DE10327719A1 - VEGFR-2 and VEGFR-3 Inhibitory anthranylamide pyridones - Google Patents

Abstract

Selected novel VEGFR-2 and VEGFR-3 inhibitory anthranylamide pyridones and their use as drugs for the treatment of diseases induced by persistent angiogenesis are proposed.

Description

The This invention relates to novel VEGFR-2 and VEGFR-3 inhibitory anthranylamide pyridones and their use as medicaments for the treatment of diseases, which are triggered by persistent angiogenesis.

persistent Angiogenesis can be the cause or condition for various Diseases such as tumor or metastasis growth, psoriasis, arthritis, like rheumatoid arthritis, hemangioma, Angiofibribroma, eye diseases, such as diabetic retinopathy, Neovascular glaucoma, renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplant rejections and glomerulopathy, fibrotic disorders, such as cirrhosis, mesangial cell proliferative Diseases and artheriosclerosis or aggravation lead to these diseases.

The persistent angiogenesis is due to the factor VEGF over its Receptor induced. So that VEGF can develop this effect is it necessary that VEGF binds to the receptor and causes a tyrosine phosphorylation becomes.

A direct or indirect inhibition of the VEGF receptor (VEGF = vascular endothelial Growth factor) can be used to treat such diseases and other VEGF-induced pathological angiogenesis and vascular permeable conditions, such as tumor vascularization. For example, it is known that soluble Receptors and antibodies against VEGF the growth of tumors can be inhibited.

Out WO 00/27820 (eg Example 38) are anthranylamide pyridonamides known as drugs for the treatment of psoriasis, arthritis, like rheumatoid arthritis, hemangioma, Angiofibribroma, eye diseases, such as diabetic retinopathy, Neovascular glaucoma, renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic Syndromes, transplantation rejections and glomerulopathy, fibrotic disorders, such as cirrhosis, mesangial cell proliferative disorders, arteriosclerosis, injuries of the nervous tissue and to inhibit reocclusion of vessels Balloon catheter treatment, in vascular prosthetics or after insertion of mechanical devices for holding vessels open, such as z. As stents are used.

The from WO 00/27820 known compounds are shown in the Indications are generally effective, but their effectiveness is weak pronounced.

Further are known from WO 03/040102 Anthranylsäureamide, although are well effective, but also a good inhibition of cytochrome P 450 isoenzymes 3A4 have. The cytochrome P 450 isoenzyme 3A4 is one of the key metabolic enzymes that breaks down the drug become. Inhibition of this isoenzyme leads to unwanted Drug interactions, especially in multimorbid (multiple sick) patients. Furthermore, there is the problem that in a Combination therapy with other drugs increased toxicity occurs resulting from the inhibition of the degradation of the compounds and the associated results in high serum levels.

It There is therefore a desire for active substances that are effective on the one hand and on the other hand better tolerated are, or no unwanted Have side effects.

in der
A für ein Aryl oder Heteroaryl steht,
X für Wasserstoff oder Fluor steht,
R¹ und R² unabhängig voneinander für Wasserstoff, Halogen, C₁-C₁₂-Alkyl, C₁-C₁₂-Alkoxy-C₁-C₁₀-alkylen, Halo-C₁-C₁₀-Alkyl, C₃-C₁₀-Cycloalkyl oder Halo-C₃-C₁₀-Cycloalkyl steht und
Y für eine Bindung oder für Sauerstoff oder für die Gruppe -S-, -S(O)- oder -SO₂- steht, bedeuten, sowie deren Isomeren, Enantiomeren, Diastereomeren und Salze die oben angegebenen Nachteile überwinden.It has now been found that compounds of general formula I,

in the
A is an aryl or heteroaryl,
X is hydrogen or fluorine,
R ¹ and R ² independently of one another represent hydrogen, halogen, C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy-C ₁ -C ₁₀ -alkylene, halo-C ₁ -C ₁₀ -alkyl, C ₃ -C ₁₀ -cycloalkyl or halo-C ₃ -C ₁₀ -cycloalkyl and
Y is a bond or oxygen or the group -S-, -S (O) - or -SO ₂ -, and their isomers, enantiomers, diastereomers and salts overcome the disadvantages mentioned above.

Under Alkyl is in each case a straight-chain or branched alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, Decyl, undecyl, dodecyl.

