DE10228090A1 - New N-2-(pyridon-2-yl-methyl)-anthranilamide derivatives, are tyrosine kinase KDR and FLT inhibitors and angiogenesis inhibitors, useful e.g. for treating tumors, psoriasis or restenosis - Google Patents

Abstract

N-(Bicyclic heteroaryl)-2-((6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino)-benzamides (I) are new. Pyridone derivatives of formula (I), including their enantiomers, racemates, isomers and salts, are new. [Image] R1>indazolyl, indolinyl, quinolinyl or 2-oxo-2H-chromen-3-yl (all optionally substituted by one or more halo, OH, 1-4C alkyl, 1-4C alkoxy, 1-4C haloalkyl, =O, OR3> or cyano-1-3C alkyl); R2>H or 1-3C alkyl; and R3>H or 1-4C alkyl; provided that compounds (I; R1> = unsubstituted indazolyl or quinolinyl; R2> = H or Me) are excluded. An independent claim is also included for anthranilamide derivatives of formula (II) and anthranilic acid derivatives of formula (III) as intermediates in the preparation of (I). [Image] ACTIVITY : Cytostatic; Antipsoriatic; Anti-HIV; Vasotropic; Gynecological; Antiinflammatory; Antirheumatic; Antiarthritic; Ophthalmological; Antidiabetic; Nephrotropic; Immunosuppressive; Hepatotropic; Antiarteriosclerotic; Neuroprotective; Vulnerary; Dermatological. MECHANISM OF ACTION : Tyrosine kinase KDR (VEGFR-2) inhibitor; tyrosine kinase FLT (VEGFR-3) inhibitor. N-(2-Oxo-2,3-dihydro-1H-indol-6-yl)-2-((6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino)-benzamide (Ia) had IC50 0.05 MicroM for inhibition of KDR.

Description

The invention relates to selected anthranylamidopyridinamines as VEGFR-2 and VEGFR-3 inhibitors, their production and use as a medicine for the treatment of diseases caused by persistent Angiogenesis triggered become.

Persistent angiogenesis can Cause of various diseases such as psoriasis, arthritis, such as rheumatoid Arthritis, hemangioma, Angiofribroma, eye diseases such as diabetic retinopathy, neovascular Glaucoma, kidney diseases such as glomerulonephritis, diabetic Nephropathy, malignant nephrosclerosis, thrombic microangiopatic Syndromes, transplant rejections and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferative diseases and atherosclerosis or worsen these diseases.

Persistent angiogenesis will by the factor VEGF over induced its receptor. So that VEGF can develop this effect it is necessary, that VEGF binds to the receptor and causes tyrosine phosphorylation becomes.

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

From the WO 00/27819 are known anthranylic acid amides, which are used as medicaments for the treatment of psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofribroma, eye diseases, such as diabetic retinopathy, neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant thrombosis, transplantation of malignant nephomboma, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombic syndrome, malignant nephombia fibrotic diseases, such as cirrhosis of the liver, mesangial cell proliferative diseases, atherosclerosis, injuries to the nerve tissue and to inhibit the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after the insertion of mechanical devices for keeping vessels open, such as, for. B. stents are used.

The known compounds are in the indicated indications are generally effective, but their effectiveness usually goes hand in hand with toxicity and poor tolerance of the drug.

It therefore still exists Need for more effective on the one hand and toxicologically harmless on the other Connections beyond that also better tolerated should be.

