U.S. patent application number 11/654643 was filed with the patent office on 2007-06-14 for vegfr-2 and vegfr-3 inhibitory anthranilamide pyridones.
Invention is credited to Rolf Bohlmann, Martin Haberey, Holger Hess-Stumpp, Andreas Huth, Stuart Ince, Martin Krueger, Andreas Menrad, Karl Heinz Thierauch, Ludwig Zorn.
Application Number | 20070135489 11/654643 |
Document ID | / |
Family ID | 34221969 |
Filed Date | 2007-06-14 |
United States Patent
Application |
20070135489 |
Kind Code |
A1 |
Huth; Andreas ; et
al. |
June 14, 2007 |
Vegfr-2 and vegfr-3 inhibitory anthranilamide pyridones
Abstract
Novel VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridones
and their use as pharmaceutical agents for treating diseases that
are triggered by persistent angiogenesis are selected.
Inventors: |
Huth; Andreas; (Berlin,
DE) ; Krueger; Martin; (Berlin, DE) ; Zorn;
Ludwig; (Berlin, DE) ; Ince; Stuart; (Berlin,
DE) ; Bohlmann; Rolf; (Berlin, DE) ;
Thierauch; Karl Heinz; (Berlin, DE) ; Menrad;
Andreas; (Oranienburg, DE) ; Haberey; Martin;
(Berlin, DE) ; Hess-Stumpp; Holger; (Berlin,
DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
34221969 |
Appl. No.: |
11/654643 |
Filed: |
January 18, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10866078 |
Jun 14, 2004 |
7202260 |
|
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11654643 |
Jan 18, 2007 |
|
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60482009 |
Jun 25, 2003 |
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Current U.S.
Class: |
514/332 ;
514/346; 546/261; 546/291 |
Current CPC
Class: |
C07D 213/64
20130101 |
Class at
Publication: |
514/332 ;
514/346; 546/261; 546/291 |
International
Class: |
A61K 31/444 20060101
A61K031/444; A61K 31/4412 20060101 A61K031/4412; C07D 213/62
20060101 C07D213/62 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 13, 2003 |
DE |
103 27 719.6 |
Claims
1-11. (canceled)
12. A method for treating a tumor or metastasis growth, psoriasis,
Kaposi's sarcoma, restenosis, stent-induced restenosis,
endometriosis, Crohn's disease, Hodgkin's disease, leukemia,
arthritis, rheumatoid arthritis, hemangioma, angiofibroma, an eye
disease, diabetic retinopathy, neovascular glaucoma, a renal
disease, glomerulonephritis, diabetic nephropathy, malignant
nephrosclerosis, thrombic microangiopathic syndrome, a transplant
rejection, glomerulopathy, a fibrotic disease, cirrhosis of the
liver, a mesangial cell proliferative disease, arteriosclerosis, an
injury to nerve tissue, senile keratosis or contact dermatitis; a
method for inhibiting the reocclusion of a vessel after balloon
catheter treatment, vascular prosthetics or use of a mechanical
device to keep vessels open, or use of a stent; a method for
immunosuppression or supporting scar-free healing; or a method for
inhibiting tyrosine kinases selected from KDR, FLT-1 and FLT-4 or
inhibiting VEGFR kinase 3 of lymphangiogenesis comprising
administering to a patient in need thereof an effective amount of a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of formula I ##STR30## in which A stands for
an aryl or heteroaryl, X stands for hydrogen or fluorine, R.sup.1
and R.sup.2, independently of one another, stand for hydrogen,
halogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy-C.sub.1-C.sub.10-alkylene,
halo-C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl or
halo-C.sub.3-C.sub.10-cycloalkyl, and Y stands for a bond or for
oxygen or for the group --S--, --S(O)-- or --SO.sub.2--, or a salt
thereof.
13. A method according to claim 12, which is for treating a tumor
or metastasis growth, psoriasis, Kaposi's sarcoma, restenosis,
stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's
disease, leukemia, arthritis, rheumatoid arthritis, hemangioma,
angiofibroma, an eye disease, diabetic retinopathy, neovascular
glaucoma, a renal disease, glomerulonephritis, diabetic
nephropathy, malignant nephrosclerosis, thrombic microangiopathic
syndrome, a transplant rejection, glomerulopathy, a fibrotic
disease, cirrhosis of the liver, a mesangial cell proliferative
disease, arteriosclerosis, an injury to nerve tissue, senile
keratosis or contact dermatitis; a method for inhibiting the
reocclusion of a vessel after balloon catheter treatment, vascular
prosthetics or use of a mechanical device to keep vessels open, or
use of a stent; a method for immunosuppression or supporting
scar-free healing.