Under Alkoxy is in each case a straight-chain or branched alkoxy radical, such as methyloxy, ethyloxy, propyloxy, isopropyloxy, Butyloxy, isobutyloxy, sec. Butyloxy, pentyloxy, isopentyloxy, hexyloxy, Heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy or dodecyloxy to understand.

Under Cycloalkyl are 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, to understand adamantanyl.

The Cycloalkyl radicals can instead of the carbon atoms, one or more heteroatoms, such as Oxygen, sulfur and / or nitrogen. Subjects are Such heterocycloalkyls having 3 to 8 ring atoms.

Under Halogen is to be understood in each case fluorine, chlorine, bromine or iodine.

Under Haloalkyl is an alkyl radical which is mono- or polysubstituted may be substituted with halogen.

Of the Aryl radical includes each 3 - 12 Carbon atoms and may each be benzo-fused.

For example may be mentioned: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, Cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, Anthracenyl etc.

Of the Heteroaryl radical each 3 - 16 Ring atoms and may instead of the carbon one or more, identical or different heteroatoms, such as oxygen, nitrogen or sulfur in the ring, and may be mono-, bi- or tricyclic be, and in addition each be benzo-fused.

For example:
Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof, such as. Benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof, such as. 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, oxepinyl, etc.

is contain an acidic function, are as salts the physiological acceptable Salts of organic and inorganic bases suitable such as the well soluble Alkali and alkaline earth salts and N-methyl-glucamine, dimethyl-glucamine, Ethyl glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, Tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.

is contain a basic function are the physiologically acceptable Salts of organic and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid and the like are suitable.

Particular properties have those compounds of general formula I, in the
A is a phenyl or pyridyl,
X is hydrogen or fluorine,
R ¹ and R ² independently of one another represent hydrogen, halogen, C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy-C ₁ -C ₁₀ -alkylene, halo-C ₁ -C ₁₀ -alkyl, C ₃ -C ₁₀ -cycloalkyl or halo-C ₃ -C ₁₀ -cycloalkyl and
Y is a bond or oxygen or the group -S-, -S (O) - or -SO ₂ -, and their isomers, enantiomers, diastereomers and salts.

Of particular interest are those compounds of general formula I in which
A is a phenyl,
X is hydrogen or fluorine,
R ¹ and R ² independently of one another represent hydrogen, halogen, C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy-C ₁ -C ₁₀ -alkylene, halo-C ₁ -C ₁₀ -alkyl, C ₃ -C ₁₀ -cycloalkyl or halo-C ₃ -C ₁₀ -cycloalkyl and
Y is a bond or oxygen or the group -S-, -S (O) - or -SO ₂ -, and their isomers, enantiomers, diastereomers and salts.

Preference is given to those compounds of the general formula I in which
A is a phenyl,
X is hydrogen,
R ¹ and R ² independently of one another represent hydrogen, halogen, C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy-C ₁ -C ₁₀ -alkylene, halo-C ₁ -C ₁₀ -alkyl, C ₃ -C ₁₀ -cycloalkyl or halo-C ₃ -C ₁₀ -cycloalkyl and
Y is a bond or oxygen or the group -S-, -S (O) - or -SO ₂ -, and their isomers, enantiomers, diastereomers and salts.

The Compounds of the invention of the general formula I also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, also the racemates and enantiomers.

The Compounds of formula I and their physiologically acceptable Salts are related by their inhibitory activity on phosphorylation of the VEGF receptor as a drug usable. Due to their profile of action are suitable the compounds of the invention for the treatment of diseases caused by persistent angiogenesis caused or promoted become.

There the compounds of the formula I as inhibitors of tyrosine kinases KDR, FLT-1 and FLT-4 are identified, they are particularly suitable to treat those diseases caused by the VEGF receptor triggered Persistent angiogenesis or an increase in vascular permeability caused or promoted become.

object The present invention also relates to the use of the compounds according to the invention as inhibitors of tyrosine kinases KDR, FLT-1 and FLT-4.

object The present invention thus also relates to medicaments for treatment of tumors or their use.

The compounds of the invention may be used either alone or in formulation as a medicament for the treatment of tumor or metastasis growth, psoriasis, Kaposis sarcoma, restenosis such. Stent-induced restenosis, endometriosis, Crohn's disease, Hodgkins disease, leukemia, arthritis such as rheumatoid arthritis, hemangioma, angiofibribroma, ophthalmic disorders such as diabetic retinopathy, neovascular glaucoma, renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplantation rejections and glomerulopathy, fibrotic diseases such as liver cirrhosis, mesangial cell proliferative disorders, atherosclerosis, injuries of the nervous tissue and for inhibiting the reocclusion of vessels after balloon catheter treatment, vascular prosthetics or after the insertion of mechanical devices for holding open vessels, such. As stents, as immunosuppressants, to support the scar-free wound healing, age spots and contact dermatitis are used.

at The treatment of nerve tissue injuries can be achieved with the compounds according to the invention prevents rapid scar formation at the injury sites be, d. H. it is prevented that the scarring occurs, before the axons reconnect.

In order to would one Reconstruction of nerve connections relieved.

Further can with the compounds of the invention Ascites formation in patients is suppressed. Likewise can be VEGF conditional edema suppress.

The Lymphangiogenesis plays an important role in the lymphogenous Metastasis (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).

The Compounds of the invention now also show excellent activity as VEGFR kinase 3 inhibitors and are therefore also useful as effective inhibitors of lymphangiogenesis.

By a treatment with the compounds of the invention will not only a reduction in the size development of metastases, but also a reduction in the number of metastases reached.

such Medicines, their formulations and uses are also Subject of the present invention.

The The invention thus further relates to the use of the compounds of general formula I, for the manufacture of a medicament for Use as or for the treatment of psoriasis, Kaposis sarcoma, restenosis, such as B. stent-induced Restenosis, endometriosis, Crohns disease, Hodgkins disease, leukemia, arthritis, like rheumatoid arthritis, hemangioma, Angiofibribroma, eye diseases, such as diabetic retinopathy, Neovascular glaucoma, renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic Syndromes, transplantation rejections and glomerulopathy, fibrotic disorders, such as cirrhosis, mesangial cell proliferative disorders, arteriosclerosis, injuries of the nervous tissue and to inhibit reocclusion of vessels Balloon catheter treatment, in vascular prosthetics or after insertion of mechanical devices for holding vessels open, such as z. Stents, as immunosuppressants, as a support in scar-free wound healing, for age spots and contact dermatitis.

Further can with the compounds of the invention Ascites formation in patients is suppressed. Likewise can be VEGF conditional edema suppress.

to Use of the compounds of formula I as a drug these are brought into the form of a pharmaceutical preparation, in addition to the active ingredient for enteric or parenteral administration suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, Water, gelatine, gum arabic, lactose, starch, magnesium stearate, Talc, vegetable oils, Polyalkylene glycols, etc. contains. The pharmaceutical preparations can in solid form, for example as tablets, dragees, suppositories, Capsules or in liquid Shape, for example as solutions, Suspensions or emulsions are present. If necessary included her about it In addition, auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for alteration osmotic pressure or buffer.

For the parenteral In particular, use is made of injection solutions or suspensions, in particular aqueous solutions of active compounds in polyhydroxyethoxylated castor oil.

When carrier systems can also surface-active Excipients such as salts of bile acids or animal or vegetable Phospholipids, but also mixtures thereof and liposomes or their Components are used.

For oral administration, especially tablets, dragees or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are suitable. The application may also be in liquid form, for example as a juice, optionally a sweetener or if necessary, one or more flavorings is attached.

The Dosage of active ingredients may vary depending on the route of administration, age and Weight of the patient, type and severity of the disease to be treated and similar Factors vary. The daily Dose is 0.5-1000 mg, preferably 50-200 mg, where the dose is to be administered as a single dose or once divided into 2 or more daily doses can be given.

The Also described above are formulations and dosage forms Subject of the present invention.

in der X die in der allgemeinen Formel I angegebene Bedeutung hat und R^x für Wasserstoff oder C₁-C₆-Alkyl steht, zunächst einer reduktiven Aminierung unterwirft, um zu einer Verbindung der allgemeinen Formel (III)

zu gelangen und anschließend in das entsprechende Amid der allgemeinen Formel I überführt und anschließend gegebenenfalls Verbindungen der allgemeinen Formel I zu einer Schwefelverbindung oxydiert. Die Reihenfolge der Schritte kann auch ausgetauscht werden, wobei R^x vorzugsweise für C₁-C₆-Alkyl steht. Falls R^x für C₁-C₆-Alkyl steht, kann auch gegebenenfalls zunächst verseift und anschließend in das entsprechende Amid überführt werden.The compounds of the invention are prepared by methods known per se. For example, compounds of general formula I are obtained by reacting a compound of general formula II

