JP2000506847A - 4-Amino-pyrimidine derivatives, pharmaceuticals containing these compounds, their use and production - Google Patents

Abstract

(57) [Summary] The present invention provides a 4-amino-pyrimidine derivative represented by the following general formula: (Wherein R _a , R _b , A and B are as defined in claim 1), their tautomers, stereoisomers and salts, especially their inorganic or organic Physiologically acceptable salts with the acids or bases of the invention, which have valuable pharmaceutical properties, in particular the inhibitory effect of tyrosine kinase-mediated signaling, their use in the treatment of diseases, especially neoplastic diseases , As well as their manufacture.

Description

DETAILED DESCRIPTION OF THE INVENTION   4-amino-pyrimidine derivatives, pharmaceuticals containing these compounds, their use and And manufacturing method   The present invention provides a 4-amino-pyrimidine derivative having the general formula: Their tautomers, stereoisomers and salts, particularly those with various pharmaceutical properties, inorganic or Organic acids or bases and their physiologically acceptable salts, especially tyrosine kinases Inhibition of mediated signal transduction, in the treatment of diseases, especially neoplastic diseases To their use, as well as to their production.   In the general formula I, the compound 4-[(3-bromophenyl) amino] -6- (1-piper Dinyl) -pyrido [3,4-d] -pyrimidine is subject to the exclusion of protection. ,   R_aRepresents a hydrogen atom or a methyl group,   R_bIs R₁To R_ThreeA phenyl group substituted with a₁To R_ThreeBase A substituted phenylalkyl group means:   (Where R₁Is hydrogen, fluorine, chlorine, bromine or iodine atom, alkyl, trif Fluoromethyl, ethenyl, ethynyl, alkyloxy, C_3-6-Cycloalkyl, Trifluoromethoxy, cyano, amino, alkylamino, dialkylamino, Or nitro group, R_TwoRepresents a hydrogen, fluorine, chlorine or bromine atom, or an alkyl group, and R_Three Represents a hydrogen, fluorine, chlorine or bromine atom. ),   A and B together form a bridge of the formula: -N = CR_c-CH = CH-, -CH = N-CR_c= CH-, -CH = CR_c-N = CH-, -CH = CH-CR_c= N- or -CH = N-CR_c= N-   Here, in each case, the left end of these bridges is linked to position 5 of the pyrimidine ring, The right end of these bridges is linked to position 6 of the pyrimidine ring,   (Where R_cIs a morphoyl optionally substituted with one or two alkyl groups No group,   A 1-piperazinyl group optionally substituted with one or two alkyl groups,   3-oxo-1-piperazine optionally substituted with one or two alkyl groups A nil group,   C_3-6-Cycloalkyl group, 3-tetrahydrofuranyl, 3-tetrahydropyranyl , 4-tetrahydropyranyl, 3-pyrrolidinyl, 1-alkyl-3-pyrrolidinyl, 3- Piperidinyl, 4-piperidinyl, 1-alkyl-3-piperidinyl, or 1-alkyl- A 1-piperazinyl group substituted at the 4-position by a 4-piperidinyl group,   R_Four1-azetidinyl, 1-pyrrolidinyl, 1-piperidin optionally substituted Means a dinyl or 1-azacyclohep-1-yl group:   (Where R_FourIs hydroxyl, alkyloxy, amino, alkylamino, di Alkylamino, alkylcarbonylamino, N-alkyl-alkylcarbonyl Amino-2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl, alkyloxy Carbonylamino, N-alkyl-alkyloxycarbonylamino, alkyls Ruphonylamino, N-alkyl-alkylsulfonylamino, C_3-6-Cycloalkyl , Tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1-alkyl- Pyrrolidinyl, piperidinyl, 1-alkyl-piperidinyl, morpholino, 1-pipe Radinyl, 4-alkyl-1-piperazinyl, aminoalkyl, alkylaminoal Kill, dialkylaminoalkyl, carboxyl, alkyloxycarbonyl, Aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, morpholinocarbonyl , 1-piperazinylcarbonyl, 4-alkyl-1-piperazinylcarbonyl or It means a cyano group. ),   Two hydrogen atoms in the 3-position are straight-chain alkylene bridges having 4-5 carbon atoms A substituted 1-azetidinyl group, wherein in each case the alkylene bridge described above, Wherein the methylene group is an oxygen atom, or an imino or N-alkyl-imid And may be substituted by   1-pyrroli, wherein two hydrogen atoms of the carbon skeleton are substituted by a linear alkylene bridge A dinyl group, the bridge being such that these two hydrogen atoms are located on the same carbon atom. Three to five carbon atoms, or these two hydrogen atoms are adjacent Three or four carbon atoms if they are on carbon atoms, or these two water atoms Two or three carbon atoms if the atoms are on carbon atoms separated by one atom Wherein each of the alkylene bridges described above comprises a methylene group, Substituted by an oxygen atom or by an imino or N-alkyl-imino group Get   1-piperidine in which two hydrogen atoms of the carbon skeleton are substituted by a linear alkylene bridge A bridge wherein the two hydrogen atoms are on the same carbon atom In which case 3 to 5 carbon atoms or two of these carbon atoms Three or four carbon atoms when on an elementary atom, or these two hydrogens Two or three carbon atoms if the atoms are on carbon atoms separated by one atom An atom or a carbon atom where these two hydrogen atoms are separated by two atoms Contains one or two carbon atoms, where each of the aforementioned alkylene bridges In which the methylene group is linked by an oxygen atom or by an imino or alkyl Means that it can be substituted by a mino group,   Or R_cIs (R_FiveNR₆) Means the group:   (Where R_FiveRepresents a hydrogen atom or an alkyl group, and R₆Is R_FourC replaced with_5-7-Cycloalkyl group (where R_FourIs the one defined earlier It is. )),   3-tetrahydrofuranyl group,   3- or 4-tetrahydropyranyl group,   3-pyrrolidinyl or 3- or 4-piperidinyl group, wherein the ring In each case alkyl, alkylcarbonyl, alkylsulfur Honyl, alkyloxycarbonyl, C_3-6-Cycloalkyl, 3-tetrahydrof Ranyl, 3- or 4-tetrahydropyranyl, 3-pyrrolidinyl, 1-alkyl-3-pyro Lysinyl, 3- or 4-piperidinyl, 1-alkyl-3-piperidinyl, or 1-alkyl A 4-piperidinyl group,   R_FourC substituted with a group_2-6-Alkyl group (where R_FourIs as defined above . ),   3- or 4-quinuclidinyl group, or   It means a 3-tropanyl or desmethyl-3-tropanyl group. ). ),as well as Unless stated otherwise, in each case the aforementioned alkyl group is selected from 1 to 4 carbon atoms Is included.   However, in the preferred compounds of general formula I above,   R_aRepresents a hydrogen atom or a methyl group,   R_bBut R₁To R_ThreeMeans a phenyl group substituted with a group:   (Where R₁Is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, ethyl, Trifluoromethyl, methoxy, cyclopropyl, trifluoromethoxy, shea No, nitro or amino group,   R_TwoRepresents a hydrogen, fluorine, chlorine or bromine atom,   R_ThreeRepresents a hydrogen, fluorine, chlorine or bromine atom. ),   A and B together form a bridge of the formula: -N = CR_c-CH = CH-, -CH = N-CR_c= CH-, -CH = CR_c-N = CH-, -CH = CH-CR_c= N- or -CH = N-CR_c= N-   Wherein in each case the left end of these bridges is linked to position 5 of the pyrimidine ring, And the right end of these bridges is linked to position 6 of the pyrimidine ring,   (Where R_cIs a morpholino optionally substituted with one or two methyl groups Group,   A 1-piperazinyl group optionally substituted with one or two methyl groups,   Substituted at the 4-position by a 4-piperidinyl- or 1-alkyl-4-piperidinyl group 1-piperazinyl group,   R_FourA 1-pyrrolidinyl group substituted at the 3-position by_Four3rd or 4th depending on Is a 1-piperidinyl group substituted with:   (Where R_FourIs amino, methylamino, dimethylamino, pyrrolidinyl, 1- Tylpyrrolidinyl, piperidinyl, 1-methylpiperidinyl, morpholino, 1-pipe Radinyl, 4-methyl-1-piperazinyl, hydroxyl, methoxy, carboxyl , Methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl, 1-pi Loridinylcarbonyl, 1-piperidinylcarbonyl, or morpholinocarbonyl Means group. ), Or (R_FiveNR₆) Means the group: (Where R_FiveRepresents a hydrogen atom or a methyl or ethyl group, and   R₆But R_FourIs a cyclopentyl or cyclohexyl group (where R_Four Is as defined above. )),   3-pyrrolidinyl or 3- or 4-piperidinyl groups, wherein the cyclic nitrogen of the aforementioned groups The atom is in each case methyl, ethyl, C_1-4Alkyloxycarbonyl , Acetyl, or can be substituted with a methylsulfonyl group, R_FourC substituted with a group_2-4-Alkyl group (where R_FourIs as defined above. ),   3- or 4-quinuclidinyl group, or   It means a 3-tropanyl group. Alternatively, these are tautomers, stereoisomers and salts thereof.   