14. A method according to claim 12, which is for inhibiting
tyrosine kinases selected from KDR, FLT-1 and FLT-4.
15. A method according to claim 12, which is for inhibiting VEGFR
kinase 3 of lymphangiogenesis.
16. A method according to claim 12, which is for treating
psoriasis, Kaposi's sarcoma, stent-induced restenosis,
endometriosis, Crohn's disease, Hodgkin's disease, leukemia,
rheumatoid arthritis, hemangioma, angiofibroma, diabetic
retinopathy, neovascular glaucoma, glomerulonephritis, diabetic
nephropathy, malignant nephrosclerosis, thrombic microangiopathic
syndrome, a transplant rejection, glomerulopathy, cirrhosis of the
liver, arteriosclerosis; or a method for inhibiting the reocclusion
of a vessel after balloon catheter treatment, vascular prosthetics
or use of a mechanical device to keep vessels open, or use of a
stent; or a method for supporting scar-free healing.
17. A method according to claim 12, wherein at least one of the Y
groups is oxygen, --S--, --S(O)-- or --SO.sub.2--.
18. A method according to claim 12, wherein at least one of the Y
groups is oxygen or --S--.
19. A method according to claim 12, wherein A stands for:
cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl,
indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl,
thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, benzofuranyl, benzothienyl, benzoxazolyl,
benzimidazolyl, indolyl, isoindolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, azocinyl,
indolizinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, xanthenyl, or oxepinyl.
20. A method according to claim 12, wherein R.sup.1 or R.sup.2 is
--OCF.sub.3, --OMe, -OiProp, --OEt, -OnBu, --OCH.sub.2CF.sub.3,
--OH, --SCF.sub.3, --OCH.sub.2CH.sub.2OMe, --OCHF.sub.2,
--OCH.sub.2CH.sub.2CF.sub.3, --OCH.sub.2CF.sub.2CF.sub.3,
--OCH(CF.sub.3).sub.2, --OCH(CF.sub.3).sub.2CH.sub.3, --Cl, or
--OCH.sub.2CH(CH.sub.3).sub.2.
21. A method according to claim 12, wherein A stands for a phenyl
or pyridyl, X stands for hydrogen or fluorine, R.sup.1 and R.sup.2,
independently of one another, stand for hydrogen, halogen,
C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy-C.sub.1-C.sub.10-alkylene,
C.sub.3-C.sub.10-cycloalkyl or halo-C.sub.3-C.sub.10-cycloalkyl and
Y stands for a bond or for oxygen or for the group --S--, --S(O)--
or --SO.sub.2--, or a salt thereof.
22. A method according to claim 12, wherein A stands for a phenyl,
X stands for hydrogen or fluorine, R.sup.1 and R.sup.2,
independently of one another, stand for hydrogen, halogen,
C.sub.1-C.sub.2-alkyl,
C.sub.1-C.sub.12-alkoxy-C.sub.1-C.sub.10-alkylene,
halo-C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl or
halo-C.sub.3-C.sub.10-cycloalkyl, and Y stands for a bond or for
oxygen or for the group --S--, --S(O)-- or --SO.sub.2--, or a salt
thereof.
23. A method according to claim 12, wherein A stands for a phenyl,
X stands for hydrogen, R.sup.1 and R.sup.2, independently of one
another, stand for hydrogen, halogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy-C.sub.1-C.sub.10-alkylene,
C.sub.3-C.sub.10-cycloalkyl or halo-C.sub.3-C.sub.10-cycloalkyl,
and Y stands for a bond or for oxygen or for the group --S--,
--S(O)-- or --SO.sub.2--, or a salt thereof.
