MXPA01004692A - Antrhranilic acid amides and the use thereof as medicaments - Google Patents

Abstract

The invention relates to anthranilic acid amides and the use thereof as medicaments for the treatment of diseases that are triggered by persistent angiogenesis, in addition to intermediate products in the production of anthranilic acid amides.

Description

AMIDAS OF ANTRANILIC ACID AND ITS USE AS PHARMACEUTICAL AGENTS DESCRIPTION OF THE INVENTION The invention relates to anthranilic acid amides and their use as pharmaceutical agents for the treatment of diseases that are triggered by persistent angiogenesis, as well as their intermediates for the production of anthranilic acid amides. Persistent angiogenesis can be the cause of various diseases, such as psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases, such as diabetic retinopathy, neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic nephropathy, nephrosclerosis malignant, thrombotic microangiopathic syndrome, rejections of transplants and glomerulopathy, fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, and arteriosclerosis, or may result in a progression of these diseases. A direct or indirect inhibition of the VEGF receptor can be used for the treatment of such diseases and other pathological angiogenesis induced by VEGF and vascular permeable conditions, such as tumor vascularization. For example, it is known that by the soluble receptors and antibodies against VEGF, the growth of the tumors can be inhibited. Persistent angiogenesis is induced by VEGF factor through its receptor. Thus VEFG i can exert this action it is necessary that VEGF binds to the receptor and originates a tyrosine phosphorylation. The phenyl anthranilamide derivatives are already known, so that they are used as angiotensin II antagonists (EP 564 356) and as anti-inflammatory agents and anti-ulcer compounds (U.S. 3, 409, 668). It has now been found that the compounds of the general formula I wherein A means the group = NR2 W means oxygen, sulfur, two hydrogen atoms or the group = NR8, Z means the group- = NR10 or = N-, -N (R10) - (CH2) q-, alkyl branched or unbranched from 1 to 6 carbon atoms, or the group or A, Z and R1 together form the group m, nyo mean 0-3, q means 1-6, Ra, Rb, Re-Rdí Rí fí independently of each other, they mean hydrogen, alkyl of 1 to 4 carbon atoms or the group = NR10 and / or Ra and / or Rb can form a bond with Rc, and / or R or Rc can form a bond with Re and / or Rf, or up to two of the radicals Ra -Rf can bridge a bridge with up to 3 carbon atoms each to form R1 or R2, X means the group = NR9 or = N-, Y means the group - (CH2) P, p means 1 to 4, R1 means alkyl of 1 to 6 carbon atoms which is unsubstituted or is optionally substituted on one or more sites with halogen, alkyl of 1 to 6 carbon atoms, in one or more sites with halogen, or aryl or heteroaryl which is substituted with alkoxy of 1 to 6 carbon atoms, with the exception of the compounds in which aryl is bound just in the group = NR2 in the meaning of A, R2 means hydrogen or an alkyl group of 1 to 6 carbon atoms, or forms a bridge with up to 3 members in the ring with Ra-Rf from Z or to form Ri, R3 means aryl or monocyclic or bicyclic heteroaryl, which is unsubstituted or optionally substituted at one or more sites with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or hydroxyl, R 4, R 5, R 6, and R 7 independently of one another, mean hydrogen, halogen, or alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms or carboxyalkyl of 1 to 6 carbon atoms which is unsubstituted or optionally substituted at one or more sites with halogen, or R5 and Rd together form the group H2 R8, R9, and R, independently of one another, mean hydrogen or alkyl of 1 to 6 carbon atoms, as well as their isomers and salts, stop the tyrosine phosphorylation or persistent angiogenesis and thus prevent growth and spread of tumors. If R2 forms a bridge to R1, the heterocycles to which R1 is fused are produced. For example, you can mention: If Ra, R, Rc. R-¡. and? Rfr independently of one another, represent hydrogen or alkyl of 1 to 6 carbon atoms, Z forms an alkyl chain. If Ra and / or Rb form a bond with Rc, and / or Rd or Rc, they form a bond with Re and / or Rf / Z means an alkyl or alkynyl chain. If Ra-Rf forms a bridge on their own, Z represents a cycloalkyl or cycloalkenyl group. If up to two of the Ra-Rf radicals form a bridge with up to 3 carbon atoms to R1, Z together with R1 is a benzo- or heteroaryl-fused cycloalkyl (Ar). For example, you can mention: If one of the Ra-Rf radicals closes a bridge to form R2, a nitrogenous neocycle is formed which can be separated from R1 by a group. For example, you can mention: Alkyl is defined in each case as a straight-chain or branched-chain alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, or hexyl, thereby Alkyl radicals of 1 to 4 carbon atoms are preferred. Cycloalkyl is defined respectively as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkenyl is defined respectively as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, whereby the bond can take place in the double bond and in the single bonds. Halogen is defined respectively as fluorine, chlorine, bromine or iodine.

The alkenyl and alkynyl substituents are in each case straight or branched chain and contain from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms. For example, the following radicals may be mentioned: vinyl, propen-1-yl, propen-2-yl, but-1-en-l-yl, but-l-en-2-yl, but-2-enyl l -yl, but-2-en-2-yl, 2-methyl-prop-2-en-l-yl, 2-methyl-yl-prop-1-en-l-yl, but-l-en-3 -yl, ethynyl, prop-1-yn-l-yl, but-1-yn-l-yl, but-2-yn-l-yl, but-3-en-l-yl, allyl. In each case, the aryl radical has from 6 to 12 carbon atoms, such as, for example, naphthyl, biphenyl, and especially phenyl. In each case, the heteroaryl radical can be benzocondensed. For example, there may be mentioned as five-membered heteroaromatic compounds in the ring: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and benzo derivatives thereof, and as 6-membered heteroaromatic compounds in the ring, pyridine, pyrimidine, triazine, quinoline, isoquinoline, and benzo derivatives, whereby in the case of the heteroaryl radicals, the enalce may be the heterocycle or the benzo ring. In each case the aryl radical and the heteroaryl radical can be substituted by the same or a different component in 1, 2, or 3 sites with halogen, alkoxy of 1 to 4 carbon atoms, nitro, trifluoromethyl, trifluoromethoxy, cyano, SOqR5 or alkyl of 1 to 4 carbon atoms where q means 0-2. If an acid group is included, the physiologically compatible salts of the organic and inorganic bases are suitable as salts, such as, for example, the alkali metal and alkaline earth metal salts are easily soluble 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, l-amino-2,3,4-butanetriol. If a basic group is included, the physiologically compatible salts of the organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, among others. Those compounds of the general formula I in which: A means the group = NR2, W means oxygen, sulfur, two hydrogen atoms or the group = NR8, Z means the group = NR ?, = N or -N (R , 1i0U) • - (CH2) q-, branched or unbranched alkyl of 1 to 6 carbon atoms or the group A, Z and R together form the group m, n, and o mean 0-3, m q means 1-6, Ra, Rb, RC Rd. Re and Rfí independently of each other, they mean hydrogen, alkyl of 1 to 4 carbon atoms or the group = NR10, X means the group = NR9 or = N-, Y means the group - (CH2) P, p means 1-4, R1 means phenyl, pyridyl , 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-lH-indol-3-yl, naphthyl, 1,2,3,4-tetrahydronaphthyl, benzo-1,2, 5-oxadiazole, 6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl or phenyl or pyridyl which is substituted at one or more sites with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon, hydroxyl, halogen or trifluoromethyl atoms, or the group Whereby phenyl, substituted phenyl or naphthyl is not just in the group = NR2 in the meaning of A, R2 means hydrogen or alkyl of 1 to 6 carbon atoms or forms a bridge with up to three members in the ring with Ra-Rf starting from Z or to form Rx, R means monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl, which is unsubstituted or optionally substituted at one or more positions with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon or hydroxyl atoms, R 4, R 5, R 6, and R 7, independently of one another, mean hydrogen, halogen, or alkoxy of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms which is unsubstituted or optionally substituted in one or more positions with halogen, or R5 and R6 together form the group 2 R8, R9 and R10 independently of each other, mean hydrogen or alkyl of 1 to 6, as well as their isomers and salts, have proven to be especially effective.

