SK120598A3 - 4-amino pyrimidine derivates, medicaments containing these compounds, their use and process for their production - Google Patents

Abstract

The present invention relates to 4-amino pyrimidine derivatives of general formula (I), where Ra, Rb, A and B are as defined in claim 1, their tautomers, stereoisomers and salts, especially their physiologically acceptable salts with inorganic or organic acids or bases, having valuable pharmacological properties, especially an inhibitory effect on signal transduction produced by tyrosinkinases, their use in the treatment of disorders, especially tumours, and their production.

Description

4-Amino-pyrimidine derivatives, process for their preparation, pharmaceutical composition containing them and their use. f '' J '

Technical field

The invention relates to 4-aminopyrimidine derivatives, a process for their preparation, a pharmaceutical composition containing them and their use for the treatment of benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastases, as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

SUMMARY OF THE INVENTION

The present invention provides 4-amino-pyrimidine derivatives of the general formula

R ^a

(Their tautomers, stereoisomers and salts thereof, in particular their physiologically acceptable salts with inorganic or organic acids or bases having valuable pharmacological properties, in particular having a tyrosine kinase-mediated inhibitory effect on signaling, their use in the treatment of diseases, in particular cancer, and their preparation.

In the general formula I except for 4 - [(3-bromophenyl) amino] -6- (1-piperidinyl) -pyrido [3,4-d] pyrimidine,

R ^a is a hydrogen atom or a methyl group,

R ^b is a phenyl group substituted with R ¹ to R ³ or a phenylalkyl group wherein the phenyl moiety is substituted with R ¹ to R ³ , wherein:

R ¹ is H, F, Cl, Br, I, alkyl, trifluoromethyl, ethenyl,

-2etinyl-, alkyloxy, C ₃ _ ₆ -cycloalkyl-, trifluoromethoxy, cyano, amino, alkylamino, dialkylamino, or nitro,

R ² is H, F, Cl, Br, or alkyl and

R ³ is a hydrogen, fluorine, chlorine or bromine atom,

A and B together represent 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, the left end of this bridge being connected to position 5 and the right end of this bridge being connected to position 6 of the pyrimidine ring, wherein R ^c is v in this case, a morpholino group substituted with one or two alkyl groups,

1-piperazinyl in the present case substituted by one or two alkyl groups,

3-oxo-1-piperazinyl in the present case substituted by one or two alkyl groups,

1-piperazinyl, which in position 4 is substituted by C _{3. 6-} cycloalkyl, 3-tetrahydrofuranyl-, 3-tetrahydropyranyl-, 4-tetrahydropyranyl-, 3-pyrrolidinyl-, 1-alkyl-3-pyrrolidinyl-, 3-piperidinyl-, 4-piperidinyl-, 1-alkyl-3-piperidinyl- or 1-cycloalkyl; alkyl-4piperi-dinylskupinou.

-azetidinyl-, 1-pyrrolidinyl-, 1-piperidinyl- or 1-azacyclohept-1-yl, in this case substituted by R ⁴ , wherein:

R ⁴ is hydroxy-, alkyloxy-, amino-, alkylamino-, dialkylamino-, alkylcarbonylamino-, Nalkyl-alkylcarbonylamino-, 2-oxo-1-pyrrolidinyl-, 2-oxo-1-piperidinyl-, alkyl-oxycarbonyl-amino- , Ν-alkyl-alkyloxycarbonylamino-, alkylsulfonylamino-, N-alkyl-alkylsulfonyl-amino-, C ₃ . _6- cycloalkyl-, tetrahydrofuranyl-, tetrahydropyranyl-, pyrrolidinyl-, 1-alkyl-pyrrolidinyl-, piperidinyl-, 1-alkyl-piperidinyl-, morpholino-, 1-piperazinyl-, 4alkyl-1-piperazinyl-, aminoalkyl-, alkylaminoalkyl -, dialkylaminoalkyl-, carboxy-, alkyloxy-carbonyl-, aminocarbonyl-, alkylaminocrabonyl-, dialkylaminocarbonyl-, 1-3-pyrrolidinyl-carbonyl-, 1-piperidinylcarbonyl-, morpholinocarbonyl-, 1-piperazinylcarbonyl-, 4-alkyl-1- piperazinylcarbonyl- or cyano,

1-azetidinyl in which the 2 hydrogen atoms in the 3-position are replaced by an unbranched alkylene bridge having 4 or 5 carbon atoms, wherein in the above alkylene bridges the methylene group can be replaced by an oxygen atom or an imino- or N-alkyl-imino group,

