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  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
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  • C07D213/02—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
  • 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
  • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• R a -R f from Z or to R, a bridge with up to
• Y stands for the group - (CH 2 ) P ,
• R 1 represents phenyl, pyridyl, 5-chloro-2,3-
• R 2 represents hydrogen or C ⁇ alkyl or with
• C ⁇ alkyl mean, and their isomers and salts.
• R 2 represents hydrogen or methyl
• R 3 represents pyridyl or phenyl, pyridyl or 1, 2,3,4-tetrahydronaphthyl or the group substituted by hydroxy, halogen, methyl or methoxy
• R 4 and R 7 are independently hydrogen or
• R 1 is phenyl, pyridyl, 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-1H-indol-3-yl, naphthyl, 1, 2,3,4-tetrahydronaphthyi, benzo -1, 2,5-oxadiazole or 6,7-dimethoxy-1, 2,3,4-tetrahydro-2-naphthyl or for one or more with CC 4 alkyl, CC 4 alkoxy, hydroxy, halogen, trifluoromethyl , substituted phenyl or pyridyl or for the group
• R 5 and R 6 independently of one another represent hydrogen
• R 10 represents hydrogen or methyl, and their isomers and salts.
• R 2 represents hydrogen or methyl
• R 3 represents pyridyl or phenyl, pyridyl or 1, 2,3,4-tetrahydronaphthyl substituted by one or more hydroxyl, halogen, methyl or methoxy groups, or the group
• R 4 and R 7 are independently hydrogen and
• R 9 represents hydrogen
• W represents two hydrogen atoms
• Y stands for the group -CH 2 -
• R 2 represents hydrogen or methyl
• R 3 represents pyridyl or phenyl, pyridyl or 1, 2,3,4-tetrahydronaphthyl substituted by one or more hydroxyl, halogen, methyl or methoxy groups, or the group
• R 10 represents hydrogen or methyl, and their isomers and salts.
• the compounds of the invention prevent phosphoryiation, i.e. H. certain tyrosine kinases can be selectively inhibited, whereby persistent angiogenesis can be stopped. This prevents the growth and spread of tumors, for example.
• 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.
• 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. Because of their activity profile, the compounds according to the invention are suitable for the treatment of
• 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 by the 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.
• the compounds according to the invention can be used either alone or in formulations 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 nephrosic syndrome, malignant nephrosic syndrome, Transplant rejection and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferative diseases, atherosclerosis and injuries to the nerve tissue are used.
• arthritis such as rheumatoid arthritis, hemangioma, angiofribroma
• eye diseases such as diabetic retinopathy, neovascular glaucoma
• kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosic
• the compounds of the invention can also be used to inhibit the reocclusion of vessels after balloon catheter treatment. lung, in vascular prosthetics or after the insertion of mechanical devices to keep vessels open, such as. B. Stents.
• VEGF-related edema can also be suppressed.
• Kidney diseases 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, injuries of the nerve tissue, inhibition of ballon, or inhibition of the therapy after reclamation after reocclusion after reocclusion mechanical devices to keep open vessels such.
• B. Stents 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, injuries of the nerve tissue, inhibition of ballon, or inhibition of the therapy after reclamation after reocclusion after reocclusion mechanical devices to keep open vessels such.
• 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.
• Lactose corn or potato starch, suitable. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
• the daily dose is 0.5-1000 mg, preferably 50-200 mg, and the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
• R 4 to R? have the above meaning and TH or a protective group and A is halogen or OR 13 , where R 13 denotes a hydrogen atom, C 1-4 alkyl or C 1-4 acyl or closes a ring with T, first alkylates N and then converts COA to an amide and then optionally splitting off protective groups or first converting them into that amide and then N-alkylating or b) orthometallized a compound of the formula III in which R 4 to 7 have the meaning given above and TH or a protective group and then intercepting them with an electrophile Transferred amide, then cleaves the protecting group and alkylates the amino group, or
• R 4 to R? have the above meaning and mean TH or a protective group and B halogen or O-triflate, O-tosylate or O-mesylate converted into an amide, then the protective group is split off and the amino group is alkylated
• 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.
• solvents such as toluene at temperatures from 0 ° C. to the boiling point of the solvent.
• This method can also be used for unprotected anthranilic acid esters. If the molecule contains two ester groups, both are converted into the same amide.
• amidines are obtained under analogous conditions.
• amide formation all methods known from peptide chemistry are also available for amide formation.
