.11 (1H, t),
7.83-7.90 (2H, m), 7.60 (1H, s), 7.50 (1H, m), 7.38-7.41 (2H, m),
7.27 (1H, t), 6.66 (1H, t), 6.55 (1H, d), 4.54 (2H, d), 3.91 (3H,
s).
Example 7.0
Preparation of
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-indazol-6--
yl)-benzamide
##STR00059##
[0244]
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-inda-
zol-6-yl)-benzamide was prepared from methyl
2-amino-6-fluorobenzoate in analogy to the procedures detailed in
Example 4A ; 1H-NMR (300 MHz, d.sub.6-DMSO) 10.51 (1H, s), 8.31
(1H, d), 8.26-8.28 (2H, m), 7.65 (1H, d), 7.59 (1H, s), 7.40 (1H,
d), 7.13-7.25 (2H, m), 6.73 (1H, t), 6.50 (1H, t), 6.29 (1H, d),
4.47 (2H, d), 4.13 (3H, s).
Example 8.0
Preparation of 1-(2-methoxy-ethyl)-1-methyl-urea
##STR00060##
[0246] To a stirred solution of N-(2-methoxyethyl)-methylamine (1
g, 11.21 mmol) in isopropanol (30 mL) at rt was added
trimethylsilytisocyanate (2.2 mL, 15.5 mmol) and the resulting
solution stirred overnight. The reaction was concentrated in io
vacuo to give 1-(2-methoxy-ethyl)-1-methyl-urea (1.69 g, quant.);
1H-NMR (300 MHz, d.sub.6-DMSO) 5.75 (2H, s), 3.27-3.43 (4H, m),
3.25 (3H, s), 2.79 (3H, s).
[0247] The following Examples detail the biological activity and
use of the compounds of the invention without the scope of the
claimed compounds being limited to these examples.
KDR Kinase Inhibition
[0248] Kinase activity was measured with a GST-kinase domain fusion
construct of the KDR kinase according to the following protocol to
obtain concentration response curves. Components were added into a
microtiterplate in the following sequence: 10 .mu.l of inhibitor in
threefold final concentration [3% DMSO in buffer (40 mM TrisCl pH
7.5; 1 mM DTT, 1 mM MnCl.sub.2, 10 mM MgCl.sub.2, 2.5 Promille
Polyethyleneglycol 20000)] and 10 .mu.l of substrate mixture [24
.mu.M ATP, 24 .mu.g/ml poly(Glu.sub.4Tyr) in buffer, specific
activity approx. 500 cpm/pmol .sup.32P-.quadrature.ATP]. Reaction
was started by adding 10 .mu.l of enzyme preparation diluted
appropriately in buffer that contains 10 .mu.M vanadate. After
incubation for exactly 10 min the reaction was stopped by adding of
10 .mu.l stop solution (250 mM EDTA). 10 .mu.l of the reaction
mixture were transferred to phosphocellulose filters. The filters
were washed in 0.1% phosphoric acid, dried before meltilex
scintillator was applied (Wallac, Perkin-Elmer) and the
radioactivity was counted.
VEGFR-3 Autophosphorylation
[0249] MVECs (1.5.times.10.sup.6/well) of a low passage number were
plated on collagen-G coated 48 well plates in EBM complete medium
(including EGM-2, BD-Clonetech). 5 h Later, medium was exchanged
for EBM-2 without EGM-2 but containing 0.2% BSA (EBM meager). 12 h
later medium was removed, 250 .mu.l EBM-2 meager and the respective
compound dilutions were added in 50 .mu.l EBM-2 meager. Solutions
were carefully mixed and left for 5 min at 4.degree. C. before the
addition of 200 .mu.l EBM-2 meager containing VEGF-C (final
concentration in the assay is 5 nM; Reliatech, Braunschweig). The
solution was then carefully mixed and incubated for 15 min at room
temperature. The medium was removed and cells were washed twice
with cold PBS/2mM vanadate. Cells were then lysed with 100 .mu.l
Duschl buffer [50 mM Hepes pH 7.2; 150 mM NaCl; 1 mM MgCl.sub.2;
1.5% Triton X-100; 10 mM Na-Pyrophosphate; 100 mM Na-Fluoride; 10%
glycerol+(freshly added before the experiment) 2 mM Orthovanadate
and 1 tablet per 50 ml Complete (Roche # 1836145)]
[0250] For the ELISA, Moronic MaxiSorp--MTP plates (# 3204006
Zinser)--were coated overnight at 4.degree. C. with Flt-4 antibody
(Flt-4 (C-20) # sc-321 Santa Cruz); 1 .mu.g/ml in coating buffer:
Na.sub.2CO.sub.3 pH 9.6 100 .mu.l/well). After 3.times. washing
with washing buffer (0.1% Tween 20 in Na.sub.2HPO.sub.4 pH 7.4) the
wells were incubated with 250 .mu.l blocking buffer (Roti Block
1/10 from Roth, Karlsruhe for 1 h at room temperature).
3.times.
[0251] Washing with washing buffer was followed by addition of cell
lysates and incubation over night at 4.degree. C. Then wells were
washed 3.times., anti-phosophotyrosine antibody coupled to
HRP(16-105; UPSTATE; dilution 1/20000 in TBST+3% Top Block # 37766,
Fluka) was added and incubated overnight at 4.degree. C. Washing
with washing buffer (6.times.) preceded the addition of BM
chemoluminescence ELISA reagent # 1582950 (Roche) and measurement
of luminescence.
Cytochrome P450 Inhibition
[0252] The Cytochrome P450 isoenzyme inhibition was performed
according to the publication of Crespi et al. (Anal. Biochem.,
1997, 248, 188-190) with use of the baculovirus/insect
cell-expressed, human Cytochrome P 450 isoenzymes (2C9 and
2C19).
[0253] Selected results are presented in the following Table:
TABLE-US-00005 IC50 KDR-Kinase IC50 CYP IC50 CYP Example (VEGFR-2)
(nM) 2C9 (.mu.M) 2C19 (.mu.M) 3.30 10 0.9 1.7 from WO 04/13102 3.40
40 1.1 2.3 from WO 04/13102 3.41 27 5.7 1.5 from WO 04/13102 1.0 25
6.7 19 1.1 35 3.8 9.9 1.4 24 6.6 26 2.2 36 10 6.4
[0254] The advantages of the compounds of the invention compared to
known compounds can be readily demonstrated by the above
studies.
[0255] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The preceding preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0256] In the foregoing and in the examples, all temperatures are
set forth uncorrected in degrees Celsius and, all parts and
percentages are by weight, unless otherwise indicated.
[0257] The entire disclosures of all applications, patents and
publications, cited herein and of corresponding European
application No. 04090419, filed Nov. 3, 2004 and U.S. Provisional
Application Ser. No. 60/626,914, filed Nov. 12, 2004, are
incorporated by reference herein.
[0258] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0259] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
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