24. A method according to claim 12, wherein A stands for an aryl or
heteroaryl, wherein the heteroaryl is not an indazole group, X
stands for hydrogen or fluorine, R.sup.1 and R.sup.2, independently
of one another, stand for hydrogen, halogen,
C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy-C.sub.1-C.sub.10-alkylene,
C.sub.3-C.sub.10-cycloalkyl or halo-C.sub.3-C.sub.10-cycloalkyl,
and Y stands for a bond or for oxygen or for the group --S--,
--S(O)-- or --SO.sub.2--, or a salt thereof.
25. A method according to claim 12, wherein the compound of formula
I is an isomer, enantiomer, or diastereomer of said compound.
26. A method according to claim 12, wherein the administration is
selected from enteral, parenteral and oral administration.
27. A method according to claim 12, wherein the compound of formula
I is TABLE-US-00003 ##STR31## ##STR32## ##STR33## ##STR34##
##STR35## ##STR36## ##STR37## ##STR38## ##STR39## ##STR40##
##STR41## ##STR42## ##STR43## ##STR44## ##STR45## ##STR46##
##STR47## ##STR48## ##STR49## ##STR50## ##STR51## ##STR52##
##STR53## ##STR54## ##STR55## ##STR56##
28. A method according to claim 12, wherein the compound of formula
I is ##STR57##
29. A method according to claim 12, wherein A stands for an aryl or
unsubstituted heteroaryl moiety.
30. A method according to claim 24, wherein A stands for an aryl or
unsubstituted heteroaryl moiety.
Description
[0001] This application claims the benefit of the filing date of
U.S. Provisional Application Ser. No. 60/482,009 filed Jun. 25,
2003.
[0002] The invention relates to VEGFR-2 and VEGFR-3 inhibitory
anthranilamide pyridones and their use as pharmaceutical agents for
treating diseases that are triggered by persistent
angiogenesis.
[0003] Persistent angiogenesis can be the cause or precondition of
various diseases, such as tumor or metastasis growth, 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
and arteriosclerosis, or can result in an aggravation of these
diseases.
[0004] Persistent angiogenesis is induced by the factor VEGF via
its receptor. So that VEGF can exert this action, it is necessary
that VEGF bind to the receptor, and a tyrosine phosphorylation is
induced.
[0005] Direct or indirect inhibition of the VEGF receptor
(VEGF=vascular endothelial growth factor) can be used for 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.
[0006] Anthranilamide pyridonamides that are used as pharmaceutical
agents for treating 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
reocdusion of vessels after balloon catheter treatment, in vascular
prosthetics or after mechanical devices are used to keep vessels
open, such as, e.g., stents, are known from WO 00/27820 (e.g.,
Example 38).
[0007] The compounds that are known from WO 00/27820 are generally
effective in the indications cited, but their effectiveness is not
very pronounced.
[0008] Anthranilic acid amides that are highly effective bit also
exhibit good inhibition of the Cytochrome P 450 isoenzyme 3A4 are
also known from WO 03/040102. The Cytochrome P 450 isoenzyme 3A4 is
one of the essential metabolic enzymes via which pharmaceutical
agents are degraded. An inhibition of this isoenzyme results in
undesirable pharmaceutical agent interactions, especially in the
case of multimorbid patients (patients with multiple disease
conditions). There also exists the problem that in a combination
therapy with other medications, increased toxicity occurs, which
results from the inhibition of the degradation of the compounds and
the associated excessive serum levels.
[0009] There is therefore the desire for active ingredients that on
the one hand are effective and on the other hand are more
compatible or do not exhibit any undesirable side effects.
[0010] It has now been found that compounds of general formula I
##STR1## in which [0011] A stands for an aryl or heteroaryl, [0012]
X stands for hydrogen or fluorine, [0013] R.sup.1 and R.sup.2,
independently of one another, stand for hydrogen, halogen,
C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy-C.sub.1-C.sub.10-alkylene,
halo-C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl or
halo-C.sub.3-C.sub.10-cycloalkyl, and [0014] Y stands for a bond or
for oxygen or for the group --S--, --S(O)-- or --SO.sub.2--, as
well as isomers, enantiomers, diastereomers and salts thereof,
overcome the above-indicated drawbacks.
[0015] Alkyl is defined in each case as a straight-chain or
branched alkyl radical, such as, for example, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or
hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl.
[0016] Alkoxy is defined in each case as a straight-chain or
branched alkoxy radical, such as, for example, methyloxy, ethyloxy,
propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy,
pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy,
decyloxy, undecyloxy or dodecyloxy.