A 1-pyrrolidinyl group in which 2 hydrogen atoms on a carbon skeleton are replaced by an unbranched alkylene bridge, said bridge containing 3 to 5 carbon atoms if the two hydrogen atoms are on the same carbon atom or contain 3 or 4 carbon atoms if the two hydrogen atoms are on adjacent carbon atoms, or contain 2 or 3 carbon atoms, if the two hydrogen atoms are on carbon atoms separated by one atom, wherein in the above alkylene bridges the methylene group may be replaced by an oxygen atom or an imino- or Nalkyl-imino group,

1-piperidinyl wherein 2 hydrogen atoms on the carbon skeleton are replaced by an unbranched alkylene bridge containing 3 to 5 carbon atoms if the two hydrogen atoms are on the same carbon atom or contain 3 or 4 carbon atoms if the two carbon atoms are present on adjacent carbon atoms, or contain 2 or 3 carbon atoms if the two hydrogen atoms are on carbon atoms separated by one atom, or contain 1 or 2 carbon atoms if the two hydrogen atoms are present are present on carbon atoms separated by two atoms, wherein in the above alkylene bridges the methylene group may be replaced by an oxygen atom or an imino- or alkylimino group, or R ^c is a (R ⁵ NR ⁶ ) -group in which

R ⁵ is hydrogen or alkyl; and

R ⁶ is C ₅ . _A cycloalkyl group substituted with an R ⁴ radical, wherein R ⁴ is as defined above,

3-tetrahydrofuranyl,

3- or 4-tetrahydropyranyl,

-43-pyrrolidinyl or 3- or 4-piperidinyl wherein the ring nitrogen of said groups may be substituted by alkyl, alkylcarbonyl, alkylsulfonyl, alkyloxy, C _{3. 6-} cycloalkyl-, 3-tetrahydrofuranyl-, 3- or 4-tetrahydropyranyl-, 3-pyrrolidinyl-, 1-alkyl-3-pyrrolidinyl-, 3- or 4-piperidinyl-, 1-alkyl-3-piperidinyl- or 1-alkyl -4-piperidinyl,

C ₂ . _6- alkyl substituted by R ⁴ , wherein R ⁴ is as defined above, 3- or 4-quinuclidinyl or 3-tropanyl- or desmethyl-3-tropanyl, and, unless otherwise mentioned, said alkyl moieties each contain 1 - up to 4 carbon atoms.

However, preferred compounds of formula I are those wherein R ^a is a hydrogen atom or a methyl group,

R ^b is phenyl substituted with R ¹ to R ³ , wherein

R ¹ is H, F, Cl, Br, I, methyl, ethyl, trifluoromethyl, methoxy, cyclopropyl, trifluoromethoxy, cyano, nitro or amino,

R ² is H, F, Cl, Br,

R ³ is a hydrogen, fluorine, chlorine or bromine atom,

A and B together represent a bridge of the formula

- N = ^C CR - CH = CH-,

-CH = N-CR = ^CH-C = CH R ^c - N = CH-,

- CH = CH - CR ^C = N - or

-CH = N-CR ^C = N, the left-hand end of the bridge being linked to the 5-position and the right-hand end of the bridge being linked to the 6-position of the pyrimidine ring, wherein R ^c in this case is morpholino substituted with one or two methyl groups

1-piperazinyl in the present case substituted by one or two methyl groups,

A 1-piperazinyl group which is substituted at the 4-position with a 4-piperidinyl or 1alkyl-4-piperidinyl group,

-51-pyrrolidinyl substituted at the 3-position by R ⁴ or 1-piperidinyl at the 3-position or 4 substituted by R ⁴ , wherein R ⁴ is amino-, methylamino-, dimethylamino-, pyrrolidinyl-, 1-methylpyrrolidinyl-, piperidinyl-, 1-methylpiperidinyl-, morpholino-, 1-piperazinyl-, 4-methyl-1-piperazinyl-, hydroxy-, methoxy-, carboxy-, methoxycarbonyl-, ethoxycarbonyl-, dimethyl-aminocarbonyl-, 1-pyrrolidinyl-carbonyl-, 1-piperidinylcarbonyl - or a morpholino-carbonyl group, or (R ⁵ NR ⁶ ) group in which

R ⁵ is hydrogen or methyl or ethyl; and

R ⁶ is a cyclopentyl or cyclohexyl group substituted with an R ⁴ radical, wherein R ⁴ is as defined above,

3-pyrrolidinyl- or 3- or 4-piperidinyl, wherein the ring nitrogen of said groups may be substituted by methyl-, ethyl-, C 1-4 -alkyloxycarbonyl-, acetyl- or methylsulfonyl,

C ₂ . _{A 4-} alkyl group substituted with an R ⁴ radical, wherein R ⁴ is as defined above,

3- or 4-quinuclidinyl or 3-tropanyl, their tautomers, stereoisomers and salts thereof.