in der
R¹ für Indazolyl, Indolinyl, Chinolinyl oder für die Gruppe

steht, welche gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit Halogen, Hydroxy, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, Halo-C₁-C₄-alkyl oder mit der Gruppe =O oder -OR³ oder mit Cyano-C₁-C₃-alkyl substituiert sein kann,
R² für Wasserstoff oder C₁-C₃-Alkyl steht und
R³ für Wasserstoff oder C₁-C₄-Alkyl steht, mit Ausnahme der Verbindungen, in denen R² für Wasserstoff oder Methyl steht und R¹ gleichzeitig für unsubstituiertes Indazolyl oder Chinolinyl steht, bedeuten, sowie deren Enantiomeren, Racemate, Isomeren und Salze, die oben aufgeführten Nachteile überwinden.It has now been found that compounds of the general formula I

in the
R ¹ for indazolyl, indolinyl, quinolinyl or for the group

which is optionally one or more, identical or different, with halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo-C ₁ -C ₄ alkyl or with the group = O or - Can be OR ³ or substituted with cyano-C ₁ -C ₃ alkyl,
R ^{2 represents} hydrogen or C ₁ -C ₃ alkyl and
R ^{3 represents} hydrogen or C ₁ -C ₄ alkyl, with the exception of the compounds in which R ^{2 represents} hydrogen or methyl and R ¹ also represents unsubstituted indazolyl or quinolinyl, and their enantiomers, racemates, isomers and salts that overcome the disadvantages listed above.

Prevent the compounds of the invention tyrosine phosphorylation or stop persistent angiogenesis and hence the growth and spread of tumors, being especially due to a lower inhibition of isoforms of the cytochrome P 450 (2C9 and 2C19).

Medicines over this Degrading isoforms are generally less toxic and better compatible.

Alkyl is in each case to be understood as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl, C ₁ -C ₄ -alkyl radicals being preferred.

Under alkoxy is a straight chain or branched alkoxy radical, such as methyloxy, ethyloxy, Propyloxy, isopropyloxy, butyloxy, isobutyloxy or sec-butyloxy, to understand.

Halogen is fluorine, To understand chlorine, bromine or iodine.

If an acidic function is included, are the physiologically acceptable salts of organic and inorganic salts Suitable bases such as the readily soluble alkali 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, 1-amino-2,3,4-butanetriol.

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

steht, welche gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit Methyl, Methoxy oder mit der Gruppe =O oder mit Cyanoethyl substituiert sein kann und
R² für Wasserstoff steht, mit Ausnahme der Verbindungen, in denen R² für Wasserstoff steht und R¹ gleichzeitig für unsubstituiertes Indazolyl oder Chinolinyl steht, bedeuten, sowie deren Enantiomeren, Racemate, Isomeren und Salze.Those compounds of the general formula I in which
R ¹ for indazolyl, indolinyl, quinolinyl or for the group

stands, which can optionally be substituted one or more times, identically or differently with methyl, methoxy or with the group = O or with cyanoethyl and
R ^{2 is} hydrogen, with the exception of the compounds in which R ^{2 is} hydrogen and R ^{1 is} also unsubstituted indazolyl or quinolinyl, and their enantiomers, racemates, isomers and salts.

The compounds of the general invention Formula I also include the possible ones tautomeric forms and include the E or Z isomers or, if there is a chiral center, including the racemates and enantiomers.

The compounds of the invention and their physiologically acceptable Salts prevent tyrosine phosphorylation or stop the persistent Angiogenesis and thus the growth and spread of tumors, being characterized in particular by a lower inhibition of Label isoforms of the cytochrome P 450 (2C9 and 2C19). The medication with the compounds of the invention can therefore also without consideration on concomitantly administered drugs that degrade via these isoforms will be done risk-free.

The compounds of formula I as well their physiologically tolerable Salts are related due to their inhibitory activity can be used as a drug for phosphorylation of the VEGF receptor. The compounds according to the invention are suitable on the basis of their activity profile for the treatment of diseases caused by persistent angiogenesis evoked or promoted become.

Since the compounds of formula I are identified as inhibitors of tyrosine kinase KDR and FLT they are particularly used to treat such diseases that through the over persistent the VEGF receptor Angiogenesis or an increase vascular permeability or promoted become.

Object of the present invention is also the use of the compounds according to the invention as inhibitors the tyrosine kinase KDR and FLT.