Also especially preferred are the compounds of the formula I in which: A means the group W means oxygen, sulfur or two hydrogen atoms, Z means the group = NR10, = N-, -N (R10) - (CH2) q- or the group A, Z and R1 together form the group m, nyo means 0-3, q means 1-6, Ra / Rb / RC / Rd / Re / Rf independently of one another, they mean hydrogen or methyl or the group = NR10 X means the group = NR9 or = N-, Y means the group -CH2-, R1 signifies phenyl, pyridyl, 5-chloro-2,3-dihydroindenyl, 2,3-dihiroindenyl, thienyl, 6-fluoro-lH-indol-3-yl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, benzo-1,2,5-oxadiazole, 6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl or phenyl or pyridyl which are substituted at one or more sites with alkyl from 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, halogen, trifluoromethyl, or the group whereby the phenyl or substituted phenyl or naphthyl is not used in the group = NR2 in the meaning of AR 'means hydrogen or methyl, R3 means pyridyl, or phenyl, pyridyl or 1,2,3,4-tetrahydronaphthyl which is substituted with hydroxyl, halogen, methyl or methoxy, or the group R5 and Rd independently of one another, meaning hydrogen, halogen, methyl, methoxy or trifluoromethyl, R4 and R7 independently of one another, signify hydrogen or halogen, R9 signifies hydrogen, R10 signifies hydrogen or methyl as well as their isomers and salts.

Those compounds of the general formula I in which: A means the group = NR2 W means oxygen, Z means the group = NR10, = N-, -N (R10) - (CH2) q- or the group or A, Z and R together form the group m, nyo mean 0-3, q means 1-6 Ra, Rb, R / Rd / Re / Rf / independently of one another, they mean hydrogen or methyl or the group = NR10, X means the group = NR9 or = N- , Y means the group -CH2-, Ri means phenyl, pyridyl, 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-lH-indol-3-yl, naphthyl, 1,2 , 3,4-tetrahydronaphthyl, benzo-1,2,5-oxadiazole or 6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl or a phenyl or pyridyl which is substituted at one or more positions with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, halogen, trifluoromethyl, or the group by which phenyl, or substituted phenyl or naphthyl is not just in the group = NR2 in the meaning of A , R £ signifies hydrogen or methyl, R Means pyridyl or phenyl, pyridyl or 1,2,3,4-tetrahydronaphthyl which is substituted at one or more positions with hydroxyl, halogen, methyl or methoxy, or the group.

R5 and R6, independently of one another, mean hydrogen, halogen, methyl, methoxy or trifluoromethyl R4 and R7 independently of one another mean hydrogen and halogen R- means hydrogen R10 means hydrogen or methyl as well as its isomers and salts, have proven to be very especially effective. Those compounds of the general formula I in which: A means the group = NR2, W means sulfur, Z means the group = NR10, -N (R10) - (CH2) q- or the group or A, Z and R1 together form the group CO. . TTO rm, nyo mean 0-3 q means 1-6 Ra / Rb / Rc Rd / Re Rf / independently of one another mean hydrogen or methyl or group = NR10, X means group = NR9 or = N- Y means the group -CH2-, R1 means phenyl, pyridyl, 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-lH-indol-3-yl, naphthyl, 1,2,3,4- tetrahydronaphthyl, benzo-1,2,5-oxadiazole or 6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl or phenyl or pyridyl, which is substituted at one or more positions with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, halogen, trifluoromethyl or the group whereby phenyl, or substituted phenyl or naphthyl is not just in the group = NR2 in the meaning of A, R2 means hydrogen or methyl, R3 means pyridyl or phenyl, pyridyl or 1, 2, 3, 4-tetrahydronaphthyl, which is substituted in one or more positions with hydroxyl, halogen, methyl or methoxy, or the group R5 and R6 independently of one another mean hydrogen, halogen, methyl, methoxy or trifluoromethyl, R4 and R7 independently of each other mean hydrogen and halogen, R means hydrogen, R10 means hydrogen or methyl, as well as their isomers and salts, have been tested be very effective Those compounds of the general formula I in which: A means the group = NR2, W means two hydrogen atoms, Z means the group = NR10, = N-, -N (R10) - (CH2) q- or the group A, Z and R1 together form the group m, nyo means 0-3, q means 1-6 Ra Rb / Rc Rd Re / Rf i ndependently one of the other, they mean hydrogen or methyl or the group = NR10, X means the group = NR9 or = N- , Y means the group -CH2-, R1 means phenyl, pyridyl, 5-chloro-2,3-dihydroindenyl, 2,3-d? H? Dromdenyl, thienyl, 6-fluoro-lH-indol-3-yl, naphthyl , 1,2,3,4-tetrahydronaphthyl, benzo-1,2,5-oxadiazole or 6,7-dimethoxy, 1, 2,3,4-tetrahydro-2-naphthyl or phenyl or pyridyl which is substituted in one or more positions with alkyl of one to four carbon atoms, alkoxy, of one to four carbon atoms, hydroxyl, halogen, or trifluoromethyl, or the group whereby phenyl, or naphthyl or phenyl is just in the group = NR, 2 substituted not in 'the meaning of A, R' means hydrogen or methyl, R3 means pyridyl or phenyl, pyridyl or 1, 2, 3, 4-tetrahydronaphthyl which is substituted at one or more positions with hydroxyl, halogen, methyl or methoxy, or the group 4 and R7, independently of one another, mean hydrogen, halogen, methyl, methoxy or trifluoromethyl, R5 and R6, independently of each other, signify hydrogen and halogen, R9 signifies hydrogen, R10 signifies hydrogen or methyl, as well as their isomers and salts, They have proven to be very effective. The compounds according to the invention prevent phosphorylation, for example, certain tyrosine kinases can be selectively inhibited, whereby persistent angiogenesis can be stopped. In this way, for example, the development and spread of tumors is suppressed. The compounds of the general formula I according to the invention also include the possible tautomeric forms and comprise the E or Z isomers, or if a chiral center is present, also the racemates and in enantiomers. The compounds of the formula I and their physiologically compatible salts can be used based on their inhibitory activity with respect to the phosphorylation of the VEGF receptor as a pharmaceutical agent. Based on their action profile, the compounds according to the invention are suitable for the treatment of diseases that are caused by persistent angiogenesis.