However, particularly preferred compounds of formula I are those in which:

R ^a is a hydrogen atom,

R ^b is a phenyl group substituted with R ¹ to R ³ , wherein

R ¹ is H, F, Cl, Br, methyl or amino,

R ² is H, F, Cl, Br,

R ³ is a hydrogen, fluorine, chlorine or bromine atom,

A and B together represent a bridge of the formula

- N = R ^c - H = C H -,

-CH = N-CR ^C = CH

-CH = CR ^C -N = CH

- CH = CH - CR ^C = N - or

- CH = N - CR ^C = N, the left-hand end of this bridge being connected to position 5 and the right-hand end of this bridge being connected to position 6 of the pyrimidine ring and in which

-6R ^c is morpholino,

1-piperidinyl which is substituted in the 3 or 4 position by amino, piperidinyl or 1-methylpiperidinyl, or (R ⁵ NR ⁶ ) group, wherein:

R ⁵ is a hydrogen atom or a methyl group; and

R ⁶ is a cyclohexyl group which is substituted by carboxy, methoxycarbonyl, ethoxycarbonyl, morpholinocarbonyl or hydroxy,

3- or 4-piperidinyl, wherein the ring nitrogen atom may be substituted by a methyl, ethyl or C 1-6 alkyl-oxycarbonyl group,

C ₂ . _4- amino-substituted alkyl,

3-tropanyl- or 3-quinuclidinyl, their tautomers, stereoisomers and salts thereof.

Particularly preferred compounds are:

(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, (S) 4 - [(4-amino-3,5-dibromophenyl) amino] -6 - [(trans -4-hydroxycyclohexyl)] amino] pyrido [3,4-d] pyrimidine, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (1-methyl-4-piperidinyl) piperidin-1] -yl] -pyrido [3,4-d] pyrimidine, and salts thereof.

The compounds of formula I can be prepared, for example, by the following methods:

Reaction of a compound of formula

R ^and R ^b

FROM

B '

-7 in which

R ^a and R ^b were defined initially,

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 in which

Z ¹ is a starting group such as a halogen atom, a substituted hydroxy, mercapto, sulfinyl or sulfonyl group such as a fluorine, chlorine or bromine atom, methoxy, ethoxy, phenoxy, methylsulfinyl, ethylsulfinyl, methylsulfonyl, or ethylsulfonyl, and the left end of this bridge is joined to position 5 and the right end of this bridge is joined to position 6 of the pyrimidine ring, a compound of formula

X ¹ - H (III) wherein

X ¹ is one of the residues initially mentioned for R ^c .

The reaction is conveniently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluol, chlorobenzol, dimethylformamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, for example sodium carbonate, or a potassium hydroxide, or a tertiary organic base such as triethylamine or pyridine, the latter may also serve as a solvent, and in the present case in the presence of a catalyst such as a copper salt of the corresponding amine hydrohalide or alkaline halide at temperatures between 0 and 180 ° C, but preferably at temperatures between 20 and 150 ° C. However, the reaction may also be carried out without solvent or in excess of the compound of formula III used.

When a compound of formula I containing an amino or imino group is obtained according to the invention, it can be transformed, by alkylation or reductive alkylation, into the corresponding alkyl compound of formula I, or if a compound of formula I containing carboxy- or ester is obtained group, then it can be transformed by amidization to the corresponding amide of formula I.

Subsequent alkylation is carried out in the present case in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzol, toluol, chlorobenzole, tetrahydrofuran, benzol / tetrahydrofuran or dioxane using an alkylating agent such as the corresponding halide or sulfonic acid ester, for example methyl iodide. , ethyl bromide, dimethyl sulfate or benzyl chloride, in the present case in the presence of a tertiary organic base or in the presence of an inorganic base, preferably at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C.

Subsequent reduction analysis is performed with the corresponding carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde or acetone in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride, preferably at pH 6-7 and at room temperature, or at room temperature. the presence of a hydrogenation catalyst, for example with hydrogen in the presence of palladium on charcoal, at a hydrogen pressure of 1.10 ⁵ to 5.10 ⁵ Pa (1-5 bar). However, the methylation can also be carried out in the presence of formic acid as a reducing agent at elevated temperatures, for example at temperatures between 60 and 120 ° C.

Subsequent amidization is carried out by reacting the corresponding reactive carbonic acid derivative with the corresponding amine in the solvent or solvent mixture, such as methylene chloride, dimethylformamide, benzol, toluol, chlorobenzol, tetrahydrofuran or dioxane, where appropriate, and the amine used may also serve as a solvent. , in the present case, in the presence of a tertiary organic base, or with the corresponding carbonic acid in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, 2- (1H-9benzotriazol-1-yl) -1,1, 3,3-tetramethyl-uronium tetrafluoroborate, Ν, Ν'-dicyclohexylcarbodiimide, Ν, Ν'-dicyclohexylcarbodiimide / hydroxysuccinimide or 1-hydroxybenzotriazole, and in the presence of 4-dimethylaminopyridine, N, N'fosfamide, or suitably at temperatures m between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C.