Object of the present invention are therefore also drugs for the treatment of tumors or their Use.

The compounds of the invention can be used either alone or in formulation as a medicament for the treatment of psoriasis, Kaposis sarcoma, restenosis, such as. B. Stent-induced restenosis, endometriosis, Crohns disease, Hodgkins disease, leukemia, arthritis, such as rheumatoid arthritis, hemangioma, angiofribroma, eye diseases, such as diabetic retinopathy, neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic malignant nephropathy, nephropathy , Transplant rejection and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, Mesangial cell proliferative diseases, atherosclerosis, injuries to the nerve tissue and to inhibit the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after the insertion of mechanical devices for keeping vessels open, such as, for. B. stents, as immunosuppressants, to support scar-free wound healing, for age spots and for contact dermatitis.

When treating injuries of the nerve tissue can be rapid with the compounds according to the invention Prevent scarring at the injury sites, d. H. the Scarring occurs before the axons reconnect. That would a reconstruction of the nerve connections facilitated.

Furthermore, with the compounds according to the invention the ascites formation in patients is suppressed. Likewise, VEGF-related edema suppress.

Lymphangiogenesis plays a role important role in lymphogenic 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 show also excellent effect as VEGFR Kinase 3 inhibitors and are therefore also suitable as effective inhibitors of lymphangiogenesis.

By treatment with the compounds according to the invention will not only reduce the size of metastases, but also achieved a reduction in the number of metastases.

Such drugs, their formulations and uses are also the subject of the present invention.

The invention thus also relates to the use of the compounds of general formula I for the preparation a drug for use as, or for the treatment of Psoriasis, Kaposis sarcoma, restenosis, such as B. Stent-induced restenosis, endometriosis, Crohn's disease, Hodgkins disease, leukemia, Arthritis, such as rheumatoid arthritis, hemangioma, angiofribroma, eye diseases, such as diabetic retinopathy, neovascular glaucoma, kidney disease, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopatic syndromes, transplant rejection and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferative Diseases, atherosclerosis, nerve tissue injuries and to inhibit the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after the insertion of mechanical devices to keep them open of vessels like z. B. stents, as immunosuppressants, as support for scar-free wound healing, age spots and contact dermatitis.

Furthermore, with the compounds according to the invention the ascites formation in patients is suppressed. Likewise, VEGF-related edema suppress.

To use the compounds of Formula I as a pharmaceutical, these are in the form of a pharmaceutical preparation brought that in addition to the active ingredient for enteral or parenteral Application suitable pharmaceutical, organic or inorganic inert carrier materials, such as, water, gelatin, gum arabic, milk sugar, Strength, Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains. The pharmaceutical preparations can in solid form, for example as tablets, coated tablets, suppositories, Capsules or in liquid Form, for example as solutions, Suspensions or emulsions are present. If applicable included them about it In addition auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing osmotic pressure or buffer.

For the parenteral application is in particular injection solutions or Suspensions, especially aqueous solutions of active compounds in polyhydroxyethoxylated castor oil.

As carrier systems can also surfactants Excipients such as bile acid salts or animal or vegetable Phospholipids, but also mixtures thereof as well as liposomes or their Components are used.

For oral use is particularly tablets, coated tablets or capsules with talc and / or hydrocarbon carrier or binder, such as Lactose, corn or potato starch, suitable. The application can also be in liquid form, such as Example as juice, which may include a sweetener or if necessary or several flavors are added.

The dosage of the active ingredients can depending on the route of administration, age and weight of the patient, type and The severity of the condition being treated and similar factors vary. The daily Dose is 0.5-1000 mg, preferably 50-200 mg, where the dose as a single dose to be administered or divided can be given in 2 or more daily doses.

The formulations described above and dosage forms are also the subject of the present Invention.

manufacturing of the compounds of the invention

The following examples explain the Preparation of the compounds according to the invention, without the scope of the claimed compounds on these examples to restrict.

in der R¹ die in der allgemeinen Formel I angegebene Bedeutung hat, alkyliert, und anschließend das Amin der allgemeinen Formel II einer reduktiven Alkylierung mit Aldehyden oder Ketonen unterwirft, wobei man in Gegenwart eines Reduktionsmittels wie beispielsweise Natriumcyanoborhydrid in einem geeigneten inerten Lösungsmittel wie zum Beispiel Ethanol bei Temperaturen von 0°C bis zum Siedepunkt des Lösungsmittels umsetzt. Eine Zugabe von Säuren wie Eisessig kann sich als vorteilhaft erweisen.The compounds of the invention are prepared by methods known per se by using an amine of the general formula II

in which R ^{1 has} the meaning given in general formula I, alkylated, and then the amine of general formula II is subjected to reductive alkylation with aldehydes or ketones, in the presence of a reducing agent such as sodium cyanoborohydride in a suitable inert solvent such as for example Reacts ethanol at temperatures from 0 ° C to the boiling point of the solvent. The addition of acids such as glacial acetic acid can prove to be advantageous.

If you're from a primary amino group goes out, so you can, if necessary, successively with two different Implement carbonyl compounds, whereby mixed derivatives are obtained [literature z. B. Verardo et al. Synthesis (1993), 121; Synthesis (1991), 447; Kawaguchi, Synthesis (1985), 701; Micovic et al. Synthesis (1991), 1043].

There is also the method in 1,2-dichloroethane react with triacetoxyborohydride (J. org. Chem. 1996, 3849). It can be beneficial initially the Schiff base by reacting the aldehyde with the amine in solvents such as ethanol or methanol, optionally with the addition of auxiliaries how to form glacial acetic acid and only then reducing agents such. B. Add sodium cyanoborohydride. But you can also use the Schiffsche Isolate the base and then in solvents such as diethyl ether or tetrahydrofuran with reducing agents such as lithium aluminum hydride reduce to amine.

aus, wobei hierfür die aus der Peptidchemie bekannten Verfahren zur Verfügung stehen. Beispielsweise kann die entsprechende Säure in aprotischen polaren Lösungsmitteln wie zum Beispiel Dimethylformamid über eine aktiviertes Säurederivat, zum Beispiel erhältlich mit Hydroxybenzotriazol und einem Carbodiimid wie zum Beispiel Diisopropylcarbodiimid, bei Temperaturen zwischen 0°C und dem Siedepunkt des Lösungsmittels vorzugsweise bei 80°C mit dem Amin umgesetzt werden. Auch die Methode O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluoro-phosphat (HATU) für die Aktivierung einzusetzen, liefert gute Ergebnisse. Man benutzt als Base beispielsweise N-Methylmorpholin und als Lösungsmittel Dimethylformamid. Die Reaktion läuft vorzugsweise bei Raumtemperatur ab. Für die Amidbildung kann auch das Verfahren über das gemischte Säureanhydrid, Imidazolid oder Azid eingesetzt werden. Ein vorheriger Schutz einer zusätzlichen Aminogruppe beispielsweise als Amid ist nicht in allen Fällen erforderlich, kann die Reaktion aber günstig beeinflussen.For the preparation of the amides, compounds of the general formula III are used

, for which the methods known from peptide chemistry are available. For example, the corresponding acid in aprotic polar solvents such as, for example, dimethylformamide, via an activated acid derivative, for example obtainable with hydroxybenzotriazole and a carbodiimide such as, for example, diisopropylcarbodiimide, at temperatures between 0 ° C. and the boiling point of the solvent, preferably at 80 ° C. with the amine be implemented. Using the O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) method for activation also gives good results. For example, N-methylmorpholine is used as the base and dimethylformamide is used as the solvent. The reaction preferably takes place at room temperature. The process using the mixed acid anhydride, imidazolide or azide can also be used for the amide formation. Prior protection of an additional amino group, for example as an amide, is not necessary in all cases, but can have a favorable effect on the reaction.

in denen R¹ und R² die in der allgemeinen Formel I angegebenen Bedeutungen haben, als Zwischenprodukte zur Herstellung der Verbindungen der allgemeinen Formel I.The present application therefore also relates to compounds of the general formulas II and III

in which R ¹ and R ^{2 have} the meanings given in the general formula I, as intermediates for the preparation of the compounds of the general formula I.