in which X has the meaning given in the general formula I and R ^{x is} hydrogen or C ₁ -C ₆ -alkyl, is first subjected to a reductive amination in order to obtain a compound of the general formula (III)

and then converted into the corresponding amide of general formula I and then optionally oxidized compounds of general formula I to a sulfur compound. The sequence of the steps can also be exchanged, wherein R ^{x is} preferably C ₁ -C ₆ -alkyl. If R ^{x is} C ₁ -C ₆ -alkyl, it is also possible, if appropriate, first to saponify and then to convert into the corresponding amide.

The Reductive amination is carried out with aldehydes or ketones in the presence of a reducing agent such as sodium cyanoborohydride in a suitable inert solvent such as ethanol at temperatures from 0 ° C to the boiling point of the solvent implements. An addition of acids such as glacial acetic acid may prove beneficial. This reaction sequence can be carried out as a one-pot reaction. It can prove to be prove beneficial, the first isolate the resulting amine and then in a separate step reduce, for example with sodium borohydride in solvents such as acetonitrile.

The Amide formation takes place by methods known from the literature.

For amide formation one can assume a corresponding ester. The ester is according to J. Org. Chem. 1995, 8414 with aluminum trimethyl and the corresponding amine in solvents such as toluene at temperatures of 0 ° C to the boiling point of the solvent. If the molecule contains two ester groups, both are converted to the same amide. Instead of aluminum trimethyl, one can also use sodium hexamethyldisilazide.

to However, amide formation is also known from peptide chemistry Procedure available. For example, the corresponding acid can be in aprotic polar solvents such as dimethylformamide via an activated acid derivative, available for example with hydroxybenzotriazole and a carbodiimide such as diisopropylcarbodiimide, at temperatures between 0 ° C and the boiling point of the solvent preferably at 80 ° C be reacted with the amine. One can see the reaction between carboxylic acid and Amin but also by activating reagents such as HATU (N-dimethylamino-1H-1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene] -N-methylmethanaminium hexafluorophosphate N-oxide), with polar aprotic solvent such as dimethylformamide are suitable for the reaction. Of the Addition of a base such as N-methylmorpholine is necessary. The reaction is running at temperatures of 0-100 ° C, where is preferably carried out at room temperature. For the amide formation can also do the procedure over the acid halide, the mixed acid anhydride, Imidazolide or azide can be used. A prior protection of an additional Amino group, for example as an amide, is not required in all cases, but the reaction can be cheap influence.

The Oxidation of the sulfur takes place by methods known from the literature. So you can use the sulfur compound with oxidants such as m-chloro-perbenzoic acid in solvents such as dichloromethane, to give a mixture of sulfoxide and Sulfone can be obtained. It is also possible to use hydrogen peroxide as an oxidizing agent in solvents such as using 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 are possible, in the former method, the sulfone in the latter predominantly the Sulfoxyd arises.

Preparation of the compounds of the invention

The following examples illustrate the preparation of the compounds of the invention without limiting the scope of the claimed compounds to these examples. example 1

2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) -amino] -N- (4-trifluoromethoxy-phenyl) -benzamide

441 mg (1.8 mmol) of 2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) -amino] -benzoic acid are initially introduced in 12 ml of methylene chloride with exclusion of moisture and under argon and washed successively with 456 mg of 4.5 mmol) of N-methylmorpholine and 336 mg of 4-trifluoromethoxyaniline and 822 mg (2.16 mmol) of HATU (N-dimethylamino-1H-1,2,3-triazolo [4,5-b] pyridine-1 ylmethylene] -N-methylmethanaminium hexafluorophosphate N-oxide) and stirred at room temperature for 2.5 h. The acid goes into solution. The mixture is then heated for 1.5 h at 100 ° C bath temperature. It first fails a product, which then goes back into solution. It is concentrated by evaporation in a vacuum and the residue is distributed in dilute sodium bicarbonate solution and ethyl acetate. The organic phase is washed, dried, filtered and concentrated. The residue is chromatographed over 10 g of silica gel (Isolute, flash, Si) with a gradient of CH ₂ Cl ₂ to CH ₂ Cl ₂ : MeOH = 9: 1 as eluent, giving 414 mg of a product which is treated with methylene chloride: diisopropyl ether Is stirred 5: 1 and after aspirating 364 mg (50.1% of theory) of 2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] -N- (4- trifluoromethoxy-phenyl) -benzamide of melting point 189.2 ° C results.