[0017] Cycloalkyls are defined as monocyclic alkyl rings, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl,
cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings or
tricyclic rings, such as, for example, adamantanyl.
[0018] Cycloalkyl radicals can contain, instead of the carbon
atoms, one or more heteroatoms, such as oxygen, sulfur and/or
nitrogen. Those heterocycloalkyls with 3 to 8 ring atoms are
preferred.
[0019] Halogen is defined in each case as fluorine, chlorine,
bromine or iodine.
[0020] Haloalkyl is defined as an alkyl radical, which can be
substituted in one or more places with halogen.
[0021] The aryl radical in each case comprises 3-12 carbon atoms
and can in each case be benzocondensed.
[0022] For example, there can be mentioned: cyclopropenyl,
cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl,
naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, etc.
[0023] The heteroaryl radical in each case comprises 3-16 ring
atoms, and instead of the carbon can contain one or more
heteroatoms that are the same or different, such as oxygen,
nitrogen or sulfur, in the ring, and can be monocyclic, bicyclic,
or tricyclic, and in addition in each case can be
benzocondensed.
[0024] For example, there can be mentioned:
[0025] 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,
indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives
thereof, such as, e.g., quinolyl, isoquinolyl, etc.; or azocinyl,
indolizinyl, purinyl, etc., and benzo derivatives thereof; or
quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl,
etc.
[0026] 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-glucamine, lysine, 1,6-hexadiamine,
ethanolamine, glucosamine, sarcosine, serinol,
tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base,
and 1-amino-2,3,4-butanetriol.
[0027] If a basic group is included, the physiologically compatible
salts of organic and inorganic acids are suitable, such as
hydrochloric acid, sulfuric acid, phosphoric acid, citric acid,
tartaric acid, fumaric acid, i.a.
[0028] Those compounds of general formula I in which [0029] A
stands for a phenyl or pyridyl, [0030] X stands for hydrogen or
fluorine, [0031] R.sup.1 and R.sup.2, independently of one another,
stand for hydrogen, halogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy-C.sub.1-C.sub.10-alkylene,
halo-C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl or
halo-C.sub.3-C.sub.10-cycloalkyl and [0032] Y stands for a bond or
for oxygen or for the group --S--, --S(O)-- or --SO.sub.2--, as
well as isomers, enantiomers, diastereomer and salts thereof, have
special properties.
[0033] Those compounds of general formula I in which [0034] A
stands for a phenyl, [0035] X stands for hydrogen or fluorine,
[0036] R.sup.1 and R.sup.2, independently of one another, stand for
hydrogen, halogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy-C.sub.1-C.sub.10-alkylene,
halo-C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl or
halo-C.sub.3-C.sub.10-cycloalkyl, and [0037] Y stands for a bond or
for oxygen or for the group --S--, --S(O)-- or --SO.sub.2--, as
well as isomers, enantiomers, diastereomers, and salts thereof, are
especially advantageous.
[0038] Those compounds of general formula I in which [0039] A
stands for a phenyl, [0040] X stands for hydrogen, [0041] R.sup.1
and R.sup.2, independently of one another, stand for hydrogen,
halogen, C.sub.1-C.sub.12-alkyl,
C.sub.1-C.sub.12-alkoxy-C.sub.1-C.sub.10-alkylene,
halo-C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl or
halo-C.sub.3-C.sub.10-cycloalkyl, and [0042] Y stands for a bond or
for oxygen or for the group --S--, --S(O)--or --SO.sub.2--, as well
as isomers, enantiomers, diastereomers, and salts thereof, are
preferred
[0043] The compounds of general formula I according to the
invention also contain the possible tautomeric forms and comprise
the E- or Z-isomers or, if a chiral center is present, also the
racemates and enantiomers.
[0044] The compounds of formula I as well as their physiologically
compatible salts can be used as pharmaceutical agents based on
their inhibitory activity relative to the phosphorylation of the
VEGF receptor. Based on their profile of action, the compounds
according to the invention are suitable for treating diseases that
are caused or promoted by persistent angiogenesis.
[0045] Since the compounds of formula I are identified as
inhibitors of the tyrosine kinases KDR, FLT-1 and FLT-4, they are
suitable in particular for 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.