However, in particularly preferred compounds of the above general formula I,   R_aRepresents a hydrogen atom,   R_bBut R₁To R_ThreeMeans a phenyl group substituted with a group:   (Where R₁Means hydrogen, fluorine, chlorine or bromine atom, methyl or amino group And   R_TwoRepresents a hydrogen, fluorine, chlorine or bromine atom,   R_ThreeRepresents a hydrogen, fluorine, chlorine or bromine atom. ), A and B together form a bridge of the formula: -N = CR_c-CH = CH-, -CH = N-CR_c= CH-, -CH = CR_c-N = CH-, -CH = CH-CR_c= N- or -CH = N-CR_c= N-   Wherein in each case the left end of these bridges is linked to position 5 of the pyrimidine ring, And the right end of these bridges is linked to position 6 of the pyrimidine ring,   (Where R_cIs a morpholino group,   Substituted at the 3- or 4-position with an amino, piperidinyl or 1-methylpiperidinyl group 1-piperidinyl group,   Or (R_FiveNR₆) Means the group: (Where R_FiveRepresents a hydrogen atom or a methyl group, and R₆Is carboxyl, methoxycarbonyl, ethoxycarbonyl, morpholinoca A cyclohexyl group substituted with a rubonyl or hydroxyl group, A 3- or 4-piperidinyl group, wherein the aforementioned cyclic nitrogen atom is in each case And methyl, ethyl, or C_1-4Can be substituted with an alkyloxycarbonyl group Can, C substituted with an amino group_2-4-Alkyl group, Means 3-tropanyl or 3-quinuclidinyl group Alternatively, these are tautomers, stereoisomers and salts thereof.   Examples of particularly preferred compounds are given below: (1) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- (4-amino-1-piperidinyl ) -Pyrido [4,3-d] pyrimidine, (2) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(1-methyl-4-piperidini Ru) amino] -pyrido [4,3-d] pyrimidine, (3) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (4-amino-1-piperidinyl ) -Pyrido [3,4-d] pyrimidine, (4) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(3-quinuclidinyl) amido [No] -pyrido [3,4-d] pyrimidine, (5) 4-[(4-amino-3,5-dibromo-phenyl) amino] -6-[(trans-4-hydroxy Cyclohexyl) amino] -pyrido [3,4-d] pyrimidine, (6) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (1-methyl-4-piperidini) Le) piperidin-1-yl] -pyrido [3,4-d] pyrimidine, And their salts.   Compounds of general formula I can be prepared, for example, by the following method: A compound of the following general formula: (Where R_aR_bIs as defined above, and A 'and B' together form Crosslinking: -N = CZ₁-CH = CH-, -CH = N-CZ₁= CH-, -CH = CZ₁-N = CH-, -CH = CH-CZ₁= N- or -CH = N-CZ₁= N- (Where Z₁Is substituted with a halogen atom, or a fluorine, chlorine or bromine atom, etc. Hydroxyl, mercapto, sulfinyl or sulfonyl groups, methoxy, eth Xy, phenoxy, methylsulfinyl, ethylsulfinyl, methylsulfonyl Or a leaving residue such as an ethylsulfonyl group. ) And in each case smell The left end of these bridges is linked to position 5 of the pyrimidine ring and The right end is linked to position 6 of the pyrimidine ring. ), Reacting with a compound of the following general formula;       X₁-H (III) (Where X₁Is R_cMeans the groups indicated for ).   This reaction involves isopropanol, butanol, tetrahydrofuran, dioxa , Toluene, chlorobenzene, dimethylformamide, N-methyl-pyrrolidone- 2-one, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethyl In a solvent such as lenglycol diethyl ether, or sulfolane, for example, carbonic acid An inorganic base such as sodium or potassium hydroxide, or, for example, triethyl alcohol; Tertiary organic bases such as min or pyridine, the latter may simultaneously act as a solvent But in the presence of these optionally, as well as copper salts, the corresponding amine-halogenated In the optional presence of a reaction accelerator such as hydrogen or an alkali metal halide, Properly proceed at temperatures between 0 and 180 ° C, but preferably between 20 and 150 ° C. It is. However, this reaction is generally carried out in the absence of solvent or in excess It can be carried out also among the compounds of the formula (III).   According to the present invention, a compound of the general formula (I) containing an amino or imino group is obtained. If the alkylation or reductive alkylation, the corresponding alkyl of the general formula (I) Compounds that can be converted to compounds or contain carboxyl or ester groups A compound of general formula (I) can be converted to the corresponding amide of formula (I) by amidation. Can be.   Subsequent alkylation involves methylene chloride, dimethylformamide, benzene, Ruene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran Or in a solvent or solvent mixture such as dioxane, for example, methyl iodide, odor Corresponding halides or salts such as ethyl chloride, dimethyl sulfate, or benzyl chloride Optionally a tertiary organic base or an inorganic salt with an alkylating agent such as a sulfonic acid ester In the presence of the group, suitably at a temperature of 0 to 150 ° C, preferably at a temperature of 0 to 100 ° C, Can be done at will.   Subsequent reductive alkylation involves formaldehyde, acetaldehyde, A corresponding carbonyl compound such as onaldehyde or acetone; Such as sodium hydrogen, lithium borohydride or sodium cyanoborohydride Hydrogenation in the presence of a complex metal hydride complex, suitably at pH 6-7 and room temperature, Hydrogen pressure with hydrogen in the presence of a catalyst, for example palladium / charcoal 1-5 × 10⁶dyn / cm^Two(1-5 bar). However, methylation can also be used as a reducing agent. The reaction is carried out at an elevated temperature, for example at a temperature of from 60 to 120 ° C, in the presence of any formic acid.   Subsequent amidation optionally includes methylene chloride, dimethylformamide, Such as toluene, chlorobenzene, tetrahydrofuran or dioxane, Corresponds to the corresponding reactive carboxylic acid derivative in the solvent or solvent mixture The reaction is carried out by reaction with an amine, which is used as a solvent at the same time. Can be provided, optionally in the presence of a tertiary organic base or an inorganic base, Alternatively, in the presence of a dehydrating agent, together with the corresponding carboxylic acid, for example, isobutylchloro Formate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, 2- (1H- (Nzotriazol-1-yl) -1,1,3,3-tetramethyluronium-tetrafluoropho Borate, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodi Of diimide / N-hydroxysuccinimide or 1-hydroxybenzotriazole In the presence, and optionally 4-dimethylaminopyridine, N, N'-carbonyldiimidazo Or triphenylphosphine / carbon tetrachloride, suitably at a temperature The reaction is carried out at 0-150C, preferably at a temperature of 0-80C.   