In an analogous procedure are also prepared:

Preparation of 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

4.53 g (30 mmol) of methyl anthranilate in 209 ml of methanol with 2.09 ml of glacial acetic acid and 5.76 g (42 mmol) 2-pyridone-5-carbaldehyde and added under argon and moisture exclusion Stirred for 24 h at room temperature. The mixture is then added portionwise with 2.64 g (42 mmol) of sodium cyanoborohydride and stir 3 days at room temperature. The mixture is then concentrated to dryness in vacuo one, takes in 150 ml of diluted sodium bicarbonate solution on, stir off and sucks off. As a residue receives 4.75 g (61% of theory) of 2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) -amino] -benzoic acid methyl ester.

b.) 2 - [(6-Oxo-1,6-dihydro-pyridin-3-ylmethyl) -amino] -benzoic acid

3.5 g (12.7 mmol) of methyl 2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] benzoate are added in 15 ml of dimethylformamide with 30 ml of 6N sodium hydroxide solution and for Stirred for 1.5 h at room temperature. It is then under ice cooling with about 50 ml of 4N hydrochloric acid offset, the precipitation filtered off with suction and washed with water. This gives 3.1 g, which in 29.3 ml of 1-N Sodium hydroxide solution and 142 ml of ethanol are added and for 1.5 h to 120 ° C Heated bath temperature become. The ethanol is then stripped off under reduced pressure, acidified with 2N hydrochloric acid put and the precipitated Product sucked off and dried well. 2.9 g (93.5% of theory) of 2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) -amino] -benzoic acid are obtained.

The The following application examples illustrate the biological effect and use of the compounds of the invention without limiting these to the examples.

For the experiments needed solutions

• Stock solutions Stock solution A: 3mM ATP in water pH 7.0 (-70 ° C) Stock solution B: g-33P-ATP 1 mCi / 100 μl Stock solution C: poly (Glu4Tyr) 10 mg / ml in water
• solution for dilutions Substrate solvent: 10 mM DTT, 10 mM manganese chloride, 100 mM magnesium chloride Enzyme solution: 120 mM Tris / HCl, pH 7.5, 10 μM Natriumvanadiumoxid

Application example 1

Inhibition of KDR and FLT-1 kinase activity in the presence of the compounds of the invention

In a tapered microtiter plate (without protein binding) 10 μl of substrate mix (10 μl vol ATP stock solution A + 25μGi g-33P-ATP (about 2.5 μl the stock solution B) + 30 μl poly (Glu4Tyr) stock solution C + 1.21 ml of substrate solvent), 10 μl of inhibitor solution (substances according to the dilutions, as control 3% DMSO in substrate solvent) and 10 μl enzyme solution (11.25 μg enzyme stock solution (KDR, FLT-1 or FLT-4 kinase) are diluted at 4 ° C in 1.25 ml of enzyme solution). It's going to be thorough mixed and incubated at room temperature for 10 minutes. Then there 10 μl Stop solution (250 mM EDTA, pH 7.0), mix and transfer 10 μl of the solution to a P 81 phosphocellulose filter. Subsequently is several times in 0.1 M phosphoric acid washed. The filter paper is dried, coated with Meltilex and in the microbeta counter measured.

The IC50 values are determined from the inhibitor concentration necessary for the phospha teinbau to inhibit 50% of uninhibited installation after deduction of the blank value (EDTA stopped reaction).

Application Example 2

Cytochrome P450 - inhibition

The Cytochrome P450 - inhibition was according to the publication by Crespi et al. (Anal Biochem., 248, 188-190 (1997)) using of baculovirus / insect cell-expressed and human cytochrome P 450 isoenzyme (3A4) performed.

The results of kinase inhibition IC50 in nM and the inhibition of the cytochrome P450 isoenzyme Cyt P 3A4 (IC50, nM) are shown in the following table:

Out The results clearly show the superior effect of the compounds according to the invention across from to recognize the known compounds.