[0046] The subject of this invention is also the use of the
compounds according to the invention as inhibitors of the tyrosine
kinases KDR, FLT-1 and FLT-4.
[0047] Subjects of this invention are thus also pharmaceutical
agents for treating tumors or use thereof.
[0048] The compounds according to the invention can be used either
alone or in a formulation as pharmaceutical agents for treating
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; 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 and in
contact dermatitis.
[0049] 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
would thus be facilitated.
[0050] The formation of ascites in patients can also be suppressed
with the compounds according to the invention. VEGF-induced edemas
can also be suppressed.
[0051] Lymphangiogenesis plays an important role in lymphogenic
metastasizing (Karpanen, T. et al., Cancere Res. 2001 Mar. 1,
61(5): 1786-90, Veikkola, T., et al., EMBO J. 2001, Mar. 15; 20
(6): 1223-31).
[0052] The compounds according to the invention now also show
excellent action as VEGFR kinase 3 inhibitors and are therefore
also suitable as effective inhibitors of lymphangiogenesis.
[0053] By a treatment with the compounds according to the
invention, not only a reduction of the size of metastases but also
a reduction of the number of metastases is achieved.
[0054] Such pharmaceutical agents, their formulations and uses are
also subjects of this invention.
[0055] The invention thus also relates to the use of the compounds
of general formula I for the production of a pharmaceutical agent
for use as or for treatment of 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; 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.
[0056] The formation of ascites in patients can also be suppressed
with the compounds according to the invention. VEGF-induced edemas
can also be suppressed.
[0057] 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, or capsules, or in liquid form, for
example as solutions, suspensions or emulsions. They optionally
contain, moreover, adjuvants such as preservatives, stabilizers,
wetting agents or emulsifiers, salts for changing osmotic pressure
or buffers.
[0058] For parenteral administration, especially injection
solutions or suspensions, especially aqueous solutions of the
active compounds in polyhydroxyethoxylated castor oil, are
suitable.
[0059] 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.
[0060] 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 flavoring substances, is
added.
[0061] 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.
[0062] The above-described formulations and forms for dispensing
are also subjects of this invention.
[0063] The production of the compounds according to the invention
is carried out according to methods that are known in the art. For
example, compounds of general formula I are obtained in that a
compound of general formula II ##STR2## in which X has the meaning
that is indicated in general formula I and Rx stands for hydrogen
or C.sub.1-C.sub.6-alkyl, is first subjected to reductive amination
to obtain a compound of general formula (III) ##STR3## and then is
converted into the corresponding amide of general formula I, and
then optionally compounds of general formula I are oxidized to a
sulfur compound. The sequence of the steps can also be exchanged,
whereby Rx preferably stands for C.sub.1-C.sub.6-alkyl. If Rx
stands for C.sub.1-C.sub.6-alkyl, it can also optionally first be
saponified and then converted into the corresponding amide.
[0064] The reductive amination is carried out with aldehydes or
ketones, whereby the reaction is performed in the presence of a
reducing agent, such as, for example, sodium cyanoborohydride in a
suitable inert solvent, such as, for example, ethanol, at
temperatures of 0.degree. C. up to the boiling point of the
solvent. An addition of acids, such as glacial acetic acid, can
also prove advantageous. This reaction sequence can be performed as
a single-pot process. It can prove advantageous to isolate the
amine that is first produced and then in a separate step to reduce
it, for example, with sodium borohydride in solvents such as
acetonitrile.
[0065] The amide formation is carried out according to methods that
are known in the literature.
[0066] For amide formation, it is possible to start from a
corresponding ester. The ester is reacted according to J. Org.
Chem. 1995, 8414 with aluminum trimethyl and the corresponding
amine in solvents such as toluene 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
aluminum trimethyl, sodium hexamethyldisilazide can also be
used.
[0067] For amide formation, however, all processes that are known
from peptide chemistry are also available. For example, the
corresponding acid can be reacted with the amine in aprotic polar
solvents, such as, for example, dimethylformamide, via an activated
acid derivative that can be obtained, for example, with
hydroxybenzotriazole 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.
The reaction between carboxylic acid and amine, however, can also
be produced by activation reagents such as HATU
(N-dimethylamino-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methyl-
methanaminium hexafluorophosphate-N-oxide), whereby polar aprotic
solvents, such as, for example, dimethylformamide, are suitable for
the reaction. The addition of a base such as N-methylmorpholine is
necessary. The reaction proceeds at temperatures of 0-100.degree.