Preparation of N- (2-oxo-2,3-dihydro-1H-indol-6-yl) -2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] benzamide Example 1.0

4.5 g (16.9 mmol) 2-amino-N- (2-oxo-2,3-dihydro-1N-indol-6-yl) benzamide are in 90 ml of absolute methanol together with 2.5 g (20.3 mmol) Pyrid-2-one-5-carboxaldehyde presented and mixed with 2.5 ml of glacial acetic acid. The approach is about Stirred at room temperature overnight. It gets to 4 ° C chilled and with twice 750 mg sodium cyanoborohydride added and stirred for 24 hours. The solid is filtered off and washed with methanol and water. It then becomes saturated sodium bicarbonate solution stirred and vacuumed again. The solid is dried. 5.16 g are obtained (82% of theory) on N- (2-oxo-2,3-dihydro-1H-indol-6-yl) -2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) - amino] benzamide.

Herstellung von N-(1-Cyanomethyl-1H-indazol-6-yl)-2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzamid Beispiel 2.0

317 mg (1,3 mMol) N-(1H-Indazol-6-yl)-2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzamid werden in 15 ml Dimethylformamid mit 280 mg (1,6 mMol) (6-Amino-indazol-1-yl)-acetonitrile, 330 mg N-Methylmorpholin und 591 mg (1,55 mMol) O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluoro-phosphat (HATU) versetzt und 3 Stunden bei Raumtemperatur gerührt. Der Ansatz wird dann am Vakuum zur Trockene eingeengt und in 30 ml Essigester und 30 ml Wasser verteilt, wobei nochvom Feststoff abgesaugt wird. Die Essigesterphase wird getrocknet, filtriert und eingeengt. Der Rückstand wird über eine Flashmaster-Säule mit einem Gradienten von Methylenchlorid : Ethanol = 100 : 0 bis 90 : 10 als Elutionsmittel gereinigt. Man erhält 286 mg/55% der Theorie) an N-(1-Cyanomethyl-1N-indazol-6-yl)-2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzamid.The following are also produced in an analogous manner:

Preparation of N- (1-cyanomethyl-1H-indazol-6-yl) -2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] benzamide Example 2.0

317 mg (1.3 mmol) of N- (1H-indazol-6-yl) -2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] benzamide are dissolved in 15 ml of dimethylformamide with 280 mg (1.6 mmol) (6-amino-indazol-1-yl) acetonitrile, 330 mg N-methylmorpholine and 591 mg (1.55 mmol) O- (7-azabenzotriazol-1-yl) -1 , 1,3,3-tetramethyluronium hexafluorophosphate (HATU) was added and the mixture was stirred at room temperature for 3 hours. The mixture is then evaporated to dryness in vacuo and distributed in 30 ml of ethyl acetate and 30 ml of water, the solid being filtered off with suction. The ethyl acetate phase is dried, filtered and concentrated. The residue is purified on a Flashmaster column using a gradient of methylene chloride: ethanol = 100: 0 to 90: 10 as the eluent. 286 mg / 55% of theory) of N- (1-cyanomethyl-1N-indazol-6-yl) -2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] are obtained. benzamide.

Preparation of N- (2-cyanomethyl-2N-indazol-6-yl) -2 - [(6-oxo-l, 6-dihydro-pyridin-3-ylmethyl) amino] benzamide Example 2.1

N- (2-Cyanomethyl-2N-indazol-6-yl) -2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] benzamide becomes analogous produced for example 2.0.

Production of raw materials

Process variant A

So much for the production of the interconnections is not described, these are known or analogous to known Connections or the methods described here can be produced.

i Level 1

Is 2-methoxypyridine-5-carbaldehyde Merchandise (Aldrich)

ii

2-pyridone-5-carbaldehyde is e.g. B. after Hoppe Seylers magazine for physiological chemistry vol. 325, S239, (1961).

Stage 1 process variant B

22,6 g (100 mMol) 2,4-Dinitrophenylessigsäure werden in einer Mischung von 200 ml Methanol und 830 ml Toluol gelöst und bei Raumtemperatur mit 83 ml Trimethylsilyldiazomethan (2 molar in Toluol; 166 mMol) versetzt und 3 Stunden bei Raumtemperatur gerührt. Nach Einengen zur Trockene und Trocknen bei 70°C am Vakuum erhält man 24 g (100% der Theorie) an 2,4-Dinitrophenylessigsäuremethylester.5-nitro-1,3-dihydro-indol-2-one is prepared according to RT Courts, J. Org. Chem. 48, 3747, 1970)

22.6 g (100 mmol) of 2,4-dinitrophenylacetic acid are dissolved in a mixture of 200 ml of methanol and 830 ml of toluene, and 83 ml of trimethylsilyldiazomethane (2 molar in toluene; 166 mmol) are added at room temperature and the mixture is stirred at room temperature for 3 hours. After concentration to dryness and drying at 70 ° C. in vacuo, 24 g (100% of theory) of methyl 2,4-dinitrophenylacetate are obtained.

26.6 g (83 mmol) methyl 2,4-dinitrophenylacetate are in 500 ml of ethanol with 5.4 g Palladium / coal (10%) under 1 bar hydrogen Hydrogenated for 1.5 hours at room temperature. After filtering off the catalyst is restricted. You get 18.8 g (94% of theory) of methyl 2,4-diaminophenylacetate.

18.8 g (104 mmol) 2,4-diaminophenylacetic acid methyl ester in 500 ml of absolute toluene at 4 ° C with 52 ml a 2 molar solution of trimethyl aluminum in toluene and then 60 min to 60 ° C heated. After cooling is adjusted to pH 7 with a 2N sodium hydroxide solution, over diatomaceous earth filtered and extracted against ethyl acetate. The organic phase is washed, dried, filtered and concentrated. 8.7 g are obtained (55% of theory) 6-amino-1,3-dihydro-indol-2-one.

Level 2

356 mg 5-nitro-1,3-dihydro-indol-2-one are dissolved in 30 ml Tetrahydrofuran: ethanol = 1: 1 with 400 mg palladium on carbon (10%) hydrogenated at room temperature and normal pressure for 1 hour. After suction from the catalyst Diatomaceous earth and concentration 320 mg (100% of theory) of 5-amino-1,3-dihydro-indol-2-one.

level 3

In 1 ml Dimethylacetamide become 320 mg of 5-amino-1,3-dihydro-indol-2-one solved and dropwise with 371 mg (2 mmol) 2-nitrobenzoyl chloride added, with a slight warming. After stirring overnight at room temperature is concentrated in vacuo and the residue taken up in ethyl acetate and water. Sucking off an insoluble Solid gives 130 mg (21.9% of theory) 2-nitro-N- (2-oxo-2,3-dihydro-1N-indole-5-yl) -benzamide. After shaking the organic phase washed, filtered and concentrated and one receives another 400 mg (67% of theory) of 2-nitro-N- (2-oxo-2,3-dihydro-1H-indol-5-yl) benzamide melting point 265 ° C.

In an analogous procedure also 2-nitro-N- (2-oxo-2,3-dihydro-1H-indol-6-yl) -benzamide with a melting point> 300 ° C.

Level 4

In an analogous procedure to the stage 2 becomes 2-amino-N- (indol-2-one-5-yl) benzoic acid amide melting point 219 ° C manufactured

Herstellung von 2-Amino-N-(7-methoxy-2-oxo-2H-chromen-3-yl)-benzamid Verfahrensvariante C

In an analogous procedure to step 2 of this example, 2-amino-N (indol-2-one-6-yl) benzoic acid amide with a melting point of 230 ° C.

Preparation of 2-amino-N- (7-methoxy-2-oxo-2H-chromen-3-yl) benzamide Process variant C

step 1

13 g (85.4 mmol) of 2-hydroxy-4-methoxybenzaldehyde in 300 ml of toluene with 9.8 g (102.5 mmol) of n-propylamine hydrochloride and 11.5 ml (102.5 mmol) of nitroacetic acid ethyl ester in the water for 15 hours heated by a separator. A further 3 ml of ethyl nitroacetate are then added and the mixture is boiled for a further 5 hours on a water separator. After cooling, it is diluted with ethyl acetate and shaken out with water. The ethyl acetate phase is dried, filtered and concentrated. The residue is chromatographed on silica gel with methylene chloride as the eluent. 6.14 g (33% of theory) of 3-nitro-7-methoxy-chromen-2-one are obtained.

Level 2

In an analogous procedure to level 2 from Example B becomes 3-nitro-7-methoxy-chromen-2-one in ethanol 3-amino-7-methoxy-chromen-2-one manufactured.

level 3

In an analogous procedure to level 3 of Example B is made from 2-nitrobenzoyl chloride and 3-amino-7-methoxy-chromen-2-one 2-nitro-N- (7-methoxy-2-oxo-2H-chromen-3-yl) benzamide 2-Nitro-N- (7-methoxybenzopyran-2-on-3-yl) benzoic acid amide manufactured. 2-amino-N- (7-methoxy-2-oxo-2H-chromen-3-yl) -benzamide

Level 4

In an analogous procedure to level 2 Example B is made from 2-nitro-N- (7-methoxy-2-oxo-2N-chromen-3-yl) benzamide in ethanol: tetrahydrofuran = 5: 2 2-amino-N- (7-methoxy-2-oxo-2H-chromen-3-yl) -benzamide manufactured.

The following interconnections are also produced in an analogous manner:

process variant D

step 1

Analogously to Example 1, anthranilic and 2-pyridone-5-carbaldehyde in 72% yield, methyl 2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] benzoate manufactured.

Level 2

450 mg (1.74 mmol) 2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] benzoic acid methyl ester are in 20 ml of ethanol with 4 ml 1N sodium hydroxide solution added and heated to a bath temperature of 120 ° C. for 1 hour. After distilling off of the ethanol in vacuo with 10 ml Diluted water and with 2N hydrochloric acid adjusted to pH 7. The precipitated product is suctioned off. you receives 242 mg (57% of theory) of yield 2 - [(6-oxo-1,6-dihydro-pyridin-3-ylmethyl) amino] benzoic acid.

The following application examples explain the biological effect and use of the compounds according to the invention without restricting it to the examples.

For the trials needed solutions

Stock solutions

Stock solution A: 3 mM 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: 10mM DTT, 10mM manganese chloride, 100mM magnesium chloride
Enzyme solution: 120 mM Tris / HCl, pH 7.5, 10 μM sodium vanadium oxide

Application example 1

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

In a pointed microtiter plate (without protein binding) 10 ul substrate mix (10 ul Vol ATP stock solution A + 25 μCi g-33P-ATP (approx. 2.5 μl of stock solution B) + 30 μl poly- (Glu4Tyr) stock solution C + 1.21 ml substrate solvent), 10 μl inhibitor solution (substances according to the dilutions, as a control 3% DMSO in substrate solvent) and 10 μl enzyme solution (11.25 μg enzyme stock solution (KDR or FLT-1 kinase) at 4 ° C diluted in 1.25 ml enzyme solution). It is mixed thoroughly and incubated at room temperature for 10 minutes. Then there 10 μl stop solution (250 mM EDTA, pH 7.0), mixes and transfers 10 μl of the solution a P 81 phosphocellulose filter. Then several times in 0.1 M phosphoric acid washed. The filter paper is dried and coated with Meltilex and in the micro beta counter measured.

The IC50 values are determined the inhibitor concentration that is necessary for the phosphate incorporation to 50% of uninhibited installation after deducting the blank value (EDTA inhibited reaction).

The results of the kinase inhibition IC50 in μM are shown in the table below:

Example of use 2

Cytochrome P450 inhibition

Cytochrome P450 inhibition was according to the release by Crespi et al. (Anal. Biochem., 248, 188-190 (1997)) using of baculovirus / insect cell-expressed human cytochrome P 450 isoenzymes (1A2, 2C9, 2C19, 2D6, 3A4) were carried out.

The results are as follows Shown in the table.

Inhibition of the cytochrome P450 isoenzymes (IC50, μM)

The result is clearly the superior one Effect of the compounds of the invention across from to recognize the known connections.

Claims (10)

Compounds of the general formula I

in the R ¹ for indazolyl, indolinyl, quinolinyl or for the group

which is optionally one or more, identical or different, with halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo-C ₁ -C ₄ alkyl or with the group = O or - OR ³ or can be substituted with cyano-C ₁ -C ₃ alkyl, R ^{2 represents} hydrogen or C ₁ -C ₃ alkyl and R ^{3 represents} hydrogen or C ₁ -C ₄ alkyl, with the exception of the compounds, in which R ^{2 is} hydrogen or methyl and R ^{1 is} also unsubstituted indazolyl or quinolinyl, and their enantiomers, racemates, isomers and salts. Compounds of the general formula I, in which R ^{1 is} for indazolyl, indolinyl, quinolinyl or for the group

stands, which can optionally be substituted one or more times, identically or differently with methyl, methoxy or with the group = O or with cyanoethyl and R ^{2 is} hydrogen, with the exception of the compounds in which R ^{2 is} hydrogen and R ^{1 is} also unsubstituted indazolyl or quinolinyl, and their enantiomers, racemates, isomers and salts. Medicament containing at least one compound according to claims 1 and Second Medicament according to claim 3, to treat tumors, psoriasis, Kaposis sarcoma, restenosis, stent-induced Restenosis, endometriosis, Crohns disease, Hodgkins disease, leukemia, arthritis, rheumatoid arthritis, hemangioma, Angiofribroma, eye diseases, diabetic retinopathy, neovascular glaucoma, Kidney disease, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopatic syndromes, Transplant rejections, Glomerulopathy, fibrotic diseases, cirrhosis of the liver, mesangial cell proliferative diseases, Atherosclerosis, nerve tissue injuries and inhibition the reocclusion of vessels Balloon catheter treatment, during vascular prosthetics or after insertion stents to keep vessels open, and immune diseases as immunosuppressants, to support scar-free wound healing for age spots and contact dermatitis. Compounds according to claims 1 and 2 and pharmaceuticals, according to claims 3 and 4, with suitable formulation and carriers. Use of the compounds of formula I, according to claims 1 and 2, as inhibitors of tyrosine kinase KDR and FLT. Use of the compounds of general formula I, according to claims 1 and 2, in the form of a pharmaceutical preparation for the enteral, parenteral and oral application. Use of the compounds of general formula I, according to claims 1 and 2, as VEGFR kinase 3 inhibitors in lymphangiogenesis. Use of the compounds of general formula I, according to claims 1 and 2, for suppression ascites formation and suppression of VEGF-related edema. Compounds of general formulas II and III

in which R ¹ and R ^{2 have} the meanings given in the general formula I, as intermediates for the preparation of the compounds of the general formula I.