In the above reactions, the reactive groups present, such as amino or imino or carboxy groups, may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example, a protecting group for an amino or imino group is formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tertiary butoxycarbonyl, benzyloxycarbonylbenzyl, methoxybenzyl or 2,4-dimethoxybenzyl, and additionally phthalyl for the amino group, a carboxy protecting group is trimethylsilyl-, methyl-, ethyl-, tert-butyl-, benzyl- or tetrahydropyranyl.

In the present case, the subsequent cleavage of the protecting group used is carried out, for example, hydrolytically in an aqueous solvent such as water, methanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid. or sulfuric acid, or in the presence of an alkaline base such as sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

However, the cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl moiety is carried out, for example, by hydrogenolysis, for example with hydrogen in the presence of a catalyst such as palladium on activated carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid. hydrochloric acid at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1.10 to 7.10 ⁵ Pa (1 to 7 bar), preferably at a pressure of 3 to 5.10 Pa ( 3 to 5 bars). However, the cleavage of the 2,4-dimethoxybenzyl residue is preferably carried out in trifluoroacetic acid in the presence of anisole.

The cleavage of the tert-butyl or tert-butyloxycarbonyl moiety is preferably effected by exposure to an acid such as trifluoroacetic acid or hydrochloric acid, or by exposure to iodotrimethylsilane in the present case using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

Cleavage of the trifluoroacetyl residue is preferably performed by exposure to an acid such as hydrochloric acid in the present case in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C, or exposure to sodium hydroxide in the present case in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.

The cleavage of the phthalyl residue is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

Furthermore, the compounds of the formula I obtained above can be decomposed into their enantiomers and / or diastereomers. Thus, for example, cis / trans mixtures can be decomposed into cis- and trans-isomers, and compounds with at least one active carbon atom into enantiomers.

Thus, for example, the obtained cis / trans mixtures can be decomposed chromatographically into the cis and trans isomers, the obtained compounds of formula I which occur as racemates according to known methods (see Allinger N.L. and Eliel EL in "Topics in Stereochemistry"). , vol. 6, Wiley Interscience, 1971), to optical counterparts and compounds of formula I with at least two asymmetric carbon atoms based on physicochemical differences by known methods, e.g.

by chromatography and / or fractional crystallization, to diastereomers which, when present in racemic form, can then be resolved into the enantiomers as described above.

The decomposition to enantiomers is preferably carried out by column chromatography on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance forming salts or derivatives such as esters or amides, in particular esters or amides, in particular acids and their activated derivatives, or

-11 alcohols, and separation of the diastereomeric mixture of salts or derivatives thus obtained, for example on the basis of different solubility, wherein free antipodes can be released from the pure diastereomeric salts or derivatives by suitable reagents. Particularly common optically active acids are, for example, the D- and L-forms of tartaric or dibenzoyltartaric, di-o-tolyltartaric, malic, almond, camphorsulfonic, glutamine, aspartic or quinic acids. Suitable optically active alcohol is, for example, (+) - or (-) - menthol and, as optically active acyl residue in amides, for example, it is (+) - or (-) - mentyloxycarbonyl.

Furthermore, the compounds of the formula I obtained can be transformed into their salts, especially in the case of pharmaceutical use, into physiologically acceptable salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric, hydrobromic, methanesulfonic, sulfuric, phosphoric, fumaric, succinic, lactic, citric, tartaric or maleic acids.

The compounds of formulas II and III used as starting materials are partly known from the literature or can be obtained by methods known from the literature (see, for example, WO 95/19774).

As mentioned above, the compounds of the formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular a specific inhibitory effect on signal transduction mediated by epidermal growth factor (EGF-R) receptors, which transduction can be influenced for example by inhibiting ligand binding. , receptor dimerization or tyrosine kinases alone. In addition, it is possible that the transmission of signals to downstream components is blocked.

The biological properties of the novel compounds were tested as follows:

For example, inhibition of EGF-R signal transduction can be demonstrated by cells that express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha. An interleukin-3 (IL-3) -dependent murine cell line was used that was genetically altered to express a functional human EGF-R. Proliferation of these cells, called F / LHERc, can therefore be stimulated either by murine IL-3 or by EGF (see von R

12 January, T. et al. in EMBO J. 7: 2749-2756 (1988) and Pierce, J. H. et al. in Science 239. 628-631 (1988)).

The starting material for F / L-HERc cells was the FDC-Pl cell line prepared by Dexter, T. M. et al. in J. