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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

• the invention relates to VEGFR-2 and VEGFR-3 inhibitory anthranylamidopyridines, their production and use as medicaments for the treatment of diseases which are triggered by persistent angiogenesis and intermediates for the production of the compounds.
• Persistent angiogenesis can be the cause or prerequisite for various diseases such as tumor or metastatic growth, psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofribroma,
• Eye disorders such as diabetic retinopathy, neovascular glaucoma, kidney disorders 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 disorders
• Persistent angiogenesis is exceeded by its factor VEGF
• VEGF Receptor induced. In order for VEGF to exert this effect, it is necessary that VEGF binds to the receptor and tyrosine phosphorylation is caused.
• VEGF vascular endothelial growth factor
• VEGF vascular endothelial growth factor
• anthranylamidopyridones are known 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 nephrosclerosis, thrombic microangiopathic syndromes, transplant rejections and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferative disorders, and neurodegenerative disorders, arteriosclerosis, arteriosclerosis, arteriosclerosis, arteriosclerosis, arteriosclerosis, and atherosclerosis, arteriosclerosis, arteriosclerosis, arteriosclerosis, arteriosclerosis, and arteriosclerosis Vascular prosthetics or after the insertion of mechanical devices to keep vessels open, such
• anthranyl amides are known which are effective, but also show good inhibition of the cytochrome P 450 isoenzyme 3A4.
• the cytochrome P 450 isoenzyme 3A4 is one of the essential metabolic enzymes through which drugs are broken down. Inhibition of this isoenzyme leads to undesirable drug exchange effects, especially in multimorbid (multiple-disease) patients. There is also the problem that a combination therapy with other drugs leads to increased toxicity, which results from the inhibition of the breakdown of the compounds and the associated excessive serum levels.
• X represents CH or N
• W represents hydrogen or fluorine
• R 1 represents aryl or heteroaryl, which may be one or more, identical or different, with halogen, hydroxy, C, -C 12 -
• Alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 alkenyl, C 2 -C 6 alkynyl, aralkyloxy, C, - C 12 alkoxy, halo-C r C 6 -aikyl, cyano-C r C 6 -alkyl or can be substituted with the group O, -SO 2 R 6 or -OR 5 , where the CC 6 -alkyl can optionally also be substituted with the group -OR 5 or - NR 9 R 10 ,
• R 2 and R 3 independently of one another for hydrogen or for the group
• R 4 represents C 1 -C 12 alkyl, aryl or heteroaryl
• R 5 represents hydrogen, C 1 -C 4 -alkyl, C 3 -C 1Q- cycloalkyl "C 1 -C 4 -alkoxy, halo-C 1 -C 4 -alkyl or halo-C 3 -C 6 -cycloalkyl,
• R 6 is hydrogen, C ⁇ C ⁇ alkyl, halo-C ⁇ C ⁇ alkyl, aryl or
• R 7 and R 8 are independently hydrogen or C, -C 12 alkyl
• R 9 and R 10 independently of one another are hydrogen, C r C 6 -alkyl, C 2 -C, 6
• R 11 for C r C 6 alkyl, C r C 6 alkoxy, hydroxy-C r C 6 alkyl, hydroxy-C r C 6 alkoxy, C 3 -C 6 cycloalkyl, phenyl, pyridyl, biphenyl or naphthyl is, where the phenyl itself can be substituted one or more times, identically or differently with C r C 6 alkyl or halo-C r C 6 alkyl, and their isomers, diastereomers, tautomers and salts have improved properties, ie have good efficacy and at the same time lower CYP450 3A4 inhibition.
• the compounds according to the invention prevent tyrosine phosphorylation or stop persistent angiogenesis and thus the growth and spread of tumors, in particular being characterized by less inhibition of isoforms of the cytochrome P 450 (FIG. 3A4).
• the medication with the compounds according to the invention can therefore be carried out without risk, regardless of the medicinal products administered concurrently, which are broken down via these isoforms.
• Alkyl is in each case a straight-chain or branched alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. To understand butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl.
• Alkoxy is in each case a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec.
• alkoxy radical such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec.
• alkoxy such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec.
• alkoxy such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec.
• pentyloxy isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyl
• Cycloalkyl is to be understood as meaning 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.
• the cycloalkyl radicals can contain one or more heteroatoms, such as oxygen, sulfur and / or nitrogen, instead of the carbon atoms.
• heterocycloalkyls having 3 to 8 ring atoms are preferred.
• Cycloalkenyl is to be understood in each case as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, it being possible for the linkage to take place both on the double bond and on the single bonds.
• Halogen is to be understood as fluorine, chlorine, bromine or iodine.
• Halo-alkyl, halo-alkoxy, etc. is to be understood to mean that the alkyl, alkoxy, etc. is substituted one or more times, identically or differently, by halogen.
• Alkenyl is in each case to be understood as a straight-chain or branched alkenyl radical which contains 2-6, preferably 4-6, carbon atoms.
• the following radicals may be mentioned, for example: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl , But-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but -3-en-1-yl, allyl.
• the aryl radical contains 3 to 12 carbon atoms and can be benzo-fused.
• heteroaryl radical each comprises 3-16 ring atoms and can contain one or more identical or different heteroatoms, such as oxygen, nitrogen or sulfur in the ring, instead of carbon, and can be mono-, bi- or tricyclic, and can additionally be benzo-fused in each case ,
• Examples include:
• the heteroaryl radical can in each case be benzo-condensed.
• Examples include 5-ring heteroaromatics: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and benzo derivatives thereof, and 6-ring heteroaromatics pyridine, pyrimidine, triazine, quinoline, isoquinoline and benzo derivatives.
• Heteroatoms are understood to mean oxygen, nitrogen or sulfur atoms.
• a 3 to 8-membered ring with the meaning of R 2 , R 3 , Y and Z, which is formed together with the nitrogen atom, is to be understood as C 3 -C 8 cycloheteroalkyls and C 3 -C 8 heteroaryls.
• the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as the readily soluble alkali and alkaline earth metal salts and N-methylglucamine, 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.
• physiologically compatible salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid and others.
• the compounds of general formula I according to the invention 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.
• X stands for CH
• W stands for hydrogen
• NR 9 R 10 can be substituted, Y and Z each independently represent a bond, R 2 and R 3 independently represent hydrogen or the group
• R 4 represents C 1 -C 4 -alkyl, aryl or heteroaryl
• R 5 is hydrogen, C r C 6 alkyl, C., - C 12 alkoxy, C 3
• R 6 stands for hydrogen, C, -C 6 alkyl, halo-C C 6 alkyl, aryl, heteroaryl or for the group -NR 9 R 10 , where the aryl or heteroaryl itself may be substituted one or more times, identically or differently, with C r C 6 -alkyte, C r C 6 -alkoxy, halogen or haio-C C 6 -alkoxy, R 7 and R 8 independently from each other are hydrogen or C 1 -C 6 -alkyl, R 9 and R 10 independently of one another are hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, aryl, C 3 -C 8 -cycloalkyl or for the -CONR 7 R 8 group , or optionally one or more, identical or different with aryl, morpholino, hydroxy, halogen,
• R 11 for C ⁇ Ce alkyl, C r C 6 alkoxy, hydroxy-C 1 -C 6 alkyl, hydroxy-C ⁇ C 6, alkoxy, C 3 -C 6 cycloalkyl, phenyl, pyridyl, biphenyl or naphthyl is, the phenyl itself be substituted one or more times, identically or differently with C r C 6 alkyl or halo-C., - C 6 alkyl can mean, and their isomers, diastereomers, tautomers and salts.
• X stands for CH
• W stands for hydrogen
• A, B, D, E and Q together as a ring represent pyridyl
• R 1 represents phenyl, quinolinyl, isoquinolinyl or indazolyl, which may be one or more, identical or different, with halogen, hydroxy, C, -C 6 -alkyl, C 2 -C 6 -alkynyl, C., - C 6 -alkoxy, Halo C, -C 6 alkyl or can be substituted, the C, -C 6 alkyl optionally also with the group -OR 5 or -
• NR 9 R 10 may be substituted, Y and Z each independently for a bond or for the
• R 2 and R 3 independently represent hydrogen or the group -CONR 9 R 10 , -SO 2 R 6 , -COR 11 , -COC r C 6 alkyl, -CO-C ⁇ Ce-alkyl -R 11 ,
• R 7 and R 8 independently of one another represent hydrogen or CC 6 -alkyl
• R 9 and R 10 independently of one another represent hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -
• Halogen, C., - C 12 alkoxy or substituted with the group -NR 7 R 8 stand, where the phenyl itself can be substituted one or more times, identically or differently with C 1 -C 6 -alkoxy or halo-C r C 6 alkyl, and R 11 is Hydroxy-C r C 6 -alkyl, hydroxy-C r C 6 -alkoxy, C 3 -C 6 -cycloalkyl, phenyl, pyridyl, biphenyl or naphthyl, the phenyl itself being one or more, identical or different with C, -C 6 alkyl or halo-C r C 6 alkyl may be substituted, and their isomers, diastereomers, tautomers and salts.
• the compounds according to the invention and their physiologically tolerable salts prevent tyrosine phosphorylation or stop persistent angiogenesis and thus the growth and spread of tumors, in particular being characterized by less inhibition of isoforms of the cytochrome P 450 (3A4).
• the medication with the compounds according to the invention can therefore be carried out without risk, regardless of the medicinal products administered concurrently, which are broken down via these isoforms.
• the compounds of the formula I and their physiologically tolerable salts can be used as medicaments on account of their inhibitory activity with regard to phosphorylation of the VEGF receptor.
• the compounds according to the invention are suitable for the treatment of diseases which are caused or promoted by persistent angiogenesis.
• the compounds of the formula I are identified as inhibitors of the tyrosine kinase KDR and FLT, they are particularly suitable for the treatment of diseases which are caused or promoted by persistent angiogenesis triggered by the VEGF receptor or an increase in vascular permeability.
• the present invention also relates to the use of the compounds according to the invention as inhibitors of the tyrosine kinase KDR and FLT.
• the present invention thus also relates to medicaments for the treatment of tumors and their use.
• the compounds of the invention can either all or in formulation as a drug for the treatment of tumor or metastatic growth, 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 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 use of mechanical devices for keeping vessels open, such as. B. stents
• VEGF-related edema can also be suppressed.
• Lymphangiogenesis plays an 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 according to the invention now also show excellent activity as VEGFR kinase 3 inhibitors and are therefore also suitable as effective inhibitors of lymphangiogenesis.
• Treatment with the compounds according to the invention not only reduces the size of metastases, but also reduces the number of metastases.
• the invention thus further relates to the use of the compounds of the general formula I for the manufacture of a medicament for use as or for the treatment of tumor or metastatic growth, 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 for inhibiting the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after the insertion of mechanical devices for keeping
• VEGF-related edema can also be suppressed.
• a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, milk sugar , Starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.
• the pharmaceutical preparations can be in solid form, for example as tablets, dragées, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
• Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
• Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
• Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as a juice, to which a sweetener or, if necessary, one or more flavorings is added.
• the dosage of the active ingredients can vary depending on the route of administration, age and
• 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.
• R y is C r C 6 alkyl or hydrogen and FG is a leaving group such as halogen, O-triflate, O-mesylate, O-tosylate or sulfone, first converted into an amide and then the leaving group substituted by an N (VR 2 ) -R 3 group, or a compound III
• R 2 R 3 Y and Z have the meanings given in the general formula I and R y is C r C 6 alkyl or hydrogen, first saponified and then converted into the amide.
• the amide formation takes place according to methods known from the literature.
• An appropriate ester can be used to form the amide.
• the ester is reacted with aluminum trimethyl and the corresponding amine in solvents such as toluene at temperatures from 0 ° C. to the boiling point of the solvent. If the molecule contains two ester groups, both are converted into the same amide.
• solvents such as toluene at temperatures from 0 ° C. to the boiling point of the solvent.
• the molecule contains two ester groups, both are converted into the same amide.
• sodium hexamethyl disilazide can also be used.
• amide formation all methods known from peptide chemistry are also available for amide formation.
• aprotic polar solvents such as, for example, dimethylformamide
• 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.
• the reaction between carboxylic acid and amine can also be carried out by activating reagents such as HATU (N-dimethylamino-1H-1, 2,3-triazolo- [4,5-b] pyridin-1-ylmethylene] -N-methylmethanaminium hexafluorophosphate-N- oxide), polar aprotic solvents such as dimethylformamide being suitable for the reaction.
• HATU N-dimethylamino-1H-1, 2,3-triazolo- [4,5-b] pyridin-1-ylmethylene] -N-methylmethanaminium hexafluorophosphate-N- oxide
• polar aprotic solvents such as dimethylformamide
• the addition of a base such as N-methylmorpholine is necessary.