C., whereby the procedure is preferably performed at room
temperature. For the amide formation, the process can also be used
with the acid halide, the mixed acid anhydride, imidazolide or
azide. A previous protection of an additional amino group, for
example as an amide, is not necessary in all cases, but can
advantageously influence the reaction.
[0068] The oxidation of sulfur is carried out according to methods
that are known in the literature. The sulfur compound can thus be
reacted with oxidizing agents, such as m-chloroperbenzoic acid, in
solvents, such as dichloromethane, whereby a mixture of sulfoxide
and sulfone can be obtained. Hydrogen peroxide can also be used as
an oxidizing agent in solvents, such as, for example, glacial
acetic acid. Also, an oxidation with sodium periodate in the
presence of ruthenium trichloride, in solvents such as acetonitrile
with carbon tetrachloride or sodium periodate in methanol with
water, is possible, whereby in the former method, the sulfone is
produced and in the latter method, primarily the sulfoxide is
produced.
Production of the Compounds According to the Invention
[0069] 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.
EXAMPLE 1
[0070] ##STR4##
2-[(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-N-(4-trifluoromethoxy-phe-
nyl)-benzamide
[0071] 441 mg (1.8 mmol) of
2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid is
introduced into 12 ml of methylene chloride in a moisture-free
environment and under argon and mixed in succession with 456 mg
(4.5 mmol) of N-methylmorpholine and 336 mg of
4-trifluoromethoxyaniline and 822 mg (2.16 mmol) of HTU
(N-dimethylamino-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methyl-
methanaminium hexafluorophosphate-N-oxide, and it is stirred for
2.5 hours at room temperature. The acid goes into solution. Then,
it is heated for 1.5 hours to a bath temperature of 100.degree. C.
First, a product precipitates, which then goes into solution again.
It is concentrated by evaporation in a vacuum, and the residue is
dispersed into dilute sodium bicarbonate solution and ethyl
acetate. The organic phase is washed, dried, filtered and
concentrated by evaporation. The residue is chromatographed on 10 g
of silica gel (Isolute, flash, SI) with a gradient of
CH.sub.2Cl.sub.2 on CH.sub.2Cl.sub.2:MeOH=9:1 as an eluant, and 414
mg of a product is obtained that is absorptively precipitated with
methylene chloride:diisopropyl ether=5:1, and after suctioning off,
364 mg (50.1% of theory) of
2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-N-(4-trifluoromethoxy-ph-
enyl)-benzamide with a melting point of 189.2.degree. C. is
produced.
[0072] Similarly produced are also: TABLE-US-00001 ##STR5## Example
##STR6## Molecular Weight Melting Point (.degree. C.) or Molar Peak
m/e 1.1 ##STR7## 349.39 150.6 1.2 ##STR8## 377.44 Resin 1.3
##STR9## 363.42 172.2 1.4 ##STR10## 405.50 159 1.5 ##STR11## 417.39
1.6 ##STR12## 335.36 1.7 ##STR13## 403.36 1.8 ##STR14## 419.43 1.9
##STR15## 419.43 1.10 ##STR16## 393.544 111.2 1.11 ##STR17## 417.39
191 1.12 ##STR18## 385.37 178.8 1.13 ##STR19## 379.41 1.14
##STR20## 385.37 1.15 ##STR21## 385.37 110.6 1.16 ##STR22## 349.39
1.17 ##STR23## 377.44 1.18 ##STR24## 431.42 1.19 ##STR25## 467.40
1.20 ##STR26## 485.39 1.21 ##STR27## 513.44 1.22 ##STR28## 383.84
1.23 ##STR29## 391.30
Production of the Starting Materials:
2-[(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic Acid
a.) 2-[(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic Acid
Methyl Ester
[0073] 4.53 g (30 mmol) of anthranilic acid methyl ester is mixed
in 209 ml of methanol with 2.09 ml of glacial acetic acid and 5.76
g (42 mmol) of 2-pyridone5-carbaldehyde, and it is stirred for 24
hours at room temperature under argon and in a moisture-free
environment. It is then mixed in portions with 2.64 g (42 mmol) of
sodium cyanoborohydride, and it is stirred for 3 days at room
temperature. It is then evaporated to the dry state in a vacuum,
taken up in 150 ml of dilute sodium bicarbonate solution,
absorptively precipitated and suctioned off. As a residue, 4.75 g
(61% of theory) of
2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid
methyl ester is obtained.