Since the compounds of formula I are identified as inhibitors of KDR and FLT tyrosine kinases, they are particularly suitable for the treatment of those diseases that are caused by persistent angiogenesis that is triggered by the VEGF receptor., or an increase in vascular permeability. The object of this invention is also the use of the compounds according to the invention as inhibitors of the tyrosine kinases KFR and FLT. The objects of this invention are thus also pharmaceutical agents for the treatment of tumors. The compounds according to the invention can be used either alone or in a formulation with pharmaceutical agents for the treatment of psoriasis, arthritis, such as rheumatoid arthritis, in hemangioma, angiofibrone, diseases of the eyes, such as diabetic retinopathy, neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, .replacements to transplants and glomerulopathy, fibrotic diseases, such as liver cirrhosis, proliferative diseases of mesangial cells, arteriosclerosis, and nerve tissue damage The compounds according to the invention can also be used in the inhibition of reocclusion of the vessels after balloon catheter treatment, in vascular prostheses or after mechanical devices are used to keep the vessels open, such as, for example, stents. In the treatment of nerve tissue damage, rapid scar formation at damaged sites can be prevented with the compounds according to the invention, for example, scars are prevented before the axons are reconnected to one another . In this way, the reconstruction of the nervous reconnections could be facilitated. The formation of ascites in patients can also be suppressed with the compounds according to the invention. The edema induced by VEGF can also be suppressed. Such pharmaceutical agents, their formulations and uses are also the object of this invention. The invention also relates to the use of the compounds of the general formula I, for the production of a pharmaceutical agent for the treatment of tumors, psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, diseases of the eyes, such as diabetic retinopathy, neovascular glaucoma, renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, microangiopathic thrombotic syndrome, rejection of transplants and glomerulopathy, fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, arteriosclerosis, damage to nervous tissue , inhibition of vessel resolution after balloon catheter treatment, in vascular prostheses or after mechanical devices are used to maintain open vessels such as, for example, stents. To use the compounds of formula I as pharmaceutical agents, the latter are put in the form of a pharmaceutical preparation, which in addition to the active ingredient for enteral or parenteral administration contains suitable inert, inorganic or pharmaceutical support media, pharmaceutical, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talcum, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be present in solid form, for example as tablets, coated tablets, suppositories, capsules, or in liquid form, such as for example solutions, suspensions or emulsions. In addition, these may optionally contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. For parenteral use, suspensions or solutions for injection, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable. As vehicle systems, surface active adjuvants such as salts of bile acids or animal or vegetable phospholipids can also be used., but also, mixtures thereof, as well as liposomes or components thereof. For oral use, especially tablets, coated tablets or capsules with talc and / or hydrocarbon vehicles or binders such as, for example, lactose, corn starch or potato starch are suitable. The application can be carried out in liquid form, such as, for example, juice, to which a sweetener is optionally added.

The dose of the active ingredients may vary depending on the method of administration, the age and weight of the patient, the type and severity of the disease to be treated, and similar factors. The daily dose may be 0.5-1000 mg, preferably 50-200 mg, whereby the dose may be administered as a single dose to be administered once or subdivided into two or more daily doses. The formulations described above and the forms for dispensing them are also the object of this invention. The production of the compounds according to the invention is carried out according to methods that are known in the art. For example, the compounds of formula I are obtained by: a) a compound of formula II wherein R4 to R 'have the above meaning and T is hydrogen or a protecting group, and A is halogen or OR13, wherein R13 means a hydrogen atom, alkyl of 1 to 4 carbon atoms or acyl of 1 to 4 carbon atoms, or a ring is connected to T, first alkylates N and then converts COA to an amide and then the optionally protective groups are cleaved or first converted to the amide and then N-alkylated, or b) a compound of the formula III lll wherein R 4 to R 7 have the above meanings and T means hydrogen or a protecting group, is ortometalated, and then converted to an amide upon being trapped with an electrophile, then the protecting group is cleaved, and the amino group is alkylated, or c) a compound of formula IV wherein R4 to R7 have the above meanings, and T means hydrogen or a protecting group and B means halogen or O-filtrate, O-tosylate or 0-mesylate, is converted to an amide. Then the protecting group is cleaved, and the amino group is rented. The sequence of the stages can be reversed in all three cases. The formation of the amide is carried out according to the methods that are known in the literature. For the formation of the amide, a start can be made from the corresponding ester. The ester is reacted according to J. Org. Chem. 1995, 8414 with aluminum-trimethyl ilo and the corresponding amine in solvents, such as toluene, at temperatures from 0 ° C to the boiling point of the solvent. This method can also be used in unprotected anthranilic acid esters. If the molecule contains two ester groups, both are converted to the same amide. When the nitriles are used instead of ester, the amidines are obtained, under analogous conditions. For the formation of the amide, however, all the processes that are known for the chemistry of the peptides are also available. For example the corresponding acid can be reacted in polar aprotic solvents, such as, for example, dimethylformamide on an activated acid derivative, which can be obtained, for example, with hydroxybenzotriazole and a carbodiimide such as, for example, diisopropylcarbodiimide or even with preformed reagents, such as, for example, 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 in HATU, preferably at room temperature. These methods can also be used in unprotected anthranilic acids. For the formation of the amide, the process can also be used on the mixed acid, imidazolide or azide anhydride. A prior protection of the amino group, for example as an amide, is not necessary in all cases, but it can advantageously affect the reaction. The anhydrides of isatoic acid, in which the protection of the amino group and the activation of the acid functional group are present at the same time, are a special starting material. If the amine is already converted to the BOC-protected compound, the ortho position can be metalated by reaction with organometallic compounds, such as, for example, n-butyllithium, and then trapped with isocyanates or isothiocyanates to form the anthranilamides or anthranilothioamides. A bromo or iodo substituent in this ortho position facilitates ortho-metalation by halogen-metal exchange. As solvents, ethers such as diethyl ether or tetrahydrofuran or hydrocarbon such as hexane, but also mixtures thereof are suitable. The addition of complexing agents, such as tetramethylethylenediamine (TMEDA), is advantageous. Temperatures vary between -78 ° C and room temperature. The cleavage of the BOC-amides is carried out 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 acid aqueous hydrochloric, preferably 1N hydrochloric acid, in solvents such as ethanol or dioxane at temperatures from ambient temperatures to the boiling point of the solvent. However, the amide group can also be introduced by carbonylation. For this purpose, a starting is made from the corresponding compounds of formula IV (o-iodo, o-bromo or o-trifliloxianilina), which are reacted with carbon monoxide at normal pressure or even at increased pressure and an amine in the presence of transition metal catalysts, such as, for example, palladium (II) chloride or palladium acetate (II) or even tetrakis-triphenylphosphine palladium in solvents such as dimethylformamide. The addition of a ligand such as triphenylphosphine and the addition of a base such as tributylamine may be advantageous (see, for example, J. Org. Chem. 1974, 3327; J. Org. Chem 1996, 7482; Synth. Comm. 1997 , 367; Tetr. Lett 1998, 2835). If various amide groups are to be introduced into the molecule, the second ester group must be introduced into the molecule, for example, after the production of the first amide group, and then it must be amidated, or there is a molecule in which it is present one ester group and the other as acid, and the two groups are amidated in succession according to various methods. The thioamides can be obtained from the anthranilamides by reaction with diphosphodies according to Bull Soc. Chim. Belg. 87, 229, 1978 or by reaction with phosphorus pentasulfide in solvents such as pyridine or even without solvent at temperatures of 0 ° C to 200 ° C. As electron-rich aromatic compounds, the products can also be subject to aromatic electrophilic substitutions. The substitution is then carried out in the ortho position or in the para position, to form the amino group or one of the amino groups. This can be acylated by Friedel-Crafts acylation with acid chlorides in the presence of Friedel-Crafts catalysts, such as, for example, aluminum trichloride in solvents such as nitromethane, carbon disulfide, methylene chloride or nitrobenzene. at temperatures between 0 ° C and the boiling point of the solvent, preferably at room temperature. One to more nitro groups can be entered according to. the processes that are known in the literature, for example, by nitration acid, various concentrated nitric acids without solvent or by metal nitrates, such as, for example, copper (II) nitrate or iron (III) nitrate in polar solvents , such as, ethanol or glacial acetic acid or even in acetic anhydride. The introduction of the hhalogens is carried out according to processes that are known in the literature, for example, by reaction with bromine, N-bromine, or N-iodosuccinimide or urotropin tribromhydrate in polar solvents, such as tetrahydrofuran, acetonitrile , methylene chloride, glacial acetic acid or dimethylformamide. The reduction of the nitro group is carried out in polar solvents at room temperature or at elevated temperature. As catalysts for the reduction, metals such as Raney nickel or noble metal catalysts such as palladium or platinum or even palladium hydroxide optionally on vehicles are suitable. Instead of hydrogen, for example, the ammonium formate, cyclohexane or hydrazine can also be used in a known manner. Reducing agents such as tin (II) chloride or titanium (III) chloride can also be used, such as complex metal hydrides, optionally 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, for example, acetic acid or ammonium chloride, optionally with the addition of a solvent, such as, for example, water, methanol, etc. In the case of the prolonged reaction time, the acylation of the amino group can occur in this variant. If an alkylation of the amino group is desired, the alkylation can be carried out according to commonly used methods - for example with alkyl halides - or according to the Mitsunobu variant by reaction with an alcohol in the presence of, for example, triphenylphosphine and azodicarboxylic acid ester. The amine can also be subjected to reductive alkylation with aldehydes or ketones, whereby it is reacted in the presence of a reducing agent, such as, for example, sodium cyanoborohydride in a suitable inert solvent, such as, for example, ethanol , at temperatures from 0 ° C to the boiling point of the solvent. If the start is made from a primary amino group, a reaction can optionally be carried out in succession with two different carbonyl compounds, whereby mixed derivatives are obtained [literature, for example, Verardo et al. Synthesis (1993), 121; Synthesis (1991), 447; Kawaguchi, Synthesis (1985), 701; Micovic et al. Synthesis (1991), 1043]. It may be advantageous to form the Schiff base first by reacting the aldehyde with the amine in solvents such as ethanol or methanol, optionally with the addition of adjuvants such as glacial acetic acid, and then adding only the reducing agent, such as, for example, sodium cyanoborohydride. The hydrogenation of the alkene or alkyne groups in the molecule is carried out in the usual manner, for example, by catalytically activated hydrogen. As catalysts, heavy metals such as palladium or platinum, optionally on a carrier or Raney nickel can be used. As solvents, alcohols are suitable, such as, for example, ethanol. The process is carried out at temperatures of 0 ° C up to the boiling point of the solvent and at pressures of up to 20 bar, but preferably at room temperature and at normal pressure. By using catalysts, such as, for example, a Lindlar catalyst, the triple bonds can be partially hydrogenated in double bonds, whereby the Z-form is preferably produced.

The acylation of an amino group is carried out in the usual manner with, for example, 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 weakly alkaline pH or by reaction with an anhydride in glacial acetic acid. The introduction of the halogen chlorine, bromine, iodine or the azido group via an amino group can also be carried out, for example, according to Sandmeyer, by the diazonium salts which are formed as intermediary products with nitrites which are reacted with copper (I) chloride or copper (I) bromide in the presence of the corresponding acid such as hydrochloric acid or hydrobromic acid or with potassium iodide. If an organic nitrite is used, the halogens can be introduced into a solvent, such as, for example, dimethylformamide, for example, by the addition of methylene iodide or tetrabromomethane. The elimination of the amino group can be achieved either by reaction with an organic nitrite in tetrahydrofuran or by diazotization and reductive boiling of the diazonium salt with, for example, phosphorous acid optionally with the addition of copper (I) oxide. The introduction of fluorine can be carried out by, for example, the Balz-Schiemann reaction of the diazonium tetrafluoroborate or according to J. Fluor. Chem. 76, 1996, 59-62 by diazotization in the presence of HF-pyridine and subsequent boiling optionally in the presence of a source of fluoride ions, such as, for example, tetrabutylammonium fluoride. The introduction of the azido group can be carried out after diazotization by reaction with sodium azide at room temperature. Escisions with ether are made according to the processes that are common in the literature. In this case, selective excision can also be carried out in several groups that are present in the molecule. In this case, the ester is treated with, for example, boron tribromide in solvents such as dichloromethane at temperatures between -100 ° C to the boiling point of the solvent, preferably at -78 ° C. It is also possible, however, to break the ether with sodium thiomethylate, in solvents such as dimethylformamide. The temperature may fall between the ambient temperature and the boiling point of the solvent, preferably at 150 ° C. The N- or O-alkylation of the amides such as pyrid-2-one or 2-hydroxypyridine can be carried out according to methods that are known in the literature. An N-alkylation can thus be achieved with bases such as sodium hydride or potassium carbonate in solvents such as dimethylformamide and alkylation with alkyl halides such as methyl iodide. An O-alkylation with bases such as silver carbonate in solvents such as tetrahydrofuran or toluene or preferably mixtures thereof with alkyl halides, such as methyl iodide. A 0-alkylation is also obtained during the conversion with trialkyloxonium tetrafluoroborate in inert solvents, such as methylene chloride. The mixtures of the N- and O-alkyl derivatives are obtained in the reaction with diazomethane or trimethylsilyldiazomethane in solvents such as methanol or toluene, preferably in mixtures thereof at temperatures up to the boiling point of the solvent, but preferably at room temperature . The methods make possible a selective alkylation of the pyridone relative to the benzoic acid amide.

According to the commonly used methods, such as, for example, crystallization, chromatography or salt formation, mixtures of isomers can be separated into enantiomers or E / Z isomers. The production of the salts is carried out in a usual manner, by a solution of the compound of the formula I which is mixed with the equivalent amount or an excess of a base or acid, which is optionally in solution, and the precipitate which is separate or the solution that is treated in the usual way. If the production of the initial compounds is not described, the latter are known or can be produced analogously to the known compounds or processes described herein. Also the objects of this invention are the isatoic acid derivatives of the general formula V V in which R3-R7, X, Y and W have the meanings described in formula I and in which A means the group = NR2 or oxygen, and Z and R1 together form a group = C = 0 which is bound to X, as well as its isomers and salts, as valuable intermediates for the production of the compounds of the general formula I according to the invention. Especially valuable are those intermediary products of the general formula V in which A and W mean oxygen, Z and R 'together form a group = C = 0 which is attached to X, X means the group = NR9 or = N-, Y means the group -CH2-, R3 means pyridyl or phenyl or 1,2,3,4-tetrahydronaphthyl which is substituted by hydroxyl, bromo, methyl or methoxy, R5 and R6 signify hydrogen, chlorine, methyl, methoxy or trifluoromethyl, R4 and R7 signifies hydrogen, R9 signifies hydrogen, as well as its isomers and salts. The intermediates are partially active on their own or can thus also be used for the production of a pharmaceutical agent for the treatment of tumors, psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, diseases of the eyes, such as diabetic retinopathy, neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, microangiopathic thrombotic syndrome, rejection of transplants and glomerulopathy, fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, arteriosclerosis, damage to nervous tissue , inhibition of vessel reocclusion after balloon catheter treatment, in vascular prostheses or after mechanical devices are used to keep vessels open, such as, for example, stents. The following examples explain the production of the compounds according to the invention, without limiting the scope of the claimed compounds to these examples.

Example 1.0 Production of N- (4-pyridylmethyl) -anthranilic acid methyl ester Under a nitrogen atmosphere, a mixture of 7.5 g of the anthranilic acid methyl ester and 8.6 g of pyridine-4-carbaldehyde in 300 ml of methanol is mixed with 3 ml of acetic acid and stirred for 12 hours at room temperature. Then, the reaction mixture is mixed with 5.7 g of sodium cyanoborohydride (85%) and stirred for another 3 hours at room temperature. After this time, 1.14 g of sodium cyanoborohydride (85%) are again added and stirred for another 12 hours at room temperature. The reaction mixture is concentrated by evaporation. The residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution. The dried organic phase is concentrated by evaporation, and the residue is purified with the use of column chromatography on silica gel with the use of hexane / ethyl acetate (1/1). 1.2 g of the title compound are obtained with a melting point of 85.6 ° C.

Example 2.0 Production of N- (3-phenylprop-1-yl) -N2- (4-pyridylmethyl) -anthranilic acid amide 242 mg of the N- (4-pyridylmethyl) -anthranilic acid methyl ester are introduced into 3.5 ml of toluene, mixed with 202 mg of 3-phenylpropylamine and mixed rapidly at 0 ° C with 0.75 ml of a 2 molar solution of trimethylaluminum in toluene. The reaction mixture is then heated for 1 hour at room temperature and then heated to reflux for 1 hour. After cooling, the reaction mixture is added to the saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is washed, dried, filtered and concentrated by evaporation in vacuo. The residue is then recrystallized from ethyl acetate. 265 mg of the title compound are obtained with a melting point of 117.4 ° C. Produced similarly to Example 2.0 are also the following compounds: R2, R '= H Example 3.0 Production of N- (4-chlorobenzyl) -N2- (4-methoxybenzyl) anthranilamide 425 mg of the acid anhydride was dissolved N- (4-methocephenyl) isatoic in 20 ml of tetrahydrofuran p.A., mixed with 234 mg of 4-chlorobenzylamine and heated at reflux for 4 hours. The reaction solution is concentrated by evaporation in vacuo, taken up in ethyl acetate, washed, dried, filtered and concentrated by evaporation in vacuo. The residue is recrystallized from ethyl alcohol. The title compound is obtained with a melting point of 130.5 ° C. The following compounds are. also produced in a similar way: R 'Ra = H Example 4.0 Production of N- [2- (4-chlorophenyl) ethyl] -N2- (4-hydroxybenzyl) anthranilamide 71 mg of N- [2- (4-chlorophenyl) ethyl] -N2- (4-methoxybenzyl) anthranilamide are dissolved under nitrogen atmosphere in 2 ml of absolute dimethylformamide and mixed with 76 mg of sodium thiomethylate. The reaction mixture is heated to reflux for 1.5 hours. After cooling, it is mixed with 30 ml of water and then extracted with ethyl acetate. The organic phase is washed, dried, filtered and evaporated to dryness in vacuo. The residue is chromatographed on silica gel with hexane + ethyl acetate (7 + 3) as an eluent. 23 mg of the title compound are obtained with a melting point of 103-105 ° C.

Example 5.0 Production of 2- [(2-chloropyridin-4-yl) methyl] amino] -N- (isoquinolin-3-yl) benzoic acid amide 300 mg of the amide of 2 - [amino] - (isoquinolin-3-yl) benzoic acid are mixed in 6 ml of methanol with 0.06 ml of glacial acetic acid and 523 mg of a 39% solution of 2-chloro-4 pyridinecarbaldehyde in methylene chloride and ethyl acetate, and stirred for 20 hours at room temperature under argon. Then, add 96 mg of sodium cyanoborohydride, and stir for 6 hours at room temperature. After concentration by evaporation in vacuo, the residue is taken up in 30 ml of a dilute solution of sodium bicarbonate in water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate as a Gvaporac. The corresponding fractions are combined and concentrated by evaporation to obtain 56 mg of 2- [(2-chloropyridin-4-yl) methyl] amino] -N- (isoquinolin-3-yl) benzoic acid amide. .

The following compounds are also produced nera similar: The following compounds are also produced in a similar manner: • Example 6.0 Production of 2- [[(1,2-dihydro-l-methyl-2-oxopyridin-4-yl) amide methyl] amino] -N- (isoquinolin-3-yl) benzoic acid 80 mg of the amide of 2- [[(1,2-dihydro-2-oxopyridin-4-yl) methyl] amino] -N- (isoquinolin-3-yl) benzoic acid in 2 ml of dimethylformamide is mixed under an atmosphere of argon with 10 mg of sodium hydride (80%) and heated for 30 minutes at 60 ° C. Then, 0.015 ml of methyl iodide in 0.5 ml of dimethylformamide are added dropwise and heated for 1 hour at 60 ° C. After cooling, the batch is added to a solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate phase is washed, dried and concentrated by evaporation, and the residue on silica gel with methylene chloride: ethanol = 97: 3 as an eluent. 30 mg of the 2- [[(1, 2-dihydro-1-methyl-2-oxopyridin-4-yl) methyl] amino] -N- (isoquinolin-3-yl) benzoic acid amide are obtained.

The following compounds are also produced similar nera: Example 7. Production of 2- [(2-methoxypyridin-4-yl) methyl] amino] -N- (isoquinolin-3-yl) benzoic acid amide and 2- [[(1, 2)] amide -dihydro-l-methyl-2-oxopyridin-4-yl) methyl] amino] -N- (isoquinolin-3-yl) benzoic acid 130 mg of the 2- [[(1,2-dihydro-2-oxopyridin-4-yl) methyl] amino] -N- (isoquinolin-3-yl) benzoic acid amide are introduced into 4 ml of a mixture that consists of toluene: methanol = 1: 3.5 and is mixed with 0.2 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane, and stirred for 8 hours at room temperature. After the repeated addition of 0.2 ml of trimethylsilyldiazomethane solution and 1 hour of stirring, the batch is evaporated to the dry state, chromatographed on silica gel with methylene chloride: ethanol = 97: 3 as an eluent. 20 mg of the amide of 2 - [(2-methoxypyridin-4-yl) methyl] amino] -N- (isoquinolin-3-yl) benzoic acid and 10 mg of the amide of the 2 - [[( , 2-dihydro-1-methyl-2-oxopyridin-4-yl) methyl] amino] -N- (isoquinolin-3-yl) benzoic acid.

The following compounds are also produced in a similar manner: Example 8.0 Production of N- (indazol-5-yl) -N2- (4-pyridylmethyl) -anthranilic acid amide 228 mg of N- (4-pyridylmethyl) -anthranilic acid are introduced into 10 ml of dimethylformamide under an argon atmosphere and in a moisture-free environment. 226 mg of 5-aminoindazole, 0.27 ml of methylmorpholine and 456 mg of 0- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate are added.

(HEY YOU) . The mixture is then stirred for 4 hours at room temperature. This is then mixed with dilute sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried, filtered and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with ethyl acetate as an eluent. By absorptive precipitation in acetone, 245 mg of the title compound are obtained with a melting point of 209.8 ° C.

The following compounds are also produced was similar: The following example explains the production of intermediary products according to the invention, without limiting the invention to these examples. Example 9.0 Production of N- (4-methoxybenzyl) isatoic acid anhydride as an intermediate product for the production of the final products according to to the invention. Under a nitrogen atmosphere, a solution consisting of 5 g of isatoic anhydride and 100 ml of N, N-dimethylacetamide is cooled on an ice bath and mixed in portions with 1.35 g of hydride. sodium (approximately 60% oil). The reaction mixture is then stirred for 30 minutes at room temperature and for another 30 minutes at a bath temperature of 60 ° C. After cooling to room temperature, 5 ml of 4-? methoxybenzaldehyde in drops while stirring, and stirring overnight at room temperature. The reaction mixture is concentrated by evaporation in vacuo and is poured into 100 ml of ice / water. The precipitate is separated, taken up in 50 ml of methylene chloride, washed, dried, filtered and concentrated by evaporation in vacuo. The residue is recrystallized from alcohol. 3.4 g of the title compound are obtained with a melting point of 143 ° C. The following compounds are also produced in a similar way: Example 10.0 Production of N- (-pyridylmethyl) -anthranilic acid as an intermediate product for the production of the final products according to the invention 2 g of the N- (4-pyridylmethyl) -anthranilic acid methyl ester are dissolved in 15 ml of methanol, mixed with 16 ml of 1 N sodium hydroxide solution and heated at reflux for 1 hour. After cooling, the methanol is distilled in vacuo, and the residue is mixed with 20 ml of water and 20 ml of 1 N citric acid solution. The crystals are sucked, washed with water and dried. 1.7 g of the title compound are obtained with a melting point of 208.0 ° C.

Example 11.0 Production of N- (indazol-5-yl) -5-chloroanthranilic acid amide as an intermediate product for the production of the final products according to the invention. 171 mg of 5-chloroanthranic acid are introduced into 10 ml of dimethylformamide under an argon atmosphere in a moisture-free environment and mixed in succession with 253 mg of N-methylmorpholine, 266 mg of 5-aminoindazole and 456 mg of hexafluorophosphate. 0- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium (HATU) and stir for 4 hours at room temperature. After standing overnight, it is mixed with 50 ml of water and extracted with 30 ml of ethyl acetate. The organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate as an eluent. 266 mg of the N- (indazol-5-yl) -5-chloroanthranilic acid amide are obtained. The following sample applications explain the biological action and the use of the compounds according to the invention, without limiting the latter to the examples.

Solutions required for the tests Reserve solutions Reserve solution A: 3 mmol of ATP in water, pH 7.0 (-70 ° C) Reserve solution B: g-33P-ATP 1 mCi / 100 μl Reserve solution C: poly- (Glu4Tyr) 10 mg / ml in water Solution for dilutions Solvent of the substrate: 10 mmol of DTT, 10 mmol of manganese chloride, 100 mmol of magnesium chloride Solution of enzyme: 120 mmol of tris / HCl, pH 7.5, 10 μm of sodium and vanadium oxide.

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

In a microtitre plate (without protein binding) that tapers to a point, add 10 μl of the substrate mixture (10 μl vol of ATP A stock solution + 25 μCi of g-33P-ATP ( approximately 2.5 μl of reserve solution B) + 30 μl of buffer solution C poly- (Glu4Tyr) + 1.21 ml of substrate solvent), 10 μl of inhibitor solution (substances corresponding to the dilutions, as a 3% control of DMSO in substrate solvent), and 10 μl of enzyme solution (11.25 μg of the enzyme stock solution (KDR or FLT-1 kinase) is diluted at 4 ° C in 1.25 ml of the enzyme solution). This is mixed thoroughly and incubated for 10 minutes at room temperature. Then, 10 μl of the stop solution (250 mmol of EDTA, pH 7.0) is added, mixed, and 10 μl of the solution is transferred to a P 81 focellulose filter. Then, it is washed several times in acid. 0.1 M phosphoric. The filter paper is dried, coated with Meltilex and measured in a microbeta counter. The IC 50 values are determined from the concentration of the inhibitor, which is necessary to inhibit phosphate incorporation at 50% of the uninhibited incorporation after the removal of the blank reading (reaction stopped by EDTA). The results of the inhibition of kinase, IC50 in μmol are described in the following table: KH = Without Inhibition

Claims (12)

CLAIMS The compounds of the general formula I A means the group = NR W means oxygen, sulfur, two hydrogen atoms or the group = NR8, Z means the group = NR10, = N-, or -N (R10) - (CH2) q-, branched alkyl or not branched from 1 to 6 carbon atoms, or the group A, Z and R1 together form the group m, nyo mean 0-3, q means 1-6, Ra / Rb RC Rd / Re / Rf independently of one another, meaning hydrogen, alkyl of 1 to 4 carbon atoms or the group = NR10 and / or Ra and / or Rb can form a bond with Rc, and / or Rd or Rc can form a bond with Re and / or Rf, X means the group = NR9, Y means the group - (CH2) P, p means 1 to 4, R1 means alkyl of 1 to 6 carbon atoms which is unsubstituted or is optionally substituted at one or more sites with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, nitro, cyano or substituted in one or more sites with halogen, or naphthyl substituted by alkoxy-from 1 to 6 carbon atoms, biphenyl, phenyl, thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl or isoquinolinyl; or 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-lH-indol-3-yl, 1, 2, 3, 4-tetrahydronaphthyl, benzo-l, 2,5-oxadiazole , 6, 7-dimethoxy-1,2; 3, 4-tetrahydro-2-naphthyl, or by group whereby phenyl, substituted phenyl or naphthyl is not just in the group = NR2 in the meaning of A, R2 means hydrogen or alkyl of 1 to 6 carbon atoms, R3 signifies naphthyl, biphenyl, phenyl, thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl or isoquinolinyl which is unsubstituted or optionally substituted at one or more sites with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or hydroxyl, or for the group R4, R5, R6, and R7 independently of one another, mean hydrogen, halogen, or alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms or carboxyalkyl of 1 to 6 carbon atoms which is unsubstituted or optionally substituted at one or more sites with halogen, or R5 and R6 together form the group R8, R9, and R10, independently of one another, mean hydrogen or alkyl of 1 to 6 carbon atoms, as well as their isomers and salts, whereby a) If R9 means hydrogen, Y means the group ~ (CH2) P , wherein p = 1, R 3 signifies phenyl and means oxygenate, R 1 does not mean imidazol-1-yl, and b) If it means oxygen, R 2 signifies hydrogen, R 9 signifies hydrogen, Y signifies the group - (CH 2) P-, in which p =

1-4 and R1 means pyridyl, or Y means the group - (CH2) P-, in which p = l, and R1 means phenyl or phenyl which is substituted at one site by methyl, chlorine or bromine, and Z means methyl or ethyl, R3 must not mean pyridyl, phenyl or phenyl which is substituted at one site by methyl, chlorine or bromine. 2. Compounds of the general formula I, according to claim 1, wherein A means the group = NR2 W means oxygen, sulfur, two hydrogen atoms or the group = NR8, Z means the group = NR10, = N-, or -N (R10) - (CH2) q-, branched or unbranched alkyl of 1 to 6 carbon atoms, or the group A, Z and R1 with just form the group m, n, I mean 0-3, q means 1-6, Ra R, Rc / Rd / Re / Rf independently of each other, mean hydrogen, alkyl of 1 to 4 carbon atoms or group = NR10, X means the group = NR9, Y means the group - (CH2) P, p means 1-4, R1 means phenyl, pyridyl, 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-lH -indol-3-yl, naphthyl, 1,2,3,4-tetrahydronaphthyl, benzo-1,2,5-oxadiazole, 6,7-dimethoxy-1,2,3,4-tetrahydro-

2-naphthyl or phenyl or pyridyl which is substituted at one or more sites with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, halogen, or trifluoromethyl, or the group whereby, phenyl, substituted phenyl or naphthyl is not just in the group = NR2 in the meaning of A R2 means hydrogen or alkyl of 1 to 6 carbon atoms, R3 signifies naphthyl, biphenyl, phenyl, thiophenyl, furanyl, Oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl or isoquinolinyl which is unsubstituted or which is optionally substituted at one or more sites with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or hydroxyl, or- the group R4, R5, R6 and R7, independently of one another, mean hydrogen, halogen or alkoxy of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms, - which is unsubstituted or optionally substituted at one or more sites with halogen, or R5 and R6 together form the group R8, R9 and R10, independently of one another, mean hydrogen or alkyl of 1 to 6 carbon atoms, as well as their isomers and salts, whereby, if W means oxygen, R2 means hydrogen, R9 means hydrogen, Y means the group - (CH2) P, in which p = 1-4, and R1 signifies pyridyl, or Y signifies the group - (CH2) p / in which p = 1, and R1 signifies phenyl or phenyl which is substituted in ' a site with methyl, chlorine or bromine, and z means methyl or ethyl, R3 should not mean pyridyl, phenyl? phenyl that is substituted at a site with methyl, chlorine or bromine. 3. Compounds of the general formula I according to claims 1 and 2, in which: A means the group = NR2, W means oxygen, sulfur or two hydrogen atoms, Z means the group = NR10, = N-, or -N (R10) - (CH2) q- or the group or A, Z and R1 together form the group -y, nyo means 0-3, q means 1-6, Ra / b / RC / R / Re / Rf, independently of one another, mean hydrogen or methyl or group = NR10, X means group = NR9, Y means the group -CH2-, R1 signifies phenyl, pyridyl, p-chlorophenyl, p-methylphenyl, p-methoxyphenyl, 5-chloro-2,

3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-lH-indole 3-yl, naphthyl, 1,2,3,

4-tetrahydronaphthyl, benzo-1,2,

5-oxadiazole, 6,7-dimethoxy-1, 2,3,4-tetrahydro-2-naphthyl, or phenyl or pyridyl which is substituted at one or more places with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, halogen, or trifluoromethyl, or the group whereby phenyl, or substituted phenyl or naphthyl is not just in the group = NR2 in the meaning of A, R means hydrogen or methyl, R means pyridyl or phenyl or 1,2,3,4-tetrahydronaphthyl which is substituted at one or more places with hydroxyl, halogen, methyl or methoxy, or the group R = and R ", independently of one another, mean A. • i mafn? I or trifluoromethyl, hydrogen, halogen, methox, methoxy R. and" ', independently of each other, mean hydrogen, R9 signifies hydrogen, R10 signifies hydrogen or methyl, as well as their isomers and salts, whereby «it means oxygen, R > means hydrogen, R > it means hydrogen, R1 means pyridyl, -1- or phenyl which is substituted in a R1 means phenyl or femio qu methyl chloro or bromo, and Z means methyl or site with methyl, ciozu, f. aridyl or phenyl which is ethyl, R3 must not mean pyridium-1. . e-parrot or bromine, substituted at a site with methyl, chloro 4. Compounds of the general formula I according to claims 1 to 3, wherein: A means the group = NR2, W means oxygen, Z means the group = NR10, = N-, or -N (R10) - (CH2) p- or the group A, Z and R1 together form the group m, nyo means 0-3, q means 1-6, R. Rb / Rr Rd / Rβ Rf, independently of each other, they mean hydrogen or methyl or the group X means the group = NR9, Y means the group -CH2- , R1 means phenyl, pyridyl, 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl,

6-fluoro-lH-indol-3-yl, naphthyl, 1,2,3,4-tetrahydronaphthyl, benzo -1, 2, 5-oxadiazole, or 6,

7-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl or phenyl or pyridyl which is substituted at one or more sites with alkyl of 1 to 4 carbon atoms , alkoxy of 1 to 4 carbon atoms, hydroxyl, halogen, or trifluoromethyl, or the group whereby phenyl, or substituted phenyl or naphthyl is not just in the group = NR2 in the meaning of A, R2 means hydrogen or methyl, R3 means pyridyl or phenyl, pyridyl or 1,2,3,4-tetrahydronaphthyl which is substituted at one or more sites with hydroxyl, halogen, methyl or methoxy, or the group R5 and R6, independently of one another, mean hydrogen, halogen, methyl, methoxy, or trifluoromethyl, R4 and R7, independently of one another, mean hydrogen and halogen, R9 signifies hydrogen, R10 signifies hydrogen or methyl, as well as their isomers and salts, whereby if R means hydrogen, R1 means pyridyl, or R1 means phenyl or phenyl which is substituted at one site by methyl, chlorine or bromine, and Z means methyl or ethyl, R3 does not mean pyridyl or phenyl which is substituted in a place with methyl, chlorine or bromine. 5. Compounds of the general formula I according to claims 1 to 3, in which A means the group = NR2, means sulfur, Z means the group = NR10, = N-, -N (R10) - (CH2) q- or the group A, Z and R together form the group m, nyo mean 0-3, q means 1-6, Ra, Rb / RC R / Re / f / independently of each other, they mean hydrogen or methyl or the group = NR10, X means the group = NR9, Y means the group -CH2-, R1 means phenyl, pyridyl, 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-lH-indol-3-yl, naphthyl, 1,2,3,4 -tetrahydronaphthyl, benzo-1,2,5-oxadiazole, or 6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl 'or phenyl or pyridyl which is substituted at one or more sites with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, halogen, or trifluoromethyl, or the group which phenyl, or substituted phenyl or naphthyl not co n is just in the group = NR2 in the meaning of A, R2 means hydrogen or methyl, R, 33 s..i ^ gni ^ fi ca npi: ridyl or phenyl, pyridyl or 1,2,3,4-tetrahydronaphthyl which is substituted at one or more sites with hydroxyl, halogen, methyl or methoxy, or the group R5 and R6, independently of one another, mean hydrogen, halogen, methyl, methoxy, or trifluoromethyl, R4 and R7, independently of one another, mean hydrogen and halogen, R9 signifies hydrogen, R10 signifies hydrogen or methyl, as well as their isomers and salts. 6. Compounds of the general formula I according to claims 1 to 3, wherein A means the group = NR W means two hydrogen atoms, Z means the group = NR10, = N-, or -N (R10) - ( CH2) q- or the group or A, Z, and R1 together form the group m, nyo mean 0-3, q means 1-6, Ra, Rb / Rc / Rd Re Rf / independently of each other, mean hydrogen or methyl or group = NR10, X means group = NR9, Y means group -CH2-, R1 means phenyl, pyridyl, 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-lH-indol-3-yl, naphthyl, 1,2,3,4- tetrahydronaphthyl, benzo-1,2,5-oxadiazole, or 6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl or phenyl or pyridyl which is substituted at one or more sites with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, halogen, or trifluoromethyl, or the group whereby phenyl, substituted phenyl or naphthyl is not just in the group = NR2 in the meaning of A, R2 means hydrogen or methyl, R3 means pyridyl or phenyl, pyridyl or 1,2,3,4-tetrahydronaphthyl which is substituted at one or more sites with hydroxyl, halogen, methyl or methoxy, or the group R4 and R7, independently of one another, mean hydrogen, halogen, methyl, methoxy, or trifluoromethyl, R5 and R6, independently of one another, mean hydrogen and halogen, R9 signifies hydrogen, R10 signifies hydrogen or methyl, as well as their isomers and salts. The use of the compounds of the general formula I in which A means the group = NR2, W means oxygen, sulfur, two hydrogen atoms or the group = NR3, Z means the group or -N (R10) - (CH2) q, alkyl of 1 to 6 carbon atoms branched or unbranched, or group or A, Z and R * together form the group m, n, I mean 0-3, q means 1-6, Ra / Rb / RC / Rd / Re and Rf / independently of one another, meaning hydrogen, alkyl of 1 to 4 carbon atoms or group = NR10, and / or Ra and / or Rb can form a bond with Rc and / or R, or Rc can form a bond with Re and / or Rf, X means the group = NR9, Y means the group - (CH2) P, p means 1-4, R1 means alkyl of 1 to 6 carbon atoms which is unsubstituted or optionally substituted at one or more sites with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, nitro, cyano, or at one or more sites with halogen, naphthyl substituted by alkoxy of 1 to 6 carbon atoms, biphenyl, phenyl, thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, triazinyl, quinolyl or isoquinolinyl; or 5-chloro-2,3-dihydroindenyl, 2,3-dihydroindenyl, thienyl, 6-fluoro-lH-indol-3-yl, 1, 2, 3, 4-tetrahydronaphthyl, benzo-1,2,5-oxadiazole , 6,7-dimethoxy-1, 2, 3, 4-tetrahydro-2-naphthyl, or the group whereby, 'phenyl, substituted phenyl or naphthyl nc is just in the group = NR2 in the meaning of A R2 means hydrogen or alkyl of 1 to 6 carbon atoms, R3 signifies naphthyl, biphenyl, phenyl, thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl or isoquinolinyl which is unsubstituted or which is optionally substituted at one or more sites with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, carbon or hydroxyl, or the group R4, R5, R6 and R7, independently of one another, mean hydrogen, halogen, or alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms or carboxyalkyl of 1 to 6 carbon atoms which is unsubstituted or optionally substituted at one or more sites with halogen, or R5 and R6 together form the group -XO 2 R 8, R 9 and R 10, independently of one another, mean hydrogen or alkyl of 1 to 6 carbon atoms, as well as their isomers and salts, for the production of a pharmaceutical agent for the treatment of tumors, psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases, such as diabetic retinopathy, neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, microangiopathic thrombotic syndrome, rejection of transplants and glomerulopathy, fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, and arteriosclerosis, damage to nervous tissue, and for the inhibition of vessel reocclusion after balloon catheter treatment, in vascular prostheses or after mechanical devices are used to maintain the open vessels, such as, for example, stents.

8. Pharmaceutical agent containing at least one compound according to claims 1 to 6.

9. Pharmaceutical agent according to claim 8, for the treatment of tumors, psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, diseases of the eyes, such as diabetic retinopathy, neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic nephropathy , malignant nephrosclerosis, microangiopathic thrombotic syndrome, rejection of transplants and glomerulopathy, fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, and arteriosclerosis, damage to nervous tissue, and for the inhibition of vessel reocclusion after treatment with balloon catheter, in vascular prostheses or after mechanical devices are used to keep vessels open, such as, for example, stents.

10. Compounds according to claims 1 to 6 and the pharmaceutical agents according to claims 6 and 8, with suitable formulations and vehicles.

11. The use of the compounds of the formula I according to claims 1 to 7, as inhibitors of the tyrosine kinases KDR and FLT.

12. The use of the compounds of the general formula I according to claims 1 to 6 in the form of a pharmaceutical preparation for enteral, parenteral and oral administration.