MXPA04012948A - Vegfr-2 and vegfr-3 inhibitory anthranylamidopyridines. - Google Patents

Abstract

VEGFR-2 and VEGFR-3 inhibitory anthranylamidopyridinamides, the production and use thereof as medicaments for the treatment of diseases caused by persistent angiogenesis and intermediates for production of the compounds are disclosed. Said compounds can be used, for example, in tumour or metastasis growth, psoriasis, Kaposi's sarcoma, restenosis, such as for example, stent-induced restenoses, endometriosis, Crohn's disease, Hodgkin's disease, leukaemia, arthritis, such as rheumatoid arthritis, haemangioma, angiofibroma, eye disease, such as diabetic retinopathy, neovascular glaucoma, renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplant rejection and glomerulopathy, fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, artherosclerosis, injuries to nervous tissue and inhibition of the reocclusion of vessels after balloon catheter treatment, in vessel prosthetics, or after the application of mechanical devices to hold open vessels, such as for example, stents, as immune suppressants, as a support for scar-free wound healing, age spots and contact dermatitis. Said compounds may also be used as VEGFR-3 inhibitors in lymphangiogenesis.

Description

ANTRANIIAMIDOPIRIDINES INHIBITORS VEGFR-2 AND VEGFR-3 DESCRIPTION OF THE INVENTION The invention relates to antranilamido pyridines inhibitors of VEGFR-2 and VEGFR-3, their production and use as pharmaceutical agents to treat diseases that are activated by persistent angiogenesis, as well as intermediates for the production of the compounds. Persistent angiogenesis can be the cause or precondition of several diseases, such as tumor growth or metastasis, 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, thrombotic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver, mesangial cell proliferative diseases and arteriosclerosis, or they can result in an aggravation of these diseases. Persistent angiogenesis is induced by VEGF factor via its receptor. For VEGF to be able to exert this action, it is necessary that VEGF binds to the receptor, and tyrosine phosphorylation is induced.

Direct or indirect inhibition of VEGF receptor (VEGF = vascular endothelial growth factor) can be used to treat those diseases and other pathological angiogenesis induced by VEGF and vascular permeable conditions, such as tumor vascularization. For example, it is known that tumor growth can be inhibited by soluble receptors and antibodies against VEGF. The anthranilamido pyridones which are used as pharmaceutical agents to treat 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 cirrhosis of the liver, mesangial cell proliferative diseases, arteriosclerosis, damage to nervous tissue, and to inhibit reocclusion of vessels after balloon catheter treatment, in vascular or mechanical posterior prosthetic devices are used to maintain Open vessels, such as, for example, stent devices, are known from WO 00/27820 (for example, Example 38). The compounds which are known from WO 00/27820 are generally effective in the cited indications, but their effectiveness is not very pronounced. Anthranilic acid amides that are highly effective but also have a good inhibition of cytochrome P 450 isoenzyme 3A4 are also known from O 00/27819 (Example 2.54). The isoenzyme 3A4 of Cytochrome P 450 is one of the essential metabolic enzymes via which pharmaceutical agents are degraded. An inhibition of this isoenzyme results in undesirable interactions of the pharmaceutical agent, especially in the case of multimorbid patients (patients with multiple disease conditions). There is also the problem that in a combination therapy with other drugs, an increase in toxicity occurs, which results from the inhibition of the degradation of the compounds and the associated excessive serum levels. Therefore there is a desire for active ingredients on the one hand to be effective and on the other to be more compatible or to exhibit no undesirable side effects. Therefore there is a desire for, on the one hand, more effective compounds, and on the other, more compatible. It has now been found that the compounds of general formula (I) in which, X means CH or N, means hydrogen or fluorine, A, B, D, E and Q, in each case independently of one another, means a nitrogen or carbon atom, so that only a maximum of two nitrogen atoms in the ring. R1 means aryl or heteroaryl, which may be optionally substituted in one or more places in the same manner or differently with halogen, hydroxy, Ci-C12 alkyl, C3-C3 cycloalkyl, C3-C6 alkenyl, C2-C3 alkynyl, aralkyloxy , C1-C12 alkoxy, Ci-C6 haloalkyl, cyanoCi-Cg alkyl or with the group = 0, -S02R6 or -0R5, whereby the Ci-C6 alkyl, can also be optionally substituted with the group -0R5 or -NR9R10, Y and Z, in each case independently of each other means a bond or group = C0, = CS or = S02. R2 and R3, independently of one another, mean hydrogen or the group -CONR9R10, -S02Rs, -COR11, -C0 Ci-C3 alkyl, -CO-alkyl of d-Cg-R11, -NR¾T10 or by Cx-C6 alkyl , C3-C10 cycloalkyl, C3-C3 cycloalkenyl, aryl or heteroaryl which is optionally substituted in one or more places in the same manner or differently with halogen, cyano, C1-C12 alkyl, ¾-012 alkoxy, hydroxy-alkyl of Q1-C6l haloalkyl of Cx-Cs, or with the group -NR7R8, -0R5, alkyl of Ci-Cg-OR5, -SR4, -SOR4, or -S02R6, or R2, R3, Y and Z together the nitrogen atom forms a saturated or unsaturated ring of 3 to 8 members, which may optionally obtain additional heteroatoms in the ring and may be optionally substituted in one or more places in the same way or differently with halogen, cyano , C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 6 haloalkyl, C 6 -C 6 hydroxy alkyl, or with the group = 0, -0R 5, -SR 4, -SOR 4 or -S0 2 Rs, R 4 means C1-C12 alkyl, ar ilo or heteroaryl, R5 means hydrogen, Ci-C12 alkyl, C3-C10 cycloalkyl, Ci-C12 alkoxy, halo-Cx-Ci2 alkyl, or halo-C3-C6 cycloalkyl / s means hydrogen, C1 alkyl -C12, halo-C1-C12 alkyl, aryl or heteroaryl or the group -NR9R10, whereby the aryl or heteroaryl in s £ may be optionally substituted in one or more places in the same way or differently with alkyl of C ^ -C ^, C3-C6 alkoxy, halogen or haloC1-C6alkoxy, R7 and RB, independently of one another, mean hydrogen or alkyl of OL-C ^, and R9 and R10 independently of each other, mean hydrogen, Ci-C3 alkyl, C2-C6 alkenyl, aryl, C3-C8 cycloalkyl or the group -CONR7R8, or Ci-C12 alkyl, which is optionally substituted in one or more places in the same manner or manner different with aryl, morpholino, hydroxy, halogen, Ci-Ci2f alkoxy or with the group -NR7R8, whereby the aryl itself can be optionally substituted in one or more in the same manner or differently with Cx-C6 alkoxy or halo-C-C6 alkyl or R9 and R10 together form a 5- to 8-membered ring which may contain additional heteroatoms, and R11 means Ci-C6 alkyl , Ci-C6 alkoxy, hydroxy-alkyl from <; ¾-06, hydroxy-Ci-C6 alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, biphenyl or naphthyl, so that the phenyl itself can be substituted in one or more places, in the same way or in a way different with Ci-C6 alkyl, or haloalkyl of Cx-Cs, as well as isomers, diastereomers, tautomers and salts thereof, exhibit improved properties i.e., high effectiveness simultaneously with less inhibition of CYP450 3A4. The compounds according to the invention prevent tyrosine phosphorylation or arrest persistent angiogenesis and thus the growth and propagation of tumors, whereby they are distinguished in particular by a lighter inhibition of cytochrome P 450 isoforms (3A4). The medication with the compounds according to the invention can therefore also be carried out without risk even without regard to pharmaceutical agents which are administered at the same time and are degraded via those isoforms. Alkyl is defined in each case as a straight or branched chain alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl , undecyl or dodecyl. Alkoxy is defined in each case as a straight or branched chain alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, is pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy or dodecyloxy. Cycloalkyls are defined as 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 may contain, instead of carbon atoms, one or more heteroatoms, such as oxygen, sulfur and / or nitrogen. Those heterocycloalkyl with 3 to 8 ring atoms are preferred. The cycloalkenyl is defined in each case as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, whereby the linkage can be carried out in double bonds and single bonds. The halogen is defined in each case as fluorine, chlorine, bromine or iodine. Haloalkyl, haloalkoxy, etc., is defined in alkyl, alkoxy, etc., is substituted in one or more places, in the same way or differently, with halogen. Alkenyl is defined in each case as a straight or branched chain alkenyl radical containing 2-6, preferably 4-6, C atoms. For example, the following radicals may be mentioned: vinyl, propen-1-yl, propen 2-yl, but-l-en-l-yl, but-l-en, 2-yl, but-l-en-l-yl, but-2-en-2-yl, 2-methyl-propyl 2-en-l-yl, 2-methyl-prop-l-en-l-yl, but-l-en-3-yl, but-3-en-l-yl, and allyl. The aryl radical in each case comprises 3-12 carbon atoms and can in each case be benzocondensate. For example, there may be mentioned: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, etc. The heteroaryl radical in each case comprises 3-16 atoms in the ring, and in place of the carbon atom it contains one or more heteroatoms which are the same or different, such as oxygen, nitrogen or sulfur, in the ring, and can be monocyclic , bicyclic or tricyclic, and also in each case can be benzocondensed. For example, there may be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof, such as, for example, quinolyl, isoquinolyl, etc.; or azocinyl, indolicinyl, purinyl, etc., and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenycinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl, etc. The heteroaryl radical can be benzocondensate in each case. For example, there may be mentioned 5-ring heteroaromatic compounds: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and benzo derivatives thereof, and 6-membered heteroaromatic compounds: pyridine, pyrimidine, triazine, quinoline, isoquinoline and benzo derivatives. The heteroatoms are defined as oxygen, nitrogen or sulfur atoms. A ring of 3 to 8 members in the meaning of R2, R3, Y and Z, which is formed together with the nitrogen atom, is defined as C3-C3 cycloheteroalkyls and C3-C8 heteroaryls. If an acid group is included, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, alkali metal salts and easily soluble alkaline earth metal salts as well as N-methyl-glucamine, dimethyl-glucamine. , ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and l-amino-2,3,4-butanediol. If a basic group is included, the 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 so on. The compounds of general formula I according to the invention also contain the possible tautomeric forms and comprise the E isomers or Z isomers, or, if a guiral center is present, also the racemates and enantiomers. Those compounds of general formula I in which X signifies CH, W signifies hydrogen, A, B, D, E and Q, as a ring together means pyridyl, R 1 signifies aryl or heteroaryl, which may be optionally substituted on one or more in the same manner or differently with halogen, hydroxy, Ci-C3 alkyl, C3-Ce cycloalkyl, C4-C3 alkenyl, C2-Ce alkynyl, aralkyloxy, Ci-Cs alkoxy, haloalkyl C6, cyanoCi-C6 alkyl or with the group = 0, -S02Rs or -0R5, whereby the Cx-C6 alkyl, can also be optionally substituted with the group -0R5 or -NR9R10, Y and Z, in each case independently of one another they mean a bond, R2 and R3, independently of one another, mean hydrogen or the group -CONR9R10, -S02R6, -COR11, -C0 C -C6 alkyl, -CO-Cx-Cg-R11 alkyl , -NR¾T10 or by Ci-C6 alkyl, C3-C3 cycloalkyl, C3-C6 cycloalkenyl, aryl or heteroaryl which is optionally substituted in one or more places of the same way or differently with halogen, cyano, Ci-C6 alkyl, 0? -06 alkoxy, hydroxy-alkyl of OL-C6, halo-C-alkyl; L-C6, or with the group -NR7R8, -0R5, Cx-Cg-OR5 alkyl, -SR4 or -S02R6, or R2,. R3, Y and Z together the nitrogen atom forms a saturated or unsaturated ring of 3 to 8 members, which may optionally contain additional heteroatoms in the ring and may be optionally substituted in one or more places in the same manner or. in a different manner with halogen, cyano, Ci-C12 alkyl, Ci-C12 alkoxy, haloCi-C6 alkyl, hydroxyCa-Ce alkyl, or with the group = 0, -0R5, -SR4, - SOR4 or -S02RS, R4 means Ci-C3 alkyl, aryl or heteroaryl, R5 means hydrogen, C-C6 alkyl, C3-C6 cycloalkyl, C1-C12 alkoxy, C3-C0 cycloalkyl or C3-haloalkyl cycloalkyl. C3, Rs means hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, aryl or heteroaryl, or the group -NR9R10, whereby the aryl or heteroaryl itself may be optionally substituted at one or more places in the same or differently with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen or C 1 -C 6 haloalkoxy, R 7 and R 8, independently of one another, mean hydrogen or C 1 -C 6 alkyl, R 9 and R 10 independently among themselves, they mean hydrogen, Cx-Cs alkyl, C2-C6 alkenyl, aryl, C3-C8 cycloalkyl or the group -CONR7R8, or Ci-Cs alkyl, which is optionally substituted in one or more lugare s in the same manner or differently with aryl, morpholino, hydroxy, halogen or Ci-Ci2 alkoxy with the group -NR7R8, whereby the aryl itself can be optionally substituted in one or more places thereof or differently with Ci-Ce alkoxy or haloCi-C6 alkyl, and R11 means Ci-C6 alkyl, Ci-C3 alkoxy, Ci-Ce hydroxy-alkyl, Ci-Cs hydroxy-alkoxy , C3-C6 cycloalkyl, phenyl, pyridyl, biphenyl or naphthyl, whereby the phenyl itself can be substituted at one or more places, in the same way or differently with Ci-C6 alkyl, or halo-alkyl of Ci-C6, as well as isomers, diastereomers, tautomers and salts thereof, has been tested advantageously. Those compounds of general formula I, in which X means CH, W means hydrogen, A, B, D, E, and Q as a ring together means pyridyl; R1 means phenyl, quinolinyl, isoquinolinyl or indazolyl, which may be optionally substituted in one or more places in the same way or differently with halogen, hydroxy, Ci-C3 alkyl, C2-C6 alkynyl, Ci-alkoxy, C6, haloalkyl of x-Cs, or cyano-Ci-Ce alkyl, whereby the C-C6 alkyl may also be optionally substituted with the group -0R5 or -NR9R10, Y and Z, in each case independently of each other, they mean a bond, or the group = C0, R2 and R3, independently of each other, mean hydrogen or the group -CONR9R10, -S02R6, -COR11, -COCalkyl of C3-C3, -C0-C3-alkyl Cg-R11, -NR9R10 or Ci-C3 alkyl or phenyl which is optionally substituted in one or more places in the same way or differently with the group -NR7R8 or -0R5, or R2, R3, Y and Z together with the nitrogen atom forms a saturated or unsaturated ring of 3 to 8 members which may optionally contain additional heteroatoms in the ring and optionally being substituted in one or more places in the same manner or different ways with halogen, cyano, C1-C12 alkyl, C1-C12 alkoxy, haloCi-C6 alkyl / hydroxyCi-C6 alkyl, or with the group = 0, -0RS, -SR4, -SOR4 or -S02RS, R5 means hydrogen or Ci-C3 alkyl, R5 means hydrogen, Ci-C6 alkyl, haloCa-C3 alkyl, phenyl, benzyl, thiophenyl, or pyridyl, whereby the phenyl, benzyl, thiophenyl and pyridyl itself may be optionally substituted in one or more places in the same manner or differently with C 1 -C 6 alkyl, C 2 -C 6 alkoxy, halogen or Halo-alkoxy of Ci-Cg, R7 and RB independently of one another, meaning hydrogen or Ci-C3 alkyl, R9 and R10 independently of one another, mean hydrogen, Cs alkyl, C2-alkenyl, phenyl, biphenyl, C3-C8 cycloalkyl naphthyl or the group -C0NR7R8 or Cx-C3 alkyl which is optionally substituted in one or more places in the same manner or differently e with phenyl, morpholino, hydroxy, halogen, C1-C12 alkoxy, or with the group -NR7R8, whereby the phenyl itself can be optionally substituted in one or more places in the same way or differently with alkoxy of Ci-C6, or Ci-Cg haloalkyl, and R11 means Ci-C6 alkyl / C-_-C6 alkoxy, Ci-Ce alkyl hydroxy, Ci-C6 hydroxy alkoxy, C3 cycloalkyl C3, phenyl, pyridyl, biphenyl or naphthyl, whereby the phenyl itself can be substituted in one or more places in the same way or differently as alkyl of 0? -O6, or halo-Ci-C6 alkyl, as well as isomers, diastereomers, tautomers and salts thereof, are of special interest. The compounds according to the invention as well as their physiologically compatible salts prevent tyrosine phosphorylation or arrest persistent angiogenesis and thus the growth and propagation of tumors, which is why they are particularly distinguished by a lighter inhibition of cytochrome P isoforms. 450 (3A4). The medication using the compounds according to the invention can therefore be carried out without any risk with respect to pharmaceutical agents that are administered at the same time and that are degraded via those isoforms. The compounds of formula I, as well as their physiologically compatible salts can be used as pharmaceutical agents on the basis of their inhibitory activity in relation to the phosphorylation of the VEGF receptor. On the basis of their action profile, the compounds according to the invention are suitable for treating diseases that are caused or promoted by persistent angiogenesis. Since the compounds of formula I are defined as inhibitors of the KDR and FLT tyrosine kinases, they are particularly suitable for treating those diseases that are caused or promoted by persistent angiogenesis that is activated via the VEGF receptor or by 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 KDR and FLT tyrosine kinases. The objects of this invention are thus also agents for the treatment of tumors or the use thereof. The compounds according to the invention can be used alone or in a formulation as pharmaceutical agents to treat tumor growth or metastasis, psoriasis, Kaposi's sarcoma, restenosis, such as restenosis induced by stent devices, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; 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 cirrhosis of the liver, proliferative diseases of mesangial cells, arteriesclerosis, damage to nervous tissues, and to inhibit the confinement of vessels after balloon catheter treatment, in vascular prosthetic devices or mechanical devices used to maintain vessels open, such as, for example, stent devices, such as immunosuppressive agents, to support scar-free healing, in senile keratosis and in contact dermatitis. In the treatment of nerve tissue damage, rapid scar formation on damaged sites can be prevented with the compounds according to the invention, i.e., the occurrence of scar formation is prevented before they are reconnected the axons. A reconstruction of the nerve compounds was thus 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. Lymphangiogenesis plays an important role in lymphogenetic metastasis (Karpanen, T. et al., Cancere Res. 2001 Mar 1, 61 (5): 1786-90, Veik'kola, T. et al., EMBO J. 2001, Mar 15; 20 (6): 1223-31). The compounds according to the invention now also show excellent action as inhibitors of VEGRF kinase 3 and therefore they are also suitable as effective inhibitors of lymphangiogenesis. By a treatment with the compounds according to the invention, not only a reduction in the size of the metastasis is achieved but also a reduction in the number of metastases. These pharmaceutical agents, their formulations and uses are also objects of this invention. The invention thus also relates to the use of the compounds of general formula I for the production of a pharmaceutical agent to be used for the treatment of. tumor growth or metastasis, psoriasis, Kaposi's sarcoma, restenosis, such as restenosis induced by stent devices, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; 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 cirrhosis of the liver, mesangial cell proliferative diseases, arteriosclerosis, damage to nervous tissues, and to inhibit reocclusion of vessels after balloon catheter treatment, in vascular or mechanical posterior prosthetic devices used to maintain vessels open, such as, for example, stent devices, such as immunosuppressive agents, to suppress scar-free scarring, in senile keratosis and in contact dermatitis. 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. In order to use the compounds of formula I as pharmaceutical agents, the latter are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient for enteral or parenteral administration contains suitable drugs, inert organic or inorganic carrier materials, 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 or capsules, or in liquid form, for example as solutions, suspensions or emulsions. They optionally contain, in addition, adjuvants, preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. For parenteral administration, especially injectable solutions or suspensions, especially the aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are suitable. As a carrier system, surface active adjuvants or surfactants such as the salt of bile acids or phospholipids of animals or plants, but also mixtures thereof as well as liposomes or mixtures thereof may also be used. For oral administration, 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 administration can also be carried out in liquid form, such as, for example, as juice, to which a sweetener is optionally added or, if necessary, one or more flavoring substances. 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 is 0.5-1000 mg, preferably 50-200 mg, so the dose can be given as a single dose to be administered once or divided into two or more daily doses. The formulations and forms described above for distribution are also objects 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 general formula I are obtained in a compound of general formula II (li) In which A, B, D, E, Q, W, X and R1 have the meanings indicated in general formula I, and M means halogen, the first is converted to an amine and then acylated, or M is replaced by a NHCOR 'group. The compounds of general formula I are also obtained in the compounds of general formula Ia, (He has) Wherein RY means alkyl of QL-CS 'or hydrogen; FG means a leaving group, such as, for example, halogen, O-triflate, O-mesylate,. O-tosylate or sulfone, is first converted to an amine, and then the leaving group is replaced by a group N (Y-R2) -R3 or a compound III (III) In which R2, R3, Y and Z have the same meanings as those indicated in the general formula I and RY means Cx-Cg alkyl or hydrogen, it is saponified first and then converted into the amide.

The formation of the amide is carried out according to methods that are known in the literature. For the formation of amide, it is possible to start from a corresponding ester. The ester is reacted according to J. Org. Chem. 1995, 8414 with trimethyl aluminum and the corresponding amine in solvents such as toluene at temperatures of 0 ° C to the boiling point of the solvent. If the molecule contains two ester groups, both are converted to the same amide. Instead of trimethyl aluminum, sodium hexamethyldisilazide can also be used. For amide formation, however, all processes known from peptide chemistry are also available. For example, the corresponding acid can be reacted with the amine in polar aprotic solvents such as, for example, dimethylformamide, via an activated acid derivative, which can be obtained, for example 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. The reaction between the carboxylic acid and the amine, however, can also be produced by activation reagents, such as HATU (hexafluorophosphate-N-dimethylamino-lH-1, 2,3-triazolo- [4-5] b) pyridin-1-ylmethylene] -N-methylmetanaminium), whereby polar aprotic solvents, such as, for example, dimethyl formamide, are suitable for the reaction. The addition of a base such as N-methylmorpholine is necessary. The reaction proceeds at temperatures of 0-100 ° C, so that the process is preferably carried out at room temperature, but in many cases heating is indispensable. For the amide formation, the process can also be used with the acid halide, the mixed acid anhydride, imidazolide or azide. No prior protection of an additional amino group is necessary, for example, as an amide, in all cases, but it can have an advantageous influence on the reaction. In the case of the bis acid chlorides, cyclic compounds can be produced. Also, in the case of halogen acid halides, cyclic compounds can be produced. The closure of the ring is then optionally completed by adding a strong base, for example, sodium alcoholate. The same is true for sulphonic acid halides, which can also occur double sulfonations. Ureas are produced from amino compounds by reaction with isocyanates. Inert solvents such as methylene chloride or dimethylphoramide at temperatures from room temperature to 100 ° C, preferably at 60 ° C. The pressure is advantageous for the reaction. The reaction of the halopyridines with amides is carried out under catalysis, for example by palladium or copper catalysis. In the case of copper catalysis (literature, see Synlett, 2002, 427), solvents such as dioxane or dimethyl formamide are used at temperatures up to the boiling point of the solvent, preferably 120 ° C. As a base, potassium phosphate or also cesium carbonate is used. Ethylenediamine is advantageous for complexing copper iodide (I) which is used as a catalyst. A pressure application is not dangerous. In the case of palladium catalysis, both palladium (II) salts, such as palladium (II) acetate and palladium (O) complexes, such as palladium (O) 2-dibenzylidene acetone3 (literature, see JACS 2002, 6043, THL 1999, 2035, Org. Lett 2001, 2539, THL 2001, 4381 or THL 2001, 3681) can ... As a solvent, toluene, dioxane and dimethylformamide are used at temperatures from room temperature to the boiling point of the solvent , preferably around 100 ° C. As a collator, BIMAP, DPPF or Xanthphos are used. A base is also necessary. Up to this point, cesium carbonate, potassium phosphate or also sodium t-butylate is used. These components can be combined in several ways.

The production of the pyridinamines from the corresponding 2-halopyridines is carried out in solvents such as pyridine or in polar protic solvents such as ethylene glycol at temperatures up to 200 ° C. Catalysis by copper (I) salts may be necessary for the reaction. The application of pressure is absolutely necessary in the case of the reaction of low boiling amines, but it can also be used advantageously in conventional amines. The cleavage of the ether is achieved according to known methods, for example, by reaction with boron tribromide in inert solvents, such as methylene chloride, at temperatures of -78 ° C to room temperature, preferably at -78 ° C. The compounds of the general formulas II, lia, And III, wherein A, B, D, E, Q, W, X, Y, Z, R2 and R3 have the meanings indicated in general formula I and means halogen, FG means a leaving group, such as, for example, halogen , O-triflate, 0-mesylate, 0-tosylate or sulfone, and RY means Cx-Cs alkyl or hydrogen, represent valuable intermediates for the production of the compounds of general formula I according to the invention and thus also they are objects of this invention.

Production of Compounds According to the Invention The following examples explain the production of the compounds according to the invention without the scope of the claimed compounds being limited to those examples.

Example 1.0 Production of 2 -. { [2 - (2-Dimethylamino-ethylamino) -pyridin-4-ylmethyl] -amino} -iV- (3-trifluoromethyl-phenyl) -benzamide 90 mg (0.2 mmol) of 2- [(2-bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide were dissolved in 3 ml of pyridine and mixed with 1 ml of ?,? - dimethylaminoethylamine and heated in a pressure vessel for 5 hours at an electrodeposition bath temperature of 200 ° C. After cooling, it was concentrated by evaporation, and 90 mg of 2- was obtained. { [2- (2-dimethylamino-ethylamino) -pyridin-4-ylmethyl] -amino} -jV- (3-trifluoromethyl-phenyl) -benzamide. Melting point: 100 ° C. In a similar manner, the following compounds were produced: Type A Type B \, R Example Type R2 R1 PM Point of Do not . Fusion [° C] or Molar Peak of EM (m / e) 1. 1 A - (C¾) 2-0H H 430.5 1. 2 A - (CH2) 2-OH H 413.5 130-132 1. 3 A - (C¾) 3-0H H 444.5 148 Example Type R * R1 PM Point of No. Fusion t ° C] or Peak Molar EM (m / e) 1. 9 A H 444.5 81 * 1.10 A (CH2) 3NMe2 H 471.5 68 1. 11 B - (CH2) 2-OH H 413.5 Resin ^^^^^ 1. 12 A Phenyl H 462.5 1.13 A - (CH2) 5- 437.54 * Example Type R2 H3 R PM Point of No. Fusion [° C] or Peak Molar EM (m / e) 1. 14 A - (C¾) 2-0- (CH2) 2- 439.52 174 * 1. 15 A - (CH2) 2 ~ NMe- 452.56 85 (C¾) 3- * 1. 16 A - (CH2) 2-S-. { CH2) 2- 455.58 158 fifteen * 1. 17 A - (C¾) 2-S02- 487.58 (CH2) 2- twenty * 1. 18 A - (CH2) 4- 423.52 148 * Example 2.0 Production of 2- [(2-jimino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide 8.747 g (19.4 mmol) of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide were heated with 175 mg of copper (I) oxide in 150 of ethanediol for 23 hours under 10 bars of ammonia pressure at 80 ° C in an autoclave. After the solvent is distilled in vacuo, the residue is purified on silica gel with a gradient of ethyl acetate: ethanol = 100: 0 to 0: 100 as eluent. 4.15 g (51% of theory) of 2- [(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide having a melting point of 64 ° C were obtained. Similarly, they produce: Example 2.1 2- [(2-Amino-pyridin-4-ylmethyl) -amino] isoquinolin-3-yl-benzamide Melting point: 202 ° C Example 2.2 2- [(2-Amino-pyridin-4-ylmethyl) -amino] indazol-5-yl) -benzamide MS: m / e 358 Melting Point Example 2.3 2- [(2-Amino-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2. £ f-indazol-6-yl) -benzamide Example 3.0 Production of 2 -. { [-2- (3-Benzyl-ureido) -pyridin-4-ylmethyl] -amino} -iV- (3-trifluoromethyl-phenyl) -benzamide 100 mg (0.26 mmol) of 2 - [(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide were mixed in 2.5 ml of methylene chloride with 37.9 mg (0.29 mmol) of benzyl isocyanate, and stirred overnight at room temperature. After concentration by evaporation, the residue is subjected to chromatography. 66 mg (49% of theory) of 2- were obtained. { [2- (3-benzyl-ureido) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) benzamide with a melting point of 153 ° C. In a similar manner, the following compounds were produced: Example Type R1 R10 PM Point of No. Fusion [° C] or Molar Peak of EM (m / e) 3. 1 A Phenyl 505.5 185 tjCCF3 3.2 A Ph (C¾) 2- 533.5 76 Examples 3.15 and 3.29 were produced in a manner analogous to Example 3.0 with the use of trimethylsilyl isocyanate.

Example 3.30 Production of 2 -. { [2 - (3,3-dimethyl-ureido) -pyridin-4-ylmethyl] -amino} -N- (3-isoquinolinyl) -benzamide 100 mg (0.23 mmol) of 2 - [(2-bromopyridin-4-ylmethyl) -amino] -N- (3-isoquinolinyl) -benzamide in 2 ml of dioxane was heated with 89 mg (0.28 mmol) of cesium carbonate. , 61 mg (0.69 mmol) of N, N-dimethylurea, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a covered gas and in a moisture-free environment for 9 hours at a time Bath temperature of 100 ° C. It was then mixed with 20 ml of methylene chloride, suctioned and concentrated by evaporation. The residue was chromatographed on silica gel with ethyl acetate as eluent, 24 mg (24% of theory) of 2- { [2- (3, 3-dimethyl-ureido) -pyridin-4 were obtained. -ylmethyl] -amino.}. -N- (3-isoquinolinyl) -benzamide. (MS (CI): 441 (M ++ H)) The following compounds were similarly produced: Type A Type Use Type R1 R9 Rlü PM Fusion Point No. [° C] or Molar Peak of EM (m / e) 3. 31 A H H 412.5 222 3. 32 A H H 429.4 JCCF3 3.33 A H Me H 415.46 3. 34 A Me H 415.46 110-113 H 3.35 A Me H 429.48 230-232 Me Example 4-0 Production of 2- [(2-Methanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) benzamide 90 mg (0.2 mmol) of 2- [(2-bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide and 23 mg (0.24 mmol) of methanesulfonic acid amide were introduced. in 5 ml of dioxane and mixed in succession with 4 mg (0.02 mmol) of copper iodide (I), 85 mg (0.4 mmol) of potassium phosphate and 2 mg (0.02 mmol) of ethylenediamine. After stirring for 1 hour at a bath temperature of 120 ° C, it was diluted with 20 ml of water and concentrated by evaporation. It was then basified with ammonia and stirred three times with 25 ml of ethyl acetate each time. The collected organic phase was washed with water, dried, filtered and concentrated by evaporation. The residue was made crystalline with ethyl acetate and a little hexane, stirred and sucked. 24 mg (26% of theory) of 2- [(2-methanesulfonyl-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide having a melting point of 214.5 were obtained ° C. In a similar way, there were: Example 1 R2 PM Point of Do not . Fusion [° C] 0 Molar Peak of EM (m / e) 4.1 526.54 259.2 * 4. 2 541.55 > 300 S02 ?. { > Me 4. 3 610.53 248.6 S02- < ^ OCF3 4.4 -S02CF3 518. 4 238.9 4. 5 -S02CH3 447.52 m / e: 447 * 20 4.6 5S2.52 252.5 Example 5.0 Production of 2 - [(2-Bismetanesulfonyl pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) benzamide 193 mg (0.5 mmol) of 2 - [(2-amino-pyridin-4-ylmethyl) -arnino] -N- (3-trifluoromethyl-phenyl) benzamide in 3 ml of dichloromethane was mixed with 69 mg (0.6 mmol) of methanesulfonic acid chloride and 61 mg (0.6 mmol) of triethylamine and stirred together for 1.5 hours at room temperature. Then, it was washed once with dilute sodium bicarbonate solution, dried, filtered and concentrated by evaporation. The residue was subjected to flash chromatography (5 g of Isolute) with a gradient of cyclohexane: ethyl acetate = 100: 0 to 50:50 as an eluent. 80 mg (30% of theory) of 2 - [(2-bismetanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide was obtained as a resin. (MS: m / e 542) Example 6.0 Production of 2 - [(2-Bryrylamino-pyridin-4-ylmethyl) -amino] -JV- (3-isoquinolinyl) -benzamide 100 mg (0.23 mmol) of 2 - [(2-bromopyridin-4-ylmethyl) -amino] -N- (3-isoquinolinyl) -benzamide in 1 mL of dioxane was heated with 89 mg (0.28 mmol) of cesium carbonate. , 24 mg (0.69 mmol) of butyramide, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a covered gas and in a moisture-free environment for 25 hours at a bath temperature of electrodeposition of 90 ° C. Then it was mixed with 20 ml of methylene chloride, it was sucked and concentrated by evaporation. The residue was chromatographed on silica gel first with hexane, then with hexane: ethyl acetate = 8.2 and then with hexane: ethyl acetate = 1: 1 as eluent. 45 mg (42% of theory) of 2- [(2-butyrylamino-pyridin-4-ylmethyl) -amino] -N- (3-isoquinolinyl) -benzamide was obtained with a melting point of 173 ° C. In a similar way, there were: Example PM Point No. Fusion [° C] or Molar Peak of EM (m / e) 6. 1 -COn-Prop 456.47 168 66. 2 -COMe 411.46 220 * 6. 3 -COEt 425.49 183 * 6. 4 -COn-Bu 453.54 167 * Example 6.32 Similarly, there was: 2 -. { . [2-Acetyl-methyl-amino) -pyridin-4-ylmethyl] -amino} -N- soquinolin-3-yl-benzamide Melting point 71 ° C Example 7.0 Production of 2-. { [2- (2-Oxo-pyrrolidin-l-yl-pyridin-4-ylmethyl] -amino.}. -iV- (3-trifluoromethyl-phenyl) -benzamide 156 mg (0.5 mmol) of 2- acid was mixed. { [2- (2-Oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino) -benzoic acid in 5 ml of dimethylformamide with 0.12 ml (1 mmol) of 3-aminobenzotrifluoride, 228 mg (0.6 mmol) of HATU hexafluorophosphate-oxide (N-dimethylamino-lH-1,2,3-triazolo- [4, 5-b] pyridin-1-ylmethylene] -N-methylmethanamonium) and 0.14 ml of N-methylmorpholine, and stirred for the night at room temperature. It was diluted with ethyl acetate and washed in succession with saturated sodium bicarbonate solution, water and saturated common salt solution. The organic phase was dried, filtered and concentrated by evaporation. The residue was chromatographed on Isolute as a mobile solvent. 95 mg (42% of theory) of 2- was obtained. { [2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide. (EM: m / e 454) Similarly, the following occurred: Example 8.0 Produced in a manner similar to Example 6.0 is: 2-. { [2- (2-Hydroxymethyl-5-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -N-isoquinolin-3-yl-benzamide similarly occurred 25 Example 9.0 Production of 2 -. { [2 - (2,5-Dioxo-pyrrolidin-1-yl) pyridin-4-ylmethyl] -a ino} -N- (3-rifluoromethyl-phenyl) -benzamide 193 mg (0.5 mmol) of 2 [(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide was mixed in 20 ml of dichloromethane with 0.21 ml (1.5 mmol) of triethylamine, and it was mixed at room temperature drop by drop with a solution of 93 mg (0.6 mmol) of succinic acid dichloride in 3 ml of methylene chloride. After stirring overnight at room temperature, it was diluted with methylene chloride and washed in succession with water, saturated sodium bicarbonate solution and saturated common salt solution. Then, the organic layer was dried, filtered and concentrated by evaporation. The residue was chromatographed on Isolute (Separtis Company) with a gradient of methylene chloride. Ethanol = 100: 0 to 95: 5. 120 mg (51% of theory) of 2- were obtained. { [2- (2, 5-dioxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trixluoromethyl-phenyl) -benzamide. (E: m / e 468) Similarly, there was: Use 9.1 2-. { [2- (3, 5-Dioxo-morpholin-4-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide Melting point 201.9 ° C Example 10.0 Production of 2- [(2- (3-chloropropansulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide 135 mg (0.35 mmol) of 2- [(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide in 10 ml of dichloromethane was mixed with 62 mg (0.35 mmol) of 3-chloropropanesulfonic acid chloride and 49 μ? (0.35 mmol) of triethylamine, and stirred for 2 hours at room temperature. Then, it was washed once with saturated sodium bicarbonate solution, filtered and concentrated by evaporation. The residue was subjected to chromatography via flash chromatography (5 g of Isolute) with a gradient of dichloromethane: ethanol = 100: 0 to 90:10 as eluent. 67 mg (36% of theory) of 2- [(2- (3-chloropropansulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide was obtained. (MS (CI): 491 (100%, M + + H-HCl)) Example 11.0 Production of 2 - { [2- (1,1-Dioxo-A6-isothiazolidin-2-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide 58 mg (0.11 mmol) of 2 - [(2- (3-chloropropansulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide was suspended in 5 ml of ethanol and mixed with 5 mg of sodium hydride (55% in mineral oil) The mixture was refluxed for 1 hour, it was mixed with 10 ml of water and extracted with ethyl acetate. The aqueous phase was saturated with sodium sulfate and extracted repeatedly with stirring with ethyl acetate overnight. After the combined extracts were concentrated by evaporation, they obtained 50 mg (93% of theory) of 2-. { [2- (1, l-dioxo-lA6-isothiazolidin-2-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide. (MS (CI): 491 (100%, M ++ H)) Example 12.0 N- [2- (2-Hydroxy-ethyl) -2H-indazol-5-yl] -2-. { [2- (3-methyl-ureido) -pyridin-methylmethyl] -amino} -benzamide 50 mg (0.11 mmol) in N- [2- (2-methoxy-ethyl) -2H-indazol-5-yl] -2- were introduced. { [2- (3-methyl-ureido) -pyridin-4-ylmethyl] -amino} -benzamide in 5 ml of methylene chloride and dropwise mixed under argon and in a humidity-free environment at -78 ° C with 0.56 ml of bromine tribromide (1 molar in methylene chloride). It was stirred for a further 15 minutes, the cold bath was removed, and then stirred for a further 2 hours. Then, it was mixed with water, the methylene chloride was removed, alkalized with the sodium bicarbonate solution and extracted twice with 15 ml of ethyl acetate each time. The collected organic phase was dried, filtered and concentrated by evaporation. The residue was exposed to chromatography on silica gel with a gradient of methylene: ethanol = 100: 0 to 90:10 as eluent, and 27 mg of N- [2- (2-hydroxy-ethyl) -2H-indazole were obtained. -5-il] -2-. { [2- (3-methyl-ureido) -pyridin-4-ylmethyl] -amino} -benzamide. Similarly, the corresponding methoxy compounds were produced: Production of intermediate compounds Example A If the production of intermediates is not described, the latter are known or can be produced analogously to known compounds or to processes described herein.

Stage 1 a) Production of 2-bromopyridin-5-carbaldehyde.

It was carried out according to F. J. Romero-Salguerra et al. THL 40,859 (1999). b) Production of 2-bromo-isonicotinic acid. 160 g (0.93 mol) of 2-bromo-4-methyl-pyridine in drops were added to 152 g (0.96 mol) of potassium permanganate in 4 1 of water. It was then stirred under reflux for one hour before adding 152 g (0.96 mol) of potassium permanganate once more. After an additional two hours of stirring under reflux, it was suctioned in a hot state on Celite and washed with water. The aqueous phase was stirred three times with dichloromethane. The aqueous phase was concentrated by evaporation to half its original volume, and the pH was set at 2 with concentrated hydrochloric acid. The precipitated solid was sucked and dried at 70 ° C under vacuum. 56.5 g of white solid product were accumulated. Production of 2-bromo-4-hydroxymethyl-pyridine .2 ml (295 ramol) of triethylamine was added to 56.5 g (280 mmol) of 2-bromo-isonicotinic acid in 1.2 1 of THF. Then, it was cooled to -10 ° C and mixed drop by drop with 38.2 ml (295 mmol) of isobutyl chloroformate. After having continued stirring for one hour at -10 ° C, it was cooled to -70 ° C and mixed drop by drop with 590 ml (590 mmol) - of LiAlH4 solution (1M in THF). After continuing to stir for one hour at -70 ° C, it was allowed to reach -40 ° C. 600 ml of 50% acetic acid are added. It was stirred overnight at room temperature. The soluble components were suctioned, and the filtrate was concentrated by evaporation. The residue was purified on silica gel with hexane and hexane / ethyl acetate 1: 1. 28.0 g of white solidifying oil were accumulated. Production of 2-bromo-4-formyl-pyridine: 149 g (1714 mmol) of manganese dioxide in measured amounts were added to 28.0 g (148.9 mmol) of 2-bromo-4-hydroxymethyl-pyridine in 500 ml of dichloromethane within 6 hours. Then, it was continued stirring at room temperature for 48 hours. It was suctioned on Celite and concentrated by evaporation. 16.4 g of solidifying white oil were accumulated. The 2-bromo ~ 4-formyl-pyridine can also be produced in accordance THL 42.6815 (2001) from 2-bromo-4-picoline in two steps.

Step 2 Production of 2- [(6-bromo-pyridin-3-ylmethyl) amino] -V = -isoquinolin-3-yl-benzamide. 3.46 g (13.17 mmol) of 2-amino-N-isoquinolin-3-yl-benzamide are introduced into 50 ml of methanol, 1.5 ml of glacial acetic acid and 2.45 g (13.17 mmol) of 2-bromopyridine are added. 5-Carbaldehyde and stirred for 24 hours under argon and in a moisture-free environment at room temperature. So, it is mixed with 828 mg (13.17 mmol) of sodium cyanoborohydride and stirred for another 24 hours at room temperature. After concentration by evaporation under vacuum, the residue is taken in dilute sodium bicarbonate solution and suctioned. The residue obtained is precipitated by absorption in little ethyl acetate and repeatedly sucked. The residue obtained in this case is subjected to chromatography on silica gel with hexane: ethyl acetate = 1: 1 as eluent. 3.27 g (57% of theory) of 2 - [(6-bromo-pyridin-3-ylmethyl) -amino] -N-isoquinolin-3-yl-benzamide were obtained. Similarly, 2- [(2-Bromo-pyridin-phenylmethyl) -amino] -N-isoquinolin-3-yl-benzamide is produced. 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] trifluoromethyl-phenyl) -benzamide Example B Step Stage Production of Methyl Ester from 2- [(2-bromo-pyridin-4-ylmethyl) -amino] benzoic acid 6.04 g (40 mmol) of anthranilic acid methyl ester are mixed in 600 ml of methanol with 3.2 ml of acetic acid and 7.4 g (40 mmol) of 2-bromopyridine-4-carbaldehyde and stirred overnight at 40.degree. ° C. 3.8 g (60 mmol) of sodium cyanoborohydride are added and stirred overnight at 40 ° C. 3.8 g (60 mmol) of sodium cyanoborohydride are again added and stirred over the weekend at 40 ° C. It is mixed with water and concentrated to a large extent by evaporation. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are dried, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with a gradient consisting of hexane and hexane / ethyl acetate 1: 3 and hexane / ethyl acetate 1: 1 as eluent. 10.0 g (78% of theory) of 2- [(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester are obtained as a colorless oil.

Example C Ira Stage Production of 2- [(2-bromo-pyridin-4-methylmethyl) -benzoic acid] .0 g (31.2 mmol) of 2- [(2-bromo-pyridin-4-ylmethyl) -araino] -benzoic acid methyl ester are dissolved in 290 ml of ethanol and mixed with 31.2 ml of sodium hydroxide solution 2 M. After having stirred overnight at room temperature, the ethanol is removed, and the aqueous phase is stirred with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid. The precipitate that forms is sucked and dried. 5.93 g (62%) of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid are accumulated as a white solid. 2nd Step Production of 2- [(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2if-indazol-6-yl) -benzamide 0.500 g (1.6 mmol) of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid, 0.471 g (3.2 mmol) of 2-methyl-2Ji-indazol-6-ylamine, 0.4 are stirred. my (3.68 mmol) of N-methylmorpholine and 0.729 g (1.92 mmol) of 0- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) in 25 ml of dimethylformamide for 16 hours hours at room temperature. The dimethylformamide is removed in an oil vacuum pump. The remaining residue is removed in saturated sodium bicarbonate solution. It was extracted three times with ethyl acetate, and the combined organic phases are dried, filtered and concentrated by evaporation. The residue is subjected to chromatography on silica gel with a gradient consisting of hexane: acetone = 100: 0 to 50:50 as eluent. 0.669 g (96% of theory) of 2- [(2-bromo-pyridin-4-ylmethyl) -amino] ~ N- (2-methyl-2H-indazol-6-yl) -benzamide is obtained in the form of a persimmon foam. In a similar manner, the following compounds are also produced 2 - [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1-methyl-1-yl-indazol-6-yl) -benzamide 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] indazol-6-yl) -benzamide Example D Stage 1 Production of Methyl Ester from Acid 2-. { [2- (2-Oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic Reflux 870 mg (2.78 mmol) of 2- [(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester, 53 mg (0.28 mmol) of copper (I) iodide, 1.126 g (5.5 mmol) of potassium phosphate and 0.26 ml (3.6 mmol) of pyrrolidin-2 -one in 15 ml of dioxane for 8 hours. After adding water, the dioxane is distilled in vacuo, made alkaline with approximately 12% ammonia solution and stirred several times with ethyl acetate. The ethyl acetate phase collected is washed, dried, filtered and concentrated by evaporation. 700 mg (77% of theory) of methyl ester of 2 ~ acid are obtained. { [2- (2-oxo-pyrrolidin-1-yl) -4-ylmethyl] -amino} -benzoic acid as a residue, as a crude product, which is used without further purification in the next stage.

It occurred in a similar way: Stage 3 2 - acid production. { [2 - (2-Oxxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic 700 mg (2.15 mmol) of methyl ester of 2- acid were mixed. { [2- (2-oxo-pyrrolidin-1-yl) -pyridin-1-methylmethyl] -amino} -benzoic acid and 15 ml of methanol with 2.7 ml of 1N sodium hydroxide solution and refluxed for 1 hour. Methanol was then distilled off in vacuo, diluted with water and stirred once with ethyl acetate. The aqueous phase was mixed with 5 ml of 1 mole of citric acid solution and stirred overnight. Solid precipitation is sucked and dried very quickly. 600 mg of 2- were obtained. { [2- (2-Oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino] -benzoic acid, which was obtained with the crude product in the next step. In a similar way, there were: Y and Z = G Example E Production of 2- [(2-Bromo-pyridin-4-ylmethyl) amino] -N- (1-methyl-lH-indazol-5-yl) -benzamide and 2 - [(2-Bromo-pyridin-4-) ilmethyl) -amino] -N- (2-methyl-2H-indazol-5-yl) -benzamide 4.22 g (10 mmol) of 2- [(2-bromo-pyridin-4-ylmethyl) -amino] -N- (lH-indazol-5-yl) -benzamide were mixed in 30 ml of dimethylformamide while cooling with ice with 3.6 g (11 mmol) of cesium carbonate and 0.68 ml (11 mmol) of methyl iodide, and stirred overnight at room temperature. It was then stirred in 250 ml of ice cold water, stirring was continued for 15 minutes, and sucked. The filter cake dried very rapidly and chromatographed on silica gel with a gradient of ethyl acetate. Hexane = 1: 1 to 100: 0 as eluent. 1.79 g (41% of theory) of 2- [(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1-methyl-lH-indazol-5-yl) -benzamide were obtained with a point of fusion of 173.8 ° C as well as 830 mg (19% of theory) of 2- [(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-5-yl) - benzamide with a melting point of 183.8 ° C. In a similar manner there were produced: 2- [(2-Bromo-pyridin-4-ylmethyl] -amino] -N- (1-Isopropyl-1H-ludazol-5-yl) -benzamide, 2- [(2-Bromo- pyridin-4-ylmethyl) -amino] -N- (2-isopropyl-2H-indazol-5-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1 -ethyl-lH-indazol-5-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2-ethyl-2H-indazol-5-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1-12-methoxyethyl] -lH-indazol-5-yl) -benzamide, 2- [(2-Bromo-pyridin-4) -ylmethyl) -amino] -N- (2- [2-raetoxyethyl] -2H-indazol-5-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- ( 1- [Cyanomethyl] -lH-indazol-5-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2- [cyanomethyl] -2H-indazole-5- il) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1- [2-dimethylaminoethyl] -lH-indazol-5-yl) -benzamide, 2- [(2) -Bromo-pyridin-4-ylmethyl) -amino] -N- (2- [2-dimethylaminoethyl] -2H-indazol-5-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) - amino] -N- (1-methyl-lH-indazol-6-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -M- (2-methyl) 2H-indazol-6-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1-isopropyl-1H-indazol-6-yl) -benzamide, 2- [ (2-Bromo-pyridin-methyl) -amino] -N- (2-isopropyl-2H-indazol-6-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] - N- (1-ethyl-lH-Indazol-5-yl) -benzamide, 2- ['(2-Bromo-pyridin-4-ylmethyl) -amino] -M- (2-ethyl-2H-indazole-6-) il) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1- [2-methoxyethyl] -IH-indazol-6-yl) -benzamide, 2- [(2) -Bromo-pyridin-4-ylmethyl) -amino] -N- (2- [2-methoxyethyl] -2H-indazol-6-yl) -benzamide, 2- [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1- [cyanomethyl] -lH-indazol-6-yl) -benzamide and 2-1 (2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2- [cyanomethyl] -2H-indazol-6-yl) -benzamide 2- [(2-Bromo-pyridin-methyl) -amino] -N- (1- [2-dimethylaminoethyl] -lH-indazol-6-yl) -benzamide and 2- [(2-Bromo-pyridin-methyl) -amino] -N- (2-12-dimethylaminoethyl] -2H-indazol-6-yl) -benzamide. The following sample applications explain the biological action and the use of the compounds according to the invention without being limited later to the examples.

Solutions Required for the Test Standard solutions Standard solution A: 3 mmol of ATP in water, pH 7.0 (-70 ° C) Standard solution B: g-33P-ATP 1 mCi / 100 μ? Standard solution C: poly- (Glu4Tyr) 10 mg / ml in water Solution for dilutions Substrate solvent: 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 μ? of sodium and vanadium oxide.

Application of Sample 1 Inhibition of the Activity of DR- and FLT-1 Kinase in the Presence of the Compounds According to the Invention In a microtiter plate (they are protein binding) that is used in a point, 10 μ? of substrate mixture (10 μ? volume of standard solution ATP + 25 μCi of g-33p-ATP (approximately 2.5 μ? of standard solution B) + 30 μ? of standard solution of poly- (Glu4Tyr) C + 1.21 my substrate solvent), 10 μ? of inhibitor solution (substances corresponding to the dilutions, 3% DMSO in substrate solvent as control) and 10 μ? of enzyme solution (11.25 μg> of enzyme standard solution (KDR or FLT-1 kinase) at 4 ° C and 1.25 ml of enzyme solution (diluted), mixed thoroughly and incubated for 10 minutes at room temperature Then, 10 μl of interruption solution (250 mmol of EDTA, pH 7.0) was added, mixed, and 10 μl of the solution was transferred to a phosphocellulose filter P 81. Then, it was washed several times with acid. Phosphoric acid 0.1 M. The filter paper was dried, coated with Meltilex and measured in a microbeta counter.The IC 50 values were determined from the inhibitory concentration, which is necessary to inhibit the phosphate incorporation to 50% of the uninhibited incorporation after removal of the blank reading (stopped reaction with EDTA) The results of the IC50 of the measurement with kinase in μ ?? are represented in the following table.

Application of Sample 2 Inhibition of Cytochrome P450 Inhibition of Cytochrome P450 is carried out according to the publication of crespi et al. (Anal. Biochem., 248, 188-190 (1997)) with the use of human cytochrome P450 isoenzyme (3A4) expressed in baculovirus / insect cells. The results are presented in the following table Example No. VEG P II (DR) [nM] Cytochrome P450 isoenzyme 3A4 2.54 out of 5 3.6 WO 00/27820 38 out of 180 4.6 WO 00/27820 1.14 52 > 30 3.24 12 14 3.30 10 5.5 6.2 41 > 30 Example No. VEGRF II (KDR) [nM] Cytochrome P450 Isoenzyme 3A4 6. 22 24 10 6.27 8 10 6.32 65 11 The superior action of the compounds according to the invention compared with the known compounds can be seen more clearly from the results.

Claims (11)

1. CLAIMS 1. The compounds of general formula (I) wherein X means CH or N, W means hydrogen or fluorine, A, B, D, E and Q, in each case independently of one another, means a nitrogen or carbon atom, so that only a maximum of two nitrogen atoms in the ring, R1 signifies aryl or heteroaryl, which may be optionally substituted in one or more places in the same manner or differently with halogen, hydroxy, Ca-Ci2 alkyl, C3-C3 cycloalkyl, C3-C6 alkenyl, C2-C6 alkynyl, aralkyloxy, C1-C12 alkoxy, haloalkyl of C ^ -Cs, cyano-C1-6 alkyl or with group = 0, -S02R6 or '-0R5, thus that the Ci-Cg alkyl can also be optionally substituted with the group -0R5 or -NRSR10, Y and Z, in each case independently of one another meaning a bond or group = C0, = CS or = S02, R2 and R3, independently of one another, they mean hydrogen or the group -CONR9R10, -S02R6, -COR11, -C0Ci-C6 alkyl, -CO-alkyl of d-Cs-R11, -NR9R10 or by alkyl that of Ci-C6, C3-Cao cycloalkyl # C3-C3 cycloalkenyl, aryl or heteroaryl which is optionally substituted in one or more luqares in the same manner or differently with halogen, cyano, Cx-C ^ alkyl, C-CZ alkoxy, hydroxyCi-C6 alkyl, haloCx-C6alkyl or with the group. -MV, -0R5, Cx-Cg-OR5 alkyl, -SR4 or -S02Rs, or R2, R3, Y and Z together with the nitrogen atom form a saturated or unsaturated ring of 3 to 8 members, which may optionally contain additional heteroatoms in the ring and may be optionally substituted in one or more places in the same manner or differently with halogen, cyano, Cx-C12 alkyl, Ci-C12 alkoxy, haloCa-C3 alkyl, hydroxy Ci-C6 alkyl, or with the group = 0, -ORs, -SR, -SOR4 or -S02R6, R4 means C1-C12 alkyl, aryl, or heteroaryl, R5 means hydrogen, C1-C12 alkyl, cycloalkyl C3-C10, Ci-C12 alkoxy, C1-Ci2 haloalkyl, or C3-C6 haloalkyl, R6 means hydrogen, C! -C12 alkyl / halo-C5-C12 aryl or heteroaryl alkyl or the group -NR9R10, whereby the aryl or heteroaryl itself may be optionally substituted in one or more places in the same manner or differently with C 1 -C 12 alkyl, C 6 -C 6 alkoxy, halogen or halo alkoxy xC 6, R7 and R8, independently of one another, mean hydrogen or C1-C12 alkyl / and Rs and R10 independently of one another, meaning hydrogen, Ci-C3 alkyl, C2-Cg alkenyl, aryl, C3-C8 cycloalkyl or the group -CONR7R8, or C1'Ca2 alkyl, which is optionally substituted at one or more places in the same manner or differently with aryl, morpholino, hydroxy, halogen, C1-C12 alkoxy, or with the group -NR7R8 , whereby the aryl itself may be optionally substituted in one or more places in the same manner or differently with Ci-Cg alkoxy or Ci-Cg haloalkyl, or R9 and R10 together form a ring of 5 to 8 members which may contain additional heteroatoms, and R11 means Ci-C6 alkyl, C1-C5 alkoxy, hydroxy-CaC6 alkyl, hydroxy-Ci-Ce alkoxy, C3-C6 cycloalkyl, phenyl, pyridyl, biphenyl or naphthyl, so the phenyl itself can be substituted in one or more places, in the same way or differently with alkyl Ci-C6, or haloalkyl of Cx-CS / itself as isomers, diastereomers, tautomers and salts thereof.
2. 2. Compounds of general formula I, according to claim 1, wherein X means CH, means hydrogen,?, B, D, E and Q, as a ring together means pyridyl, R1 signifies aryl or heteroaryl, which it may be optionally substituted in one or more places in the same way or differently with halogen, hydroxy, Cx-6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl C2-C6 alkynyl, aralkyloxy, Cx alkoxy -Cs, haloalkyl of C! -C6, cyanoalkyl of C! -C6 or with the group = 0, -S02 so -0R5, whereby the Cx-C3 alkyl, can also be optionally substituted with the group -0R5 or -NR9R10,? and Z, in each case independently signify a bond, R2 and R3, independently of each other, mean hydrogen or the group -CONR9R10, -S02R6, -COR11, -C0 Cx-C6 alkyl, -CO-alkyl of QL- CÜ-R 11, -NR 9 N 10 or by alkyl of x-C 6, cycloalkyl of C 3 -C 3, cycloalkenyl of C 3 -C 3, aryl or heteroaryl which is optionally substituted in one or more places in the same way or differently with halogen, cyano , C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 3 hydroxy alkyl, C 1 -C 6 haloalkyl, or with the group -NR 7 R 8, -OR 5, d-Cg-OR 5 alkyl, -SR 4 or -S02Rs, or R2, R3, Y and Z together the nitrogen atom forms a saturated or unsaturated ring of 3 to 8 members, which may optionally contain additional heteroatoms in the ring and may be optionally substituted in one or more sites of the same way or differently with halogen, cyano, Ci-C12 alkyl, alco- (¾) alkoxy, halo-C-alkyli.-C6, hydroxy-Ci-Cs alkyl, or with the group = 0, -0RS, -SR4, -SOR4 or -S02R6, R4 means CL-C6 alkyl, aryl or heteroaryl, R5 means hydrogen, alkyl of Cx-Cs, Ci-C6 haloalkyl, ??-?? 2 alkoxy, C3-Ci0 cycloalkyl or C3-C6 halo-cycloalkyl, R6 stands for hydrogen, ??? s alkyl, haloC1-alkyl -Cg, aryl or heteroaryl, or the group -NR9R10, whereby the aryl or heteroaryl itself can be optionally substituted at one or more places in the same way or differently with C ^ -Ce alkyl, Ci alkoxy -Cg, halogen or haloalkoxy of x-5, R7 and R8, independently of each other, mean hydrogen or Ci-C3 alkyl, and R9 and R10 independently of one another, mean hydrogen, d-C6 alkyl, C2 alkenyl -C3, aryl, C3-C8 cycloalkyl or the group -C0NR7R8, or C ± -Cs alkyl, which is optionally substituted in one or more places in the same way or differently with aryl, morpholino, hydroxy, halogen or C1-C1 alkoxy 2, or with the group -NR7R8, whereby the aryl itself may be optionally substituted in one or more places in the same way or differently with Ci-C6 alkoxy or halo-Ci-C6 alkyl, or R11 means C-C6-alkyl, Cj-Cg-alkoxy, CX-6-hydroxy-alkyl, C-C6-hydroxy-alkoxy, C3-C6-cycloalkyl, phenyl, pyridyl, biphenyl or naphthyl, so that the phenyl itself it may be substituted in one or more places, in the same manner or differently with alkyl of Ci-Cg, or halo-Cx-C6 alkyl, as well as isomers, diastereomers, tautomers and salts thereof.
3. 3. The compounds of general formula I, according to claims 1 and 2, wherein X means CH, W means hydrogen, A, B, D, E and Q, as a ring together means pyridyl, 1 means phenyl, quinolinyl, isoquinolinyl or indazolyl, which may be optionally substituted in one or more places in the same manner or differently with halogen, hydroxy, C ^ Cg alkyl, C2-C6 alkynyl, Ci-C6 alkoxy, haloalkyl of C- Cs, cyano-Ci-Cg alkyl, whereby the Ci-C3 alkyl, can also be substituted with the group -OR5 or -NRSR10, Y and Z, in each case independently of each other means a bond, or a group = CO, R2 and R3, independently of one another, mean hydrogen or the group -CONR9R10, -S02R6, -COR11, -CO alkyl of Ca-Cg, -CO-alkyl of Cx-Cg-R11, -NR9N10 or alkyl of Ci-C6 or phenyl which is optionally substituted in one or more places in the same way or differently with the group -NR7R8, or -OR5, or R2, R3, Y and Z the nitrogen atom forms a saturated or unsaturated ring of 3 to 8 members, which may optionally contain additional heteroatoms in the ring and may be optionally substituted in one or more places in the same way or differently with halogen, cyano, Ci-C12 alkyl, C ± -Cj alkoxy, 2l halo Cx-C3 alkyl, hydroxyCa-Cg alkyl, or with group = 0, -OR5, -SR4, -SOR4 or -S02R6, R5 means hydrogen or C 1 -C 6 alkyl, R 6 signifies hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl, phenyl, benzyl, thiophenyl and pyridyl itself optionally may be substituted in one or more places in the same manner or differently with Ci-C6 alkyl, Ci-C6 alkoxy / halogen or halo-alkoxy of CA-C6, R1 and R8, independently of one another, mean hydrogen or Ci-C3 alkyl, R9 and R10 independently of each other, mean hydrogen, Ci-Cg alkyl, C2-C3 alkenyl, phenyl, biphenyl, C3-C8 cycloalkyl, naphthyl or the group -CONR7R8, or C-L-CS alkyl, which is optionally substituted in one or more places in the same way or differently with phenyl, morpholino, hydroxy, halogen or Cx-C12 alkoxy, or with the group -NR7R8, so that the phenyl itself may be optionally substituted in one or more places in the same manner or differently with C1-C6 alkoxy or halo-alkyl of QL-CS, and R11 means Ci-C6 alkyl, Ca-Cg alkoxy , hydroxy-alkyl of Ca-Cs, hydroxy-alkoxy of C-Sl C3-C6 cycloalkyl, phenyl, pyridyl, biphenyl or naphthyl, whereby the phenyl itself can be substituted in one or more places, in the same way or else differently with alkyl of Ca-C6, or haloalkyl of Ci-C6, as well as isomers, diastereomers, tautomers and salts thereof.
4. 4. Pharmaceutical agents comprising at least one compound of general formula I.
5. 5. Pharmaceutical agents according to claim 4 for use in the case of tumor growth or metastasis, psoriasis, Kaposi's sarcoma, restenosis, such as, for example, restenosis induced by stent devices, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; 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 cirrhosis of the liver, mesangial cell proliferative diseases, arteriosclerosis, damage to nervous tissues, and to inhibit the reclusion of vessels after balloon catheter treatment, in vascular prosthetic devices or mechanical devices used to maintain open vessels, such as, for example, stent devices, and as immunosuppressive agents, and to support scar-free healing, in senile keratosis and in contact dermatitis.
6. 6. Pharmaceutical agents according to claim 5 for use as inhibitors of VEGFR kinase 3 of lymphagiogenesis.
7. 7. The compounds according to claims 1 to 3 and pharmaceutical agents according to claims 4 to 6, with suitable formulations and vehicles.
8. 8. The use of the compounds of formula I, according to claims 1 to 3, as inhibitors of KDR and FLT tyrosine kinases.
9. 9. The use of the compounds of general formula I, according to claims 1 to 3, in the form of a pharmaceutical preparation for enteral, parenteral and oral administration. The use of the compounds according to claims 1 to 3 in the case of tumor growth to metastasis, psoriasis, Kaposi's sarcoma, restenosis, such as, for example, restenosis induced by stent devices, endometriosis, Crohn's disease, Hodgkin's disease , leukemia; 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 cirrhosis of the liver, proliferative diseases of mesangial cells, arteriesclerosis, damage to nervous tissues, and to inhibit reocclusion of vessels after balloon catheter treatment, in vascular prosthetic devices or mechanical devices used to maintain vessels open, as, for example, stent devices, and as immunosuppressive agents, and to support scar-free healing, in senile keratosis and in contact dermatitis. 11. Compounds of general formulas II, lia and in which A, B, D, E, Q, W, X, Y, Z, R2 and R3 have the meanings indicated in general formula I and M means halogen, FG means a leaving group, such as, for example, halogen, O-triflate, O-mesylate, O-tosylate or sulfone, and RY means alkyl Ci-C3 or hydrogen, as intermediates for the production of the compounds of general formula I according to the invention. SUMMARY The production of the anthranilaminopyridinamide inhibitors VEGFR-2 and VEGFR-3 is revealed, the use of them as drugs for the treatment of diseases caused by persistent angionenesis; and the production of intermediates for the preparation of compounds. Said compounds can be used, for example: in tumors or metastases, psoriasis, Kaposi's sarcoma; restenosis, such as: restenosis induced by surgery, endometriosis, Crohn's disease, Hodking disease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases; such as diabetic retinopathy, neovascular glaucoma; kidney diseases, such as glomerulonephritis, diabetic neuropathy, malignant nephrosclerosis, microangiopathic trophic syndrome, rejection of transplants and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver; atherosclerosis; damage to nervous tissue or inhibition of vein reocclusion after balloon catheter treatment, in prosthetic veins, or after the application of devices to keep veins open, such as, for example, stents; as immune suppressors, as a support for brand-free healing, expressions of aging, and contact dermatitis. Said compounds can also be used as VEGFR-3 inhibitors in lymphangiogenesis.