In the above reaction, no amino or imino or carboxyl group Some of the reactive groups are normal protecting groups that are removed again during and after this reaction. Can be protected by   For example, protecting groups for amino or imino groups include formyl, acetyl, trifluoro Acetyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbo Benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group And for the amino group can be a phthalyl group, a carboxyl group Protecting groups for are trimethylsilyl, methyl, ethyl, t-butyl, benzyl or Can be a tetrahydropyranyl group.   Cleavage of any subsequently used protecting groups may be, for example, water, methanol Aqueous solutions such as toluene / water, acetic acid / water, tetrahydrofuran / water or dioxane / water. Medium, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or In the presence of an alkali metal base such as sodium or potassium hydroxide, or Suitably in the presence of, for example, iodotrimethylsilane, at a temperature of 0 to 120 ° C, preferably Can be carried out hydrolytically at a temperature of 10 to 100 ° C.   However, benzyl, methoxybenzyl or benzyloxycarbonyl groups are For example, in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid. And optionally an acid such as hydrochloric acid in the presence of a catalyst such as palladium / charcoal. Addition, depending on the hydrogen, at a temperature of 0-100 ° C, but preferably at a temperature of 20-60 ° C, And hydrogen pressure 1-7 × 10⁶dyn / cm^Two(1-7 bar), but preferably 3-5 × 10⁶dy n / cm^Two(3-5 bar), it can be hydrocracked. But 2,4-di The methoxybenzyl group is preferably synthesized in trifluoroacetic acid in the presence of anisole. Be cut off.   Preferably the t-butyl or t-butyloxycarbonyl group is trifluoroacetic acid or Is treated with an acid such as hydrochloric acid or with iodotrimethylsilane. Optionally, such as methylene chloride, dioxanemethanol or diethyl ether. Cleaved using solvent.   The trifluoroacetyl group is preferably added, optionally in the presence of a solvent such as acetic acid. By treatment with an acid such as hydrochloric acid at a temperature of 50 to 120 ° C or optionally NaOH at a temperature of 0 to 50 ° C in the presence of a solvent such as tetrahydrofuran It is cut by treatment with a thorium solution.   The phthalyl group is preferably selected from methanol, ethanol, isopropanol, Hydrazine, also in a solvent such as ruene / water or dioxane at a temperature of 20-50 ° C. Or a primary amine such as methylamine, ethylamine or n-butylamine. Disconnected in the presence.   In addition, the resulting compound of general formula I is obtained as described above. It can be separated into enantiomers and / or diastereomers. So the example For example, a cis / trans mixture can be separated into its cis and trans isomers. And a compound having at least one optically active carbon atom, Can be separated.   Thus, for example, the resulting cis / trans mixture can be chromatographed. Can be separated into their cis and trans isomers, and as racemic compounds The resulting compounds of the general formula I are prepared in a manner known per se (“stereochemical X ", Volume 6, Wiley Interscience, 1971, Allinger N.L. and Eliel E. L. Can be separated into their optical enantiomers, Compounds of general formula I having at least two asymmetric carbon atoms are, for example, Using methods known per se, such as torography and / or fractional crystallization Can be separated into their diastereomers based on their physicochemical differences. If they occur in racemic form, they are then enantiomerically Separated by Omar.   Separation of the enantiomers is preferably by column separation in a chiral phase, or By recrystallization from an optically active solvent or by adding the racemic compound to a salt or ester Or derivatives such as amides, especially their acids and activated derivatives or The reaction is carried out by reaction with an optically active substance such as Separation of diastereomeric mixtures of conductors can be obtained, for example, based on differences in solubility. The free enantiomer is converted to the pure diastereomeric salt by the action of a suitable reagent. Or it may be released from a derivative. Particularly common optically active acids include, for example, sake Tartaric acid or dibenzoyltartaric acid, di-o-toluyltartaric acid, maleic acid, mandel Acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid D- and Including L-form. For example, the optically active alcohol that can be used is (+)-or (- ) -Menthol, but the optically active acyl group in the amide is (+)-or (-)-menthyl Oxycarbonyl.   Furthermore, the compounds of the general formula I obtained can be converted into their salts with inorganic or organic acids. Can be converted into their physiologically acceptable salts, especially for use in medicine. it can. Acids used for this purpose include, for example, hydrochloric acid, hydrobromic acid, methane Sulfonic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or Contains maleic acid.   Some of the compounds of general formulas II and III used as starting materials are described in the literature. Or can be obtained from the literature by methods known per se. (See, for example, International Patent Publication No. WO 95/19774).   As already mentioned above, the compounds of the general formula I according to the invention and their physiologically acceptable Salts have valuable pharmaceutical properties, especially for example ligand binding, receptor dimerization Or an epidermal growth factor receptor, such as provided by inhibition of a tyrosine kinase -(EGF-R) has a specific inhibitory effect on signal transduction. This It is also a component downstream of this signal chain (componennt), Can be blocked.   The biological properties of this new compound were determined as follows:   Inhibition of EGF-R-mediated signal transduction, for example, can be caused by expression of human EGF-R. Cells can be detected and their survival and proliferation is stimulated by EGF or TGF-α. Depends on Genetically converted to express functional human EGF-R, An interleukin-3- (IL-3) -dependent cell line from a mouse was used. Therefore , The proliferation of these cells, known as F / L-HERc, is either murine IL-3 or EGF. (Von Ruden, T. et al., EMBO J.,7: 2749-2756 pp (1988), and Pierce J.H. Thesis, Science,239: 628-631 (1988) checking).   The starting material used for F / L-HERc cells was cell line FDC-P₁And its preparation The method is described in Dexter, T.M. J. Exp. Med.152: 1036-1047 (1980) Have been. Alternatively, however, other growth factor-dependent cells can be used. (Eg, a paper by Pierce, J.H. et al., Science,239: 628-631 (1988), Shib uya, H. et al., Cell,70: 57-67 (1992), and a paper by Alexander, W.S., et al., EMBO J. ,Ten: 3683-3691 (1991)). Expresses human EGF-R cDNA (Ullrich, A. et al., Nature,309: See pages 418-425 (1984) And Ruden, T. et al., EMBO J .; ,7: 2749-2756 (1988) Recombinant retorvirus is used for retroviral vector expression of EGF-R cDNA. -Using LXSN (Miller, A.D. et al., BioTechniques,7: 980-990 (19 89)) and the use of strain GP + E86 as packaging cells. (Markowitz, D. et al., J. Virol,62: 1120-1124 (1988)) Used to change.   The test was performed as follows:   F / L-HERc cells were 10% fetal calf serum (FCS, Boehringer Mannheim), 2 mM Glutamine (BioWhittaker), standard antibiotics, and 20 ng / ml human EGF ( RPMI / 1640 medium (Bio Whittaker) supplemented with Promega 37 ℃ and 5% CO_TwoAnd cultured. To investigate the inhibitory activity of the compounds of the present invention 1.5 × 10 per well in a 96-well plate^FourTransfer cells to the medium described above. (200 μl) in triplicate, while simultaneously growing these cells Stimulation was with either GF (20 ng / ml) or mouse IL-3. This IL-3 is expressed in cell line X63 / 0mIL-3 (Karasuyama, H. et al., Eur. J. Immunol.18: 97 -104 (1988)). The compound of the present invention is 100% dimethyl sulfoxide. Dissolved in Sid (DMSO) and added at various dilutions to the culture, The high concentration was 1%. These cultures were cultured at 37 ° C. for 48 hours.   In order to measure the inhibitory activity of the compound of the present invention, the relative number of cells was determined using Cell Titer. (Cell titer) using 96 (R) aqueous non-radioactive cell proliferation assay (Promega) And was measured in O.D. units. The relative number of cells was compared with the control (F / L-HERc without inhibitor). Cell) and the concentration of active substance that inhibits cell growth by 50%. Degree (IC₅₀) Was calculated from these. The following results were obtained:   Thus, the compounds of general formula I of the present invention are illustrated by the human EGF-receptor example. To inhibit signal transduction by tyrosine kinases and, as a result, It is useful for treating the pathophysiological course caused by tyrosine kinase hyperactivity. These include, for example, benign or malignant tumors, especially tumors of epithelial and neuroepithelial origin , Endothelial cell metastasis and abnormal proliferation (new angiogenesis).   Further, the compounds of general formula I and their physiologically acceptable salts are tyrosine kinases. Other diseases caused by abnormal functioning of the epidermis, such as hyperplasia of the epidermis (psoriasis), Used to treat diseases such as inflammatory processes, immune system disorders, and hyperproliferation of hematopoietic cells be able to.   The compounds of the present invention can be administered, on their own or in other medicaments, in view of their biological properties. It can be used in combination with an active compound, for example, in tumor treatment, Alone or in combination with other antitumor agents, such as topoisomerase inhibitors (D Interacts with antimitotic drugs (such as vinblastine) and nucleic acids Compounds (cisplatin, cyclophosphamide, adriamycin, etc.), formo Antagonists (such as tamoxifen), metabolic inhibitors (such as 5-FU), Used in combination with tocaines (such as interferons) and anti-inflammatory substances can do. These combinations may be administered either simultaneously or sequentially. Can be.   The use of the compounds of the invention as medicaments is generally useful for homeothermic vertebrates, especially humans. It is used in doses of 0.01 to 100 mg / kg body weight, preferably 0.1 to 15 mg / kg. Administration To this end, they may comprise one or more customary inert carriers and / or diluents, such as tow. Sorghum starch, lactose, glucose, microcrystalline cellulose, magnesium stearate , Polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / g Lycerol, water / sorbitol, water / polyethylene glycol, propylene glycol Recall, stearyl alcohol, carboxymethyl cellulose, or solid fat (hard fat) or a suitable mixture thereof, And plain or coated tablets, capsules, powders, suspensions, solutions, sp Conventional galenical preparations, such as suppositories or suppositories, are made.   The following examples are intended to illustrate the invention in more detail. Not limited:Example I 4-[(3-chloro-4-fluoro-phenyl) amino] -7-fluoro-pyrido [4,3-d] piLimi gin   230 mg of 7-fluoro-4-hydroxy-pyrido [4,3-d] pyrimidine was added to phosphorus oxychloride Refluxed in 10 ml for 3.5 hours. The reaction mixture was evaporated and the residue was treated with methylene chloride 1 Dissolved in 00 ml and stirred with 25 ml of saturated sodium carbonate solution for 15 minutes. Organic The phases were separated and the aqueous phase was extracted twice with 100 ml of methylene chloride. These organic phases Combine and wash with water and dry over magnesium sulfate. To this solution, add 1.26 g of loro-4-fluoroaniline, 20 mg of 3-chloro-4-fluoroaniline-hydrochloride and 5 ml of isopropanol was added. The methylene chloride is removed in vacuo and Was stirred at room temperature for 1 hour. The mixture is evaporated to dryness and the residue is The mixture was stirred twice with 100 ml of petroleum ether. The residue insoluble in petroleum ether Purified by chromatography on a Kagel column. Yield: 100 mg (25% of theory) Melting point: 290-295 ° C (decomposition; at about 250 ° C, its crystal structure began to change); R_fValue: 0.50 (silica gel; cyclohexane / ethyl acetate = 1: 1).   The following compounds were obtained in an analogous manner to Example I: (1) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-fluoro-pyrido [3,4-d] pyri Midines Melting point: 264-266 ° C, R_fValue: 0.58 (silica gel; petroleum ether / ethyl acetate = 1: 1). (2) 4-[(4-amino-3,5-dibromo-phenyl) amino] -6-fluoro-pyrido [3,4-d] pi Limidine Melting point: 235-237 ° C R_fValue: 0.50 (silica gel; petroleum ether / ethyl acetate = 1: 1).Example 1 4-[(3-chloro-4-fluoro-phenyl) amino] -7- (4-amino-1-piperidinyl- Pili Do [4,3-d] pyrimidine   4-[(3-chloro-4-fluoro-phenyl) amino] -7-fluoro-pyrido [4,3-d] pyri Midine 100 mg and 4-aminopiperidine 202 mg in 3 ml of isopropanol at 90 ° C. For 4 hours and at room temperature for 18 hours. This crude mixture is directly And purified with methylene chloride / methanol / concentrated aqueous ammonia (9: 1: 0.1) . Yield: 65 mg (51% of theory) Melting point: 231-233 ° C, R_fValue: 0.25 (silica gel; methylene chloride / methanol / ammonia water = 4: 1: 0.1 ), Mass spectrum: M⁺= 372/4.   The following compound was obtained in an analogous manner to Example 1: (1) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(1-methyl-4-piperidinyl) Amino] -pyrido [4,3-d] pyrimidine Melting point: 253-256 ° C, R_fValue: 0.42 (silica gel; methylene chloride / methanol / aqueous ammonia = 4: 1: 0.1) , Mass spectrum: M⁺= 386/8. (2) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-piperidinyl) piperi Zin-1-yl] -pyrido [4,3-d] pyrimidine Melting point: 272-275 ° C, R_fValue: 0.32 (reverse phase silica gel; methanol / 5% physiological saline = 6: 4), Mass spectrum: M⁺= 440/2. (3) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(1-t-butyloxycarbonyl Ru-4-piperidinyl) amino] -pyrido [4,3-d] pyrimidine Melting point: 232-235 ° C, R_fValue: 0.41 (silica gel; ethyl acetate). (4) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[[trans-4- (methoxycal Bonyl) cyclohexyl)]-amino] -pyrido [4,3-d] pyrimidine Melting point: 253-254 ° C R_fValue: 0.50 (silica gel; ethyl acetate). (5) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-morpholino-pyrido [4,3-d] pi Limidine (6) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [N-methyl-N- (1-methyl-4-pi Peridinyl) amino] -pyrido [4,3-d] pyrimidine (7) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[[trans-4-hydroxy Clohexyl)]-amino] -pyrido [4,3-d] pyrimidine (8) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(2-amino-2-methyl-1-pro Pyl) -amino] -pyrido [4,3-d] pyrimidine (9) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(3-quinuclidinyl) -amino ] -Pyrido [4,3-d] pyrimidine (10) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-morpholino-pyrido [3,4-d] Pyrimidine (11) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (4-amino-1-piperidinyl) -Pyrido [3,4-d] pyrimidine Melting point: 307-309 ℃ (decomposition) R_fValue: 0.30 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 4: 1: 0. 1). (12) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(1-methyl-4-piperidinyl ) Amino] -pyrido [3,4-d] pyrimidine (13) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(trans-4-hydroxy Clohexyl) amino] -pyrido [3,4-d] pyrimidine (14) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(trans-4- (methoxyca Rubonyl) cyclohexyl] amino] -pyrido [3,4-d] pyrimidine (15) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (4-piperidinyl) piperi Zin-1-yl] -pyrido [3,4-d] pyrimidine R_fValue: 0.45 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 2: 1: 0. 15) (16) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(2-amino-2-methyl-1-p Ropyl) amino] -pyrido [3,4-d] pyrimidine R_fValue: 0.55 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 4: 1: 0. 1) (17) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(3-quinuclidinyl) amino ] -Pyrido [3,4-d] pyrimidine R_fValue: 0.34 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 6: 1: 0. 1) (18) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[[1- (t-butyloxycarbo Nyl) -4-piperidinyl] amino] -pyrido [3,4-d] pyrimidine (19) 4-[(4-amino-3,5-dibromo-phenyl) amino] -6-[(1-methyl-4-piperidini [Amino] -pyrido [3,4-d] pyrimidine (20) 4-[(4-amino-3,5-dibromo-phenyl) amino] -6-[(trans-4-hydroxy Cyclohexyl) amino] -pyrido [3,4-d] pyrimidine Melting point: 170 ° C (decomposition), R_fValue: 0.40 (silica gel; petroleum ether / ethyl acetate / methanol = 10: 10: 3) , Mass spectrum: M⁺= 506/508/510 (2Br) (21) 4-[(4-amino-3,5-dibromo-phenyl) amino] -6- [4- (4-piperidinyl) pipe Lysin-1-yl] -pyrido [3,4-d] pyrimidine R_fValue: 0.27 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 2: 1: 0. 1) Mass spectrum: M⁺= 559/561/563 (2Br) (22) 4-[(4-amino-3,5-dibromo-phenyl) amino] -6-[(2-amino-2-methyl-1- Propyl) amino] -pyrido [3,4-d] pyrimidine R_fValue: 0.23 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 6: 1: 0.1) Mass spectrum: M⁺= 479/481/483 (2Br) (23) 4-[(3-chlorophenyl) amino] -6-morpholino-pyrido [3,2-d] pyrimidine (24) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (4-amino-1-piperidinyl) -Pyrido [3,2-d] pyrimidine (25) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[[trans-4- (methoxyca Rubonyl) cyclohexyl] amino] -pyrido [3,2-d] pyrimidine (26) 4-[(3-methylphenyl) amino] -7-morpholino-pyrido [2,3-d] pyrimidine (27) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(1-methyl-4-piperidinyl ) Amino] -pyrido [2,3-d] pyrimidine (28) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[[trans-4-hydroxy Clohexyl] amino] -pyrido [2,3-d] pyrimidine (29) 4-[(3-bromophenyl) amino] -7-morpholino-pyrimido [4,5-d] pyrimidine (30) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [N-methyl-N- (1-methyl-4- Piperidinyl) -amino] -pyrimido [4,5-d] pyrimidine (31) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(1-methyl-4-piperidinyl ) -Amino] -pyrimido [4,5-d] pyrimidine (32) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [trans-4- (methoxycal Bonyl) cyclohexyl] -amino] -pyrimido [4,5-d] pyrimidine (33) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(3-tropanyl) -amino]- Pyrido [4,3-d] pyrimidine (34) 4-[(4-amino-3,5-dibromo-phenyl) amino] -6-[(3-tropanyl) -amino ] -Pyrido [3,4-d] pyrimidine Melting point: Half-melted from 150 ° C, decomposed from 170 ° C R_fValue: 0.17 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 6: 1: 0. 1) Mass spectrum: M⁺= 531/533/535 (2Br) (35) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-aminocyclohexyl Ru-amino] -pyrido [4,3-d] pyrimidine (36) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-methylaminocyclohex Siluamino] -pyrido [4,3-d] pyrimidine (37) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-dimethylaminocyclo Xyl-amino] -pyrido [4,3-d] pyrimidine (38) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4-aminocyclohexyl- Amino] -pyrido [3,4-d] pyrimidine (39) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4-methylaminocyclohexene Sil-amino] -pyrido [3,4-d] pyrimidine (40) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4-dimethylaminocyclo Xyl-amino] -pyrido [3,4-d] pyrimidine (41) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-aminocyclohexyl- Amino] -pyrido [2,3-d] pyrimidine (42) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-methylaminocyclohexene Sil-amino] -pyrido [2,3-d] pyrimidine (43) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-dimethylaminocyclo Xyl-amino] -pyrido [2,3-d] pyrimidine (44) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-aminocyclohexyl- Amino] -pyrimido [4,5-d] pyrimidine (45) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-methylaminocyclohexene Sil-amino] -pyrimido [4,5-d] pyrimidine (46) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-dimethylaminocyclo Xyl-amino] -pyrimido [4,5-d] pyrimidine (47) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4-aminocyclohexyl- Amino] -pyrido [3,2-d] pyrimidine (48) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4-methylaminocyclohexene Sil-amino] -pyrido [3,2-d] pyrimidine (49) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4-dimethylaminocyclo Xyl-amino] -pyrido [3,2-d] pyrimidine.Example 2 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(4-piperidinyl) -amino]-Pi Lido [4,3-d] pyrimidine   4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(1-t-butyloxycarbonyl L-4-piperidinyl) -amino] -pyrido [4,3-d] pyrimidine l86mg, methylene chloride 2ml And 2 ml of trifluoroacetic acid were stirred at room temperature for 1 hour. This is evaporated to dryness and 5 ml of water And made alkaline with 1N sodium hydroxide solution. Stir at room temperature for 30 minutes Thereafter, the precipitate was filtered off with suction, washed with water and dried at 70 ° C. in vacuo. Yield: 115 mg (78% of theory) Melting point: 265-267 ℃ R_fValue: 0.50 (reverse phase silica gel; acetonitrile / water (1: 1) + 1% trifluorovinegar) acid).   The following compound was obtained in an analogous manner to Example 2: (1) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(4-piperidinyl) -amino]- Pyrido [3,4-d] pyrimidine (2) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (1-piperazinyl) -1-pipe Lydinyl] -pyrido [4,3-d] pyrimidine (3) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-piperidinyl) -1-pipe Radinyl] -pyrido [4,3-d] pyrimidine (4) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (1-piperazinyl) -1-pipe Lydinyl] -pyrido [3,4-d] pyrimidine (5) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (4-piperidinyl) -1-pipe Radinyl] -pyrido [3,4-d] pyrimidine (6) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (1-piperazinyl) -1-pipe Lydinyl] -pyrido [2,3-d] pyrimidine (7) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-piperidinyl) -1-pipe Radinyl] -pyrido [2,3-d] pyrimidine (8) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (1-piperazinyl) -1-pipe Lydinyl] -pyrimido [4,5-d] pyrimidine (9) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-piperidinyl) -1-pipe Radinyl] -pyrimido [4,5-d] pyrimidine (10) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (1-piperazinyl) -1-pi Peridinyl] -pyrido [3,2-d] pyrimidine (11) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (4-piperidinyl) -1-pi Perazinyl] -pyrido [3,2-d] pyrimidine.Example 3 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(trans-4-carboxyBlack Hexyl) -amino] -pyrido [4,3-d] pyrimidine   4-[(3-chloro-4-fluoro-phenyl) amino] -7-[[ Trans-4- (methoxycarbonyl) cyclohexyl] -amino] -pyrido [4,3-d] pyri 210 mg of midine was mixed with 2 ml of 1N sodium hydroxide solution and stirred at room temperature for 2 hours. 1N 2.1 ml of hydrochloric acid were added and the methanol was removed in vacuo. After adding 5 ml of water, The mixture is stirred for 30 minutes in an ice bath, the precipitate is filtered off with suction, washed with ice water and dried. did. Yield: 170 mg (84% of theory) Melting point: 306-310 ℃ R_fValue: 0.10 (silica gel; ethyl acetate).   The following compound was obtained in an analogous manner to Example 3: (1) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(trans-4-carboxy Clohexyl) -amino] -pyrido [3,4-d] pyrimidine (2) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(trans-4-carboxy Clohexyl) -amino] -pyrido [3,2-d] pyrimidine (3) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[(trans-4-carboxy Clohexyl) -amino] -pyrimido [4,5-d] pyrimidine.Example 4 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[[trans-4- (moorholinoMosquito Rubonyl) cyclohexyl] -amino] -pyrido [4,3-d] pyrimidine   4-[(3-chloro-4-fluoro-phenyl) using 1 ml of dimethylformamide as a solvent Ru) amino] -7-[(trans-4-carboxycyclohexyl) -amino] -pyrido [4,3-d ] Pyrimidine 140 mg solution, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetra Methyluronium-tetrafluoroborate 135 mg, triethylamine 0.19 ml and 0.06 ml of morpholine was added and the mixture was stirred at room temperature for 1.5 hours. Water 10m l was added and the mixture was stirred for 20 minutes. The precipitate is filtered off with suction and washed with water. And dried at 60 ° C. under vacuum. Yield: 130 mg (82% of theory) Melting point: 278-283 ℃ R_fValue: 0.54 (silica gel; methylene chloride / methanol = 6: 1).   The following compound was obtained in an analogous manner to Example 4: (1) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[[trans-4- (moorholino Carbonyl) cyclohexyl] -amino] -pyrido [3,4-d] pyrimidine (2) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[[trans-4- (moorholino Carbonyl) cyclohexyl] -amino] -pyrido [3,2-d] pyrimidine (3) 4-[(3-chloro-4-fluoro-phenyl) amino] -7-[[trans-4- (moorholino Carbonyl) cyclohexyl] -amino] -pyrimido [4,5-d] pyrimidine.Example 5 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (1-methyl-4-piperidiniLe) Piperidin-1-yl] -pyrido [4,3-d] pyrimidine   4-[(3-chloro-4-fluoro-phenyl) amino] -7- [using 30 ml of methanol as a solvent Suspension of 365 mg of 4- (4-piperidinyl) piperidin-1-yl] -pyrido [4,3-d] pyrimidine The solution was charged with 0.07 ml of 37% formalin solution and cyanoborohydride (cyanoborohidride) 57. mg was added. After stirring for 30 minutes at room temperature, 10 ml of methylene chloride are added and The mixture was stirred for 3 hours. Then evaporate to dryness, add 15 ml of water, and mix the mixture. Stir for 30 minutes. The residue is filtered by suction, and methylene chloride / methanol / concentrated ammonia Purified by chromatography on a silica gel column with water (9: 1: 0.1) did. Yield: 196 mg (52% of theory) Melting point: 291-292 ° C R_fValue: 0.50 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 6: 1: 0. 1).   The following compound was obtained in an analogous manner to Example 5: (1) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (1-methyl-4-piperidini) Le) piperidin-1-yl] -pyrido [3,4-d] pyrimidine Melting point: 180-185 ℃ (decomposition, half-molten from 168 ℃) R_fValue: 0.43 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 6: 1: 0. 1) (2) 4-[(4-amino-3,5-dibromo-phenyl) amino] -6- [4- (1-methyl-4-piperidi Nyl) piperidin-1-yl] -pyrido [4,3-d] pyrimidine Melting point: 220-222 ° C R_fValue: 0.24 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 10: 1: 0) .1) Mass spectrum: M⁺= 573/575/577 (2Br) (3) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-methyl-1-piperazini) Le) -1-piperidinyl] -pyrido [4,3-d] pyrimidine (4) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (1-methyl-4-piperidini) Le) -1-piperazinyl] -pyrido [4,3-d] pyrimidine (5) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (4-methyl-1-piperazini) Le) -1-piperidinyl] -pyrido [3,4-d] pyrimidine (6) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (1-methyl-4-piperidini) Le) -1-piperazinyl] -pyrido [3,4-d] pyrimidine (7) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-methyl-1-piperazini) Le) -1-piperidinyl] -pyrido [2,3-d] pyrimidine (8) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (1-methyl-4-piperidini) Le) -1-piperazinyl] -pyrido [2,3-d] pyrimidine (9) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-methyl-1-piperazini) Le) -1-piperidinyl] -pyrimido [4,5-d] pyrimidine (10) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- (1-methyl-4-piperi Dinyl) -1-piperazinyl] -pyrimido [4,5-d] pyrimidine (11) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (4-methyl-1-piperazini) Le) -1-piperidinyl] -pyrido [3,2-d] pyrimidine (12) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- [4- (1-methyl-4-piperidini) Le) -1-piperazinyl] -pyrido [3,2-d] pyrimidineExample 6 Coated tablets containing 75mg of active ingredient The core of one tablet contains: Active ingredient 75.0mg 93.0mg calcium phosphate 35.5mg corn starch Polyvinyl pyrrolidone 10.0mg Hydroxypropyl methylcellulose 15.0mgMagnesium stearate 1.5mg                                    230.0mgMethod :   This active ingredient is calcium phosphate, corn starch, polyvinylpyro Lidone, hydroxypropyl methylcellulose, and magnesium stearate Mix with half of the indicated amount. A semi-finished product with a diameter of about 13 mm is manufactured on a tablet machine. And pass them through a 1.5 mm mesh sieve to remove the remaining magnesium stearate. Mix with water. The granulated mixture is compressed with a tablet machine to form tablets of a desired shape. To manufacture. Core weight: 230mg Mouse: 9mm, convex   Thus, the core of the tablet is substantially hydroxypropyl methylcellulose. Covered with a film comprising: The final film-coated tablets are beads Polished with wax. Weight of coated tablet: 245mg Example 7 Tablet containing 100mg of active ingredient composition: One tablet contains: Active ingredient 100.0mg Lactose 80.0mg 34.0mg corn starch Polyvinyl pyrrolidone 4.0mgMagnesium stearate 2.0mg                                    220.0mgManufacturing method :   Mix the active ingredient, lactose and starch, and with an aqueous solution of polyvinylpyrrolidone, Wet evenly. This wet composition is sieved (2.0 mm mesh) and then heated at 50 ° C. Dry in a paper-type dryer, sieve again (mesh size 1.5 mm), and lubricate Add the agent. This mixture, ready for compression, is tableted. Tablet weight: 220mg Diameter: 10mm, two layers (biplaner), flat on both sides, split on one side for splitting Yes. Example 8Tablet containing 150mg of active ingredient composition: One tablet contains: Active ingredient 150.0mg 89.0mg lactose powder Corn starch 40.0mg Colloidal silica 10.0mg Polyvinyl pyrrolidone 10.0mgMagnesium stearate 1.0mg                                    300.0mg Manufacturing method :   Active ingredient mixed with lactose, corn starch and silica in 20% polyvinyl alcohol Wet with an aqueous solution of lupyrrolidone and pass through a 1.5 mm mesh sieve.   The granulated material dried at 45 ° C. is passed through the same sieve again and the specified amount of step is performed. Mix with magnesium aphosphate. From this mixture, tablets are compressed. Tablet weight: 300mg Mouse: 10mm, flatExample 9 Hard gelatin capsule containing 150mg of active ingredient One capsule contains: Active ingredient 150.0mg Dried corn starch about 180.0mg 87.0mg lactose powderMagnesium stearate 3.0mg                                 About 420.0mgMethod :   The active ingredient is mixed with the aforementioned excipients, passed through a sieve with a mesh size of 0.75 mm, and Mix uniformly with a suitable tool. Put this final mixture into the first hard gelatin capsule Fill. Capsule filling: about 320mg Capsule shell: No. 1 hard gelatin capsuleExample 10 Suppository containing 150mg of active ingredient One suppository contains the following: Active ingredient 150.0mg Polyethylene glycol 1500 550.0mg Polyethylene glycol 6000 460.0mgPolyoxyethylene sorbitan monostearate 840.0mg                                              2000.0mg Method :   After melting the suppository base (mass), the active ingredient is evenly dispersed therein, Pour into a cooled mold.Example 11 Suspension containing 50mg of active ingredient 100 ml of the suspension contains: Active ingredient 1.00g Carboxymethylcellulose Na salt 0.10g Methyl p-hydroxybenzoate 0.05g Propyl p-hydroxybenzoate 0.01g Glucose 10.0g Glycerol 5.00g 70% sorbitol solution 20.0g Perfume 0.30g Distilled water ad 100mlMethod :   Heat the distilled water to 70 ° C. In it, methyl and propyl p-hydroxybenzoate Perfume ester, glycerol and carboxymethylcellulose sodium salt, Dissolve. The solution is cooled down to room temperature and the active ingredient is added, in which Stir to disperse. Sugar, sorbitol solution and flavor added and dissolved Thereafter, the suspension is placed in a vacuum and degassed.   5 ml of the suspension contain 50 mg of the active ingredient.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/519 A61K 31/505 606 31/5377 31/535 606 C07D 487/04 148 C07D 487/04 148 519 / 00 311 519/00 311 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, KS, MW, SD, SZ, UG), UA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT , LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU (72) Inventor von Ruden Thomas Austria Ar 2500 Baden ötkerweg 12 (72) Inventor Mets Thomas Austria Ar 1010 Wien Rathausstrasse 19-2-25

Claims (1)

Claims 1. A 4-amino-pyrimidine derivative of the following general formula or a tautomer, stereoisomer or salt thereof: (Wherein, R _a represents a hydrogen atom or a methyl group; R _b is a phenyl group substituted with R ₁ to R ₃ , or a phenylalkyl substituted phenyl group with R ₁ to R ₃ Means a group wherein R ₁ is hydrogen, fluorine, chlorine, bromine or iodine atom, alkyl, trifluoromethyl, ethenyl, ethynyl, alkyloxy, C _3-6 -cycloalkyl, trifluoromethoxy, cyano, Represents an amino, alkylamino, dialkylamino, or nitro group, R ₂ represents a hydrogen, fluorine, chlorine, or bromine atom, or an alkyl group, and R ₃ represents a hydrogen, fluorine, chlorine, or bromine atom A and B together form a bridge of the formula: -N = CR _c -CH = CH-, -CH = N-CR _c = CH-, -CH = CR _c -N = CH- , -CH = CH-CR _c = N- or -CH = N-CR _c = N-, where in each case the left end of these bridges is Linked to the 5-position of the pyrimidine ring and the right end of these bridges is linked to the 6-position of the pyrimidine ring, wherein R _c is a morpholino optionally substituted with one or two alkyl groups. A 1-piperazinyl group optionally substituted with one or two alkyl groups, a 3-oxo-1-piperazinyl group optionally substituted with one or two alkyl groups, C _{3 -6} -cycloalkyl group, 3-tetrahydrofuranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 3-pyrrolidinyl, 1-alkyl-3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 1-alkyl-3- 1-piperazinyl group substituted at the 4-position by piperidinyl or 1-alkyl-4-piperidinyl group, 1-azetidinyl optionally substituted with R ₄ , 1-pyrrolidinyl, 1-piperidinyl or 1-azacyclohept -1-yl Means a group: wherein R ₄ is hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, N-alkyl-alkylcarbonylamino, 2-oxo-1-pyrrolidinyl, 2-oxo-1 - piperidinyl, alkyloxycarbonylamino, N- alkyl - alkyloxycarbonylamino, alkylsulfonylamino, N- alkyl - alkylsulfonylamino, C _3-6 - cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1-alkyl - Pyrrolidinyl, piperidinyl, 1-alkyl-piperidinyl, morpholino, 1-piperazinyl, 4-alkyl-1-piperazinyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyl, alkyloxycarbonyl, aminocarbonyl, al Le aminocarbonyl, dialkylaminocarbonyl, 1-pyrrolidinylcarbonyl, means a 1-piperidinylcarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl, 4-alkyl-1-piperazinylcarbonyl or cyano group. ), A 1-azetidinyl group in which two hydrogen atoms at the 3-position are substituted with a straight-chain alkylene bridge having 4-5 carbon atoms, wherein in each case of the aforementioned alkylene bridge, the methylene group is , An oxygen atom or by an imino or N-alkyl-imino group, wherein the two hydrogen atoms of the carbon skeleton are 1-pyrrolidinyl groups substituted by a linear alkylene bridge, the bridge being Three to five carbon atoms when two hydrogen atoms are on the same carbon atom, or three or four carbon atoms when these two hydrogen atoms are on adjacent carbon atoms Or, if these two hydrogen atoms are on carbon atoms separated by one atom, containing two or three carbon atoms, wherein each of the aforementioned alkylene bridges Has a methylene group May be substituted by an oxygen atom or by an imino or N-alkyl-imino group, wherein the two hydrogen atoms of the carbon skeleton are 1-piperidinyl groups substituted by a straight-chain alkylene bridge, the bridge comprising 3-5 carbon atoms when two hydrogen atoms are on the same carbon atom, or 3 or 4 carbon atoms when these two hydrogen atoms are on adjacent carbon atoms. A carbon atom, or two or three carbon atoms if these two hydrogen atoms are on carbon atoms separated by one atom, or two of these two hydrogen atoms Containing one or two carbon atoms when located on carbon atoms separated by an atom of the formula: wherein in each of the aforementioned alkylene bridges the methylene group is replaced by an oxygen atom or by an imino or alkylimino group. Place Or means that may be, or, R _c denotes a (R ₅ NR ₆₎ group: (wherein R ₅ denotes a hydrogen atom or an alkyl group, and R ₆ is substituted by R ₄ C _5-7 -cycloalkyl group (wherein R ₄ is as defined above)), 3-tetrahydrofuranyl group, 3- or 4-tetrahydropyranyl group, 3- A pyrrolidinyl or 3- or 4-piperidinyl group, wherein the cyclic nitrogen atom of the aforementioned groups is, in each case, alkyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, C _3-6 -cycloalkyl, 3-tetrahydrofuran Substituted with a phenyl, 3- or 4-tetrahydropyranyl, 3-pyrrolidinyl, 1-alkyl-3-pyrrolidinyl, 3- or 4-piperidinyl, 1-alkyl-3-piperidinyl, or 1-alkyl-4-piperidinyl group Can be C substituted with R ₄ groups _2-6 -alkyl group, wherein R ₄ is as defined above. ), 3- or 4-quinuclidinyl or 3-tropanyl or desmethyl-3-tropanyl. ). ), And unless otherwise stated, in each case the aforementioned alkyl groups contain 1 to 4 carbon atoms. However, the compound 4-[(3-bromophenyl) amino] -6- (1-piperidinyl) -pyrido [3,4-d] pyrimidine is excluded). 2. R _a represents a hydrogen atom or a methyl group, and R _b represents a phenyl group substituted with an R ₁ to R ₃ group: (where R ₁ is hydrogen, fluorine, chlorine, bromine or Iodine atom, methyl, ethyl, trifluoromethyl, methoxy, cyclopropyl, trifluoromethoxy, cyano, nitro or amino group, R ₂ represents hydrogen, fluorine, chlorine or bromine atom, R ₃ represents A hydrogen, fluorine, chlorine or bromine atom), A and B together form a bridge of the formula: -N = CR _c -CH = CH-, -CH = N-CR _c = CH-, -CH = CR _c -N = CH-, -CH = CH-CR _c = N- or -CH = N-CR _c = N-, where in each case the left end of these bridges is Linked to the 5-position of the pyrimidine ring, and the right end of these bridges is linked to the 6-position of the pyrimidine ring, wherein R _c is a morpholino group optionally substituted with one or two methyl groups; , One or two optionally substituted and each may be a 1-piperazinyl group with methyl group, 4-piperidinyl - or 1-alkyl-4-piperidinyl group, substituted 1-piperazinyl group at the 4-position by R ₄ A 1-pyrrolidinyl group substituted at the 3-position or a 1-piperidinyl group substituted at the 3- or 4-position by R ₄ , wherein R ₄ is amino, methylamino, dimethylamino, pyrrolidinyl , 1-methylpyrrolidinyl, piperidinyl, 1-methylpiperidinyl, morpholino, 1-piperazinyl, 4-methyl-1-piperazinyl, hydroxyl, methoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl, 1-pyrrolid nyl, means a 1-piperidinylcarbonyl, or a morpholinocarbonyl group.), or means the (R ₅ NR ₆₎ group (Is wherein R _5, represents a hydrogen atom, or a methyl or ethyl group, and R ₆ means a substituted cyclopentyl or cyclohexyl group R ₄ (wherein R ₄ is as defined above )), A 3-pyrrolidinyl or 3- or 4-piperidinyl group, wherein the cyclic nitrogen atom of said group is, in each case, methyl, ethyl, C _1-4 alkyloxycarbonyl, acetyl, or A C _2-4 -alkyl group which can be substituted by a methylsulfonyl group and substituted by an R ₄ group, wherein R ₄ is as defined above. ), 3- or 4-quinuclidinyl group or 3-tropanyl group: provided that the compound 4-[(3-bromophenyl) amino] -6- (1-piperidinyl) -pyrido [3,4-d] Except for pyrimidine: 4-amino-pyrimidine derivatives of the general formula I according to claim 1, or tautomers, stereoisomers or salts thereof. 3. R _a represents a hydrogen atom, R _b represents a phenyl group substituted with R ₁ to R ₃ group: (where R ₁ represents a hydrogen, fluorine, chlorine or bromine atom, methyl or R ₂ represents a hydrogen, fluorine, chlorine or bromine atom; R ₃ represents a hydrogen, fluorine, chlorine or bromine atom.), A and B together represent Formula crosslinking: -N = CR _c -CH = CH-, -CH = N-CR _c = CH-, -CH = CR _c -N = CH-, -CH = CH-CR _c = N- or- CH = N-CR _c = N-, where in each case the left end of these bridges is linked to position 5 of the pyrimidine ring and the right end of these bridges is linked to position 6 of the pyrimidine ring. Wherein R _c is a 1-piperidinyl group substituted at the 3- or 4-position by a morpholino group, amino, piperidinyl or 1-methylpiperidinyl group, or an (R ₅ NR ₆ ) group Wherein R ₅ is a hydrogen atom or a methyl group And R ₆ is a cyclohexyl group, 3- or 4-piperidinyl group substituted with a carboxyl, methoxycarbonyl, ethoxycarbonyl, morpholinocarbonyl or hydroxyl group, wherein the aforementioned cyclic nitrogen atom is In the above case, it can be substituted with a methyl, ethyl or C _1-4 alkyloxycarbonyl group, and means a C _2-4 -alkyl group, 3-tropanyl or 3-quinuclidinyl group substituted with an amino group. However, except for the compound 4-[(3-bromophenyl) amino] -6- (1-piperidinyl) -pyrido [3,4-d] pyrimidine.) 4-amino-pyrimidine derivatives or tautomers, stereoisomers or salts thereof. 4. The following 4-amino-pyrimidine derivatives of general formula I according to claim 1 or salts thereof: (1) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- ( 4-amino-1-piperidinyl) -pyrido [4,3-d] pyrimidine, (2) 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [1-methyl-4-piperidinyl) Amino] -pyrido [4,3-d] pyrimidine; (3) 4-[(3-chloro-4-fluoro-phenyl) amino] -6- (4-amino-1-piperidinyl) -pyrido [3,4 -d] pyrimidine, (4) 4-[(3-chloro-4-fluoro-phenyl) amino] -6-[(3-quinuclidinyl) amino] -pyrido [3,4-d] pyrimidine, (5) 4 -[(4-amino-3,5-dibromo-phenyl) amino] -6-[(trans-4-hydroxycyclohexyl) amino] -pyrido [3,4-d] pyrimidine; (6) 4-[(3 -Chloro-4-fluoro-phenyl) amino] -6- [4- (1-methyl-4-piperidinyl) piperidin-1-yl] -pyrido [3,4-d] pyrimidine 5. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 4 with inorganic or organic acids or bases. 6. A compound according to at least one of claims 1 to 4, or a physiologically acceptable salt according to claim 5, optionally together with one or more inert carriers and / or diluents. Pharmaceutical composition containing. 7. Claims for producing a pharmaceutical composition suitable for the treatment of benign or malignant tumors, especially those of epithelial and neuroepithelial origin, metastasis and abnormal proliferation of vascular endothelial cells (neovascularization). Use of the compound according to at least one of the items 1 to 5 above. 8. A compound according to claim 1, characterized in that it is mixed in a non-chemical manner with one or more inert carriers and / or diluents. A method for producing the pharmaceutical composition according to claim 6. 9. A process for the preparation of a compound of general formula I according to claims 1 to 5, characterized by the following steps: a) with a compound of general formula Wherein R _a and R _b are as defined in claims 1-4, and A ′ and B ′ together form a bridge of the formula: —N = CZ ₁ —CH = CH-, -CH = N-CZ ₁ = CH-, -CH = CZ ₁ -N = CH-, -CH = CH-CZ ₁ = N- or -CH = N-CZ ₁ = N- Wherein Z ₁ represents a leaving group, in each case the left end of these bridges is linked to position 5 of the pyrimidine ring and the right end of these bridges is linked to position 6 of the pyrimidine ring X ₁ -H (III) (wherein X ₁ is one of the groups described for R _c in Claims 1 to 4) And, if desired, subsequently converting the compound of the general formula I thus obtained containing an amino or imino group into the corresponding alkyl compound of the general formula I by alkylation or reductive alkylation. Converted and / or the carbs thus obtained A compound of the general formula I containing a di- or ester group is converted by amidation into the corresponding amide compound of the general formula I and / or, if necessary, used in the reactions indicated above. The protecting group is cleaved again and / or, if desired, the compound of the general formula I thus obtained is separated into its stereoisomers and / or the compound of the formula I thus obtained is converted into its salt Said process, especially to their physiologically acceptable salts for pharmaceutical use.