b.) 2-[(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic
Acid
[0074] 3.5 g (12.7 mmol) of
2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic
acid-methyl ester is mixed in 15 ml of dimethylformamide with 30 ml
of 6N sodium hydroxide solution and stirred for 1.5 hours at room
temperature. While being cooled with ice, it is then mixed with
about 50 ml of 4N hydrochloric acid, the precipitation is suctioned
off, and it is washed with water. 3.1 g, which is taken up in 29.3
ml of 1N sodium hydroxide solution and 142 ml of ethanol, is
obtained, and it is heated for 1.5 hours to a bath temperature of
120.degree. C. The ethanol is then drawn off in a vacuum, it is
made acidic with 2N hydrochloric acid, and the precipitated product
is suctioned off and dried well. 2.9 g (93.5% of theory) of
2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid is
obtained.
[0075] The sample applications below explain the biological action
and the use of the compounds according to the invention without the
latter being limited to the examples.
Solutions Required for the Tests
Stock Solutions
[0076] Stock solution A: 3 mmol of ATP in water, pH 7.0
(-70.degree. C.) [0077] Stock solution B: g-33P-ATP 1 mCi/100 .mu.l
[0078] Stock solution C: poly-(Glu4Tyr) 10 mg/ml in water Solution
for Dilutions [0079] Substrate solvent: 10 mmol of DTT, 10 mmol of
manganese chloride, 100 mmol of magnesium chloride [0080] Enzyme
solution: 120 mmol of tris/HCl, pH 7.5, 10 .mu.M of sodium vanadium
oxide Sample Application 1 Inhibition of the KDR- and FLT-1 Kinase
Activity in the Presence of the Compounds According to the
Invention
[0081] In a microtiter plate (without protein binding) that tapers
to a point, 10 .mu.l of substrate mix (10 .mu.l of volume of ATP
stock solution A+25 .mu.Ci of g-33P-ATP (about 2.5 .mu.l of stock
solution B)+30 .mu.l of poly-(Glu4Tyr) stock solution C+1.21 ml of
substrate solvent), 10 .mu.l of inhibitor solution (substances
corresponding to the dilutions, 3% DMSO in substrate solvent as a
control) and 10 .mu.l of enzyme solution (11.25 .mu.g of enzyme
stock solution (KDR, FLT-1 or FLT-4 kinase) are added at 4.degree.
C. in 1.25 ml of enzyme solution (dilute). It is thoroughly mixed
and incubated for 10 minutes at room temperature. Then, 10 .mu.l of
stop solution (250 mmol of EDTA, pH 7.0) is added, mixed, and 10
.mu.l of the solution is transferred to a P 81 phosphocellulose
filter. Then, it is washed several times in 0.1 M phosphoric acid.
The filter paper is dried, coated with Meltilex, and measured in a
microbeta counter.
[0082] The IC50 values are determined from the inhibitor
concentration, which is necessary to inhibit the phosphate
incorporation to 50% of the uninhibited incorporation after removal
of the blank reading (EDTA-stopped reaction).
Sample Application 2
Cytochrome P450 Inhibition
[0083] The Cytochrome P450 inhibition was performed according to
the publication of Crespi et al. (Anal. Biochem., 248, 188-190
(1997)) with use of the baculovirus/insect cell-expressed and human
Cytochrome P 450 isoenzyme (3A4).
[0084] The results of the kinase-inhibition IC50 in nM and the
inhibition of the Cytochrome P450 isoenzyme Cyt P 3A4 (IC50, nM)
are presented in the table below: TABLE-US-00002 VEGFR II
Inhibition of Cyp Example No. (KDR) [nM] 450 3A4 [nM] Example 38
from WO 00/27820 180 4600 Example 5 from WO 03/040102 25 1500
Example 1.0 56 5600 Example 1.5 59 11.000
[0085] The superior action of the compounds according to the
invention compared to the known compounds can be seen clearly from
the results.
* * * * *