• the reaction takes place at temperatures of 0-100 ° C, preferably at room temperature, but in some cases heating is essential.
• Cyclic compounds can be formed in the case of bis acid chlorides. Cyclic compounds can also be formed with haloacid halides. The ring closure is then optionally carried out by adding a strong base, such as sodium alcoholates. The same applies to the sulfonic acid halides, although double sulfonations can also occur.
• the ureas are produced from amino compounds by reaction with isocyanates.
• Inert solvents such as methylene chloride or dimethylformamide at temperatures from room temperature to 100 ° C, preferably at 60 ° C. Pressure is favorable for the reaction.
• halopyridines with amides is carried out with catalysis, for example by palladium or copper catalysis.
• copper catalysis (literature, see Synlett. 2002, 427), solvents such as dioxane or dimethylformamide are used at temperatures up to the boiling point of the solvent, preferably 120 ° C. Potassium phosphate or also gesium carbonate is used as the base. Ethylene diamine is advantageous for complexing the copper (I) iodide used as catalyst. Applying pressure is not harmful.
• palladium (II) salts such as palladium (II) acetate
• palladium (O) complexes such as palladium (O) 2 dibenzylidene acetone 3
• Solvents are preferably toluene, dioxane or dimethylformamide at temperatures from room temperature to the boiling point of the solvent 100 ° C used.
• BINAP, DPPF or Xanthphos are used as co-ligands.
• a base is also required. To do this, use cesium carbonate, potassium phosphate or sodium t-butoxide. back.
• the pyridinamines are prepared from the corresponding 2-halopyridines in solvents such as pyridine or in protic polar solvents such as ethylene glycol at temperatures up to 200 ° C. Catalysis by copper (l) salts can be beneficial for the reaction. The use of pressure is absolutely necessary in the case of the conversion of low-boiling amines, but can also be used advantageously for the other amines.
• the ether cleavage can be achieved by known methods, for example by reaction with boron tribromide in inert solvents such as methylene chloride at temperatures from -78 ° C. to room temperature, preferably at -78 ° C.
• Examples 3.15 and 3.29 are prepared analogously to Example 3.0 using trimethylsilyl isocyanate.
• Example 3.30 is prepared analogously to Example 3.0 using trimethylsilyl isocyanate.
• 2-Bromo-4-formyl-pyridine can also be prepared in 2 stages from 2-bromo-4-picoline according to THL 42, 6815 (2001). Level 2
• Methylmorpholine and 0.729 g (1.92 mmol) of O- (7-azabenzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate (HATU) in 25 ml of dimethylformamide are stirred for 16 hours at room temperature.
• the dimethylformamide is removed in an oil pump vacuum.
• the remaining residue is taken up in saturated sodium bicarbonate solution. It is extracted three times with ethyl acetate, and the combined organic phases are dried, filtered and concentrated.
• Stock solution A 3mM ATP in water pH 7.0 (-70 ° C)
• Stock solution B g-33P-ATP 1mCi / 100 ⁇ l
• Substrate solvent 10mM DTT, 10 mM manganese chloride, 100 mM
• Magnesium chloride enzyme solution 120 mM Tris / HCl, pH 7.5, 10 ⁇ M sodium vanadium oxide
• Enzyme solution 11, 25 ⁇ g enzyme stock solution (KDR or FLT-1 kinase) are diluted in 1, 25ml enzyme solution at 4 ° C). It is mixed thoroughly and incubated at room temperature for 10 minutes. Then add 10 ⁇ l stop solution (250mM EDTA, pH 7.0), mix and transfer 10 ⁇ l of the solution to a P 81 phosphocellulose filter. It is then washed several times in 0.1 M phosphoric acid. The filter paper is dried, coated with Meltilex and measured in the micro beta counter. The IC5O values are determined from the inhibitor concentration which is necessary to inhibit phosphate incorporation to 50% of the uninhibited incorporation after deduction of the blank value (EDTA-stopped reaction).
• cytochrome P450 inhibition was according to the publication by Crespi et al. (Anal. Biochem., 248, 188-190 (1997)) using baculovirus / insect cell-expressed human cytochrome P 450 isoenzyme (3A4).

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