Claims (11)

Compounds of the general formula I,

in which A is an aryl or heteroaryl, X is hydrogen or fluorine, R ¹ and R ² independently of one another are hydrogen, halogen, C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy-C ₁ -C ₁₀ is -alkylene, halo-C ₁ -C ₁₀ -alkyl, C ₃ -C ₁₀ -cycloalkyl or halo-C ₃ -C ₁₀ -cycloalkyl and Y is a bond or oxygen or the group -S-, -S ( O) - or -SO ₂ -, and their isomers, enantiomers, diastereomers and salts. Compounds of general formula I according to Claim 1, in which A represents a phenyl or pyridyl, X represents hydrogen or fluorine, R ¹ and R ² independently of one another represent hydrogen, halogen, C ₁ -C ₁₂ -alkyl, C ₁ - C ₁₂ alkoxy C ₁ -C ₁₀ alkylene, halo C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl or halo C ₃ -C ₁₀ cycloalkyl and Y represents a bond or oxygen or is the group -S-, -S (O) - or -SO ₂ -, and their isomers, enantiomers, diastereomers and salts. Compounds of the general formula I as claimed in claims 1 and 2, in which A is a phenyl, X is hydrogen or fluorine, R ¹ and R ² independently of one another are hydrogen, halogen, C ₁ -C ₁₂ -alkyl, C ₁ C ₁₂ alkoxy C ₁ -C ₁₀ alkylene, halo C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl or halo C ₃ -C ₁₀ cycloalkyl; and Y represents a bond or oxygen or for the group -S-, -S (O) - or -SO ₂ -, and their isomers, enantiomers, diastereomers and salts. Compounds of the general formula I as claimed in claims 1 to 3, in which A is a phenyl, X is hydrogen, R ¹ and R ² independently of one another are hydrogen, halogen, C ₁ -C ₁₂ -alkyl, C ₁ -C _{12 is} alkoxy C ₁ -C ₁₀ alkylene, halo C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl or halo C ₃ -C ₁₀ cycloalkyl and Y is a bond or oxygen or the group -S-, -S (O) - or -SO ₂ - stands, and their isomers, enantiomers, diastereomers and salts. Medicament containing at least one compound according to claims 1 to 4th Medicament according to claim 5, for use in tumor or metastasis growth, psoriasis, Kaposis sarcoma, restenosis, such as. Stent-induced restenosis, endometriosis, Crohn's disease, Hodgkins disease, leukemia, arthritis, such as rheumatoid Arthritis, hemangioma, Angiofibribroma, eye diseases, such as diabetic retinopathy, Neovascular glaucoma, renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic Syndromes, transplantation rejections and glomerulopathy, fibrotic disorders, such as cirrhosis, mesangial cell proliferative disorders, arteriosclerosis, injuries of the nervous tissue, inhibiting the reocclusion of vessels Balloon catheter treatment, vascular prosthetics or inserting mechanical devices for keeping open Vessels, like z. As stents, and as immunosuppressants, and in support of scar-free wound healing, and in age spots and contact dermatitis. Compounds according to claims 1 to 4 and drugs according to claims 5 and 6, with suitable formulation and excipients. Use of the compounds of the formula I as claimed in claims 1 to 4, as inhibitors of tyrosine kinases KDR, FLT-1 and FLT-4. Use of the compounds of the general formula I, according to claims 1 to 4, in the form of a pharmaceutical preparation for the enteral, parenteral and oral administration. Use of the compounds according to claims 1 to 4 in tumor or metastasis growth, psoriasis, Kaposis sarcoma, restenosis, such as. Stent-induced restenosis, Endometriosis, Crohns disease, Hodgkins disease, leukemia, arthritis, like rheumatoid arthritis, hemangioma, Angiofibribroma, eye diseases, such as diabetic retinopathy, Neovascular glaucoma, kidney disease, such as glomerulonephritis, diabetic Nephropathy, malignant nephrosclerosis, thrombic microangiopathic Syndromes, transplantation rejections and glomerulopathy, fibrotic disorders, such as cirrhosis, mesangial cell proliferative disorders, arteriosclerosis, injuries of the nervous tissue and to inhibit reocclusion of vessels Balloon catheter treatment, in vascular prosthetics or after insertion of mechanical devices for holding vessels open, such as z. As stents, and as immunosuppressants, and in support of scar-free wound healing, and in age spots and contact dermatitis. Use of the compounds of the general formula I, according to claims 1 to 4, as VEGFR kinase 3 inhibitors lymphangiogenesis.