• aprotic polar solvents such as dimethylformamide
• an activated acid derivative for example obtainable with hydroxybenzotriazole and a carbodiimide such as diisopropylcarbodiimide or with pre-formed reagents such as HATU (Chem. Comm. 1994, 201) or BTU , at temperatures between 0 ° C and the boiling point of the
• Solvent preferably at 80 ° C with the amine at HATU preferably at room temperature. These methods are also with the to use unprotected anthranilic acids.
• the process using the mixed acid anhydride, imidazolide or azide can also be used for the amide formation. Prior protection of the amino group, for example as an amide, is not necessary in all cases, but can have a favorable effect on the reaction.
• a special starting material is isatoic anhydrides, in which the protection of the amino group and the activation of the acid function are present at the same time.
• the BOC amides are cleaved by treatment with acids such as trifluoroacetic acid without solvent or in solvents such as methylene chloride at temperatures from 0 ° C. to the boiling point of the solvent or with aqueous hydrochloric acid, preferably 1 N hydrochloric acid in solvents such as ethanol or dioxane at temperatures from room temperature to the boiling point of the solvent.
• acids such as trifluoroacetic acid without solvent or in solvents such as methylene chloride at temperatures from 0 ° C. to the boiling point of the solvent or with aqueous hydrochloric acid, preferably 1 N hydrochloric acid in solvents such as ethanol or dioxane at temperatures from room temperature to the boiling point of the solvent.
• Transition metal catalysts such as palladium (II) chloride or palladium (II) acetate or palladium tetrakistriphenylphosphine in ⁇
• Solvents such as dimethylformamide are implemented.
• a ligand such as triphenylphosphine and the addition of a base such as tributylamine can be advantageous. (see for example J. Org. Chem. 1974, 3327; J. Org. Chem. 1996, 7482; Synth. Comm. 1997, 367; Tetr.Lett 1998, 2835)
• the second ester group for example, must be introduced into the molecule after the first amide group has been generated and then amidated, or one molecule has one group as an ester, the other as an acid and amidates the two groups successively according to different methods.
• Thioamides are derived from the anthranilamides by reaction with diphosphadithians according to Bull Soc.Chim.Belg. 87, 229, 1978 or by reaction with phosphorus pentasulfide in solvents such as pyridine or without solvents at temperatures from 0 ° C. to 200 ° C. .
• the reduction of the nitro group is carried out in polar solvents at room temperature or elevated temperature.
• Suitable catalysts for the reduction are metals such as Raney nickel or noble metal catalysts such as palladium or platinum or also palladium hydroxide, optionally on supports.
• metals such as Raney nickel or noble metal catalysts such as palladium or platinum or also palladium hydroxide, optionally on supports.
• hydrogen ammonium formate, cyclohexene or hydrazine, for example, can also be used in a known manner.
• Reducing agents such as tin-II-chloride or titanium - ([li) -chloride can be used as well as complex metal hydrides possibly in the presence of heavy metal salts. Iron can also be used as a reducing agent.
• the reaction is then carried out in the presence of an acid such as e.g. Acetic acid or ammonium chloride optionally carried out with the addition of a solvent such as water, methanol, etc. With an
• alkylation can be carried out by customary methods - for example using alkyl halides - or using the Mitsunobu variant by reaction with an alcohol in the presence of, for example, triphenylphosphine and azodicarboxylic acid esters.
• the amine can also be subjected to a reductive alkylation with aldehydes or ketones, the reaction being carried out 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.
• the Schiff base may be advantageous to first form the Schiff base by reacting the aldehyde with the amine in solvents such as ethanol or methanol, optionally with the addition of auxiliaries such as glacial acetic acid, and only then reducing agents such as. B. add sodium cyanoborohydride.
• the hydrogenation of alkene or alkyne groups in the molecule is carried out in the usual way, for example by catalytically excited hydrogen.
• Heavy metals such as palladium or platinum, optionally on a support or Raney nickel, can be used as catalysts.
• Alcohols such as e.g. Ethanol in question.
• the process is carried out at temperatures from 0 ° C. to the boiling point of the solvent and at pressures up to 20 bar, but preferably at room temperature and normal pressure.
• catalysts such as a Lindlar catalyst, triple bonds can be partially hydrogenated to double bonds, the Z form preferably being formed.
• acylation of an amino group is carried out in a customary manner, for example using an acid halide or acid anhydride, optionally in the presence of a base such as dimethylaminopyridine in solvents such as methylene chloride, tetrahydrofuran or pyridine, according to the Schotten-Baumann variant in aqueous solution at a weakly alkaline pH or by reaction with an anhydride in glacial acetic acid.
• a base such as dimethylaminopyridine
• solvents such as methylene chloride, tetrahydrofuran or pyridine
• the introduction of the halogens chlorine, bromine, iodine or the azido group via an amino group can also be carried out, for example, according to Sandmeyer, by reacting the diazonium salts formed intermediately with nitrites with copper (l) chloride or copper (l) bromide in the presence of the corresponding acid such as hydrochloric acid or Hydrobromic acid or reacted with potassium iodide. If an organic nitrous acid ester is used, the halogens can be introduced, for example, by adding methylene iodide or tetrabromomethane in a solvent such as dimethylformamide.
• the removal of the amino group can be accomplished either by reaction with an organic nitric acid ester in tetrahydrofuran or by diazotization and reductive boiling of the diazonium salt, for example with phosphorous acid, optionally with the addition of copper (I) oxide.
• Fluorine can be introduced, for example, by the Balz-Schiemann reaction of diazonium tetrafluoroborate or by J. Fluor. Chem. 76, 1996, 59-62 by diazotization in the presence of HFxPyridin and subsequent boiling, if necessary in the presence of a fluoride ion source such as e.g. Tetrabutylammonium fluoride.
• a fluoride ion source such as e.g. Tetrabutylammonium fluoride.
• the azido group can be introduced after diazotization by reaction with sodium azide at room temperature.
• Ether cleavages are carried out according to methods customary in the literature. Selective cleavage can also be achieved with several groups present in the molecule.
• the ether is treated, for example, with boron tribromide in solvents such as dichloromethane at temperatures between -100 ° C to the boiling point of the solvent, preferably at -78 ° C.
• solvents such as dichloromethane
• the temperature can preferably be between 150 ° C. and between room temperature and the boiling point of the solvent.
• N- or O-alkylation of amides such as pyrid-2-one or 2-hydroxypyridine is achieved using methods known from the literature.
• bases such as sodium hydride or potassium carbonate in solvents such as dimethylformamide and alkylation with alkyl halides such as methyl iodide
• alkyl halides such as methyl iodide
• an O-alkylation is also obtained in the reaction with inert trialkyloxonium tetrafluoroborate
• the isomer mixtures can be separated into the enantiomers or E / Z isomers by customary methods such as, for example, crystallization, chromatography or salt formation.
• the salts are prepared in the customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is optionally in solution, and removing the precipitate or working up the solution in the customary manner.
• Y stands for the group -CH 2 -
• R 3 is pyridyl or phenyl substituted by hydroxyl, bromine, methyl or methoxy or 1, 2,3,4-
• R 5 and R 6 are hydrogen, chlorine, methyl, methoxy or
• R 4 and R 7 are hydrogen, RR a9 is hydrogen, and their isomers and salts.
• the intermediates are partially active themselves and can thus also be used to produce a medicament for the treatment of tumors, psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofribroma, eye diseases, such as diabetic retinopathy, neovascuiar glaucoma, kidney diseases, such as glomerulonephritis, diabetic malignant nephropatia , thrombic microangiopatic syndromes, transplant rejection and glomerulopathy, fibrotic diseases such as cirrhosis of the liver, mesangial cell proliferative diseases, atherosclerosis, injuries to the nerve tissue, inhibition of reocciusion of vessels after balloon catheter treatment, in the case of vascular prosthesis or after the insertion of mechanical devices, such as after the insertion of mechanical devices, for the insertion of mechanical devices.
• a mixture of 7.5 g of methyl anthranilate and 8.6 g of pyridine-4-carbaldehyde in 300 ml of methanol is mixed with 3 ml of acetic acid under a nitrogen atmosphere and stirred for 12 hours at room temperature.
• the reaction mixture is then mixed with 5.7 g of sodium cyanoborohydride (85%) and stirred for a further 3 hours at room temperature. After this time, another 14.1 g of sodium cyanoborohydride (85%) are added and the mixture is stirred for a further 12 hours at room temperature.
• the reaction mixture is concentrated. The residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The dried organic phase is evaporated and the residue is purified by column chromatography on silica gel using hexane / ethyl acetate (1 +1).
• N- (4-pyridylmethyl) anthranilic acid are placed in 10 ml of dimethylformamide under argon and with the exclusion of moisture.
• 266 mg of 5-aminoindazole, 0.27 ml of methylmorpholine and 456 mg of 0- (7-azabenzotriazol-1-yl) -N, N, N ', N ' - tetramethyluronium hexafluorophosphate (HATU) are added.
• the mixture is then stirred for 4 hours at room temperature.
• dilute sodium hydrogen carbonate solution is added and the mixture is extracted three times with ethyl acetate.
• the combined organic phases are washed with water, dried, filtered and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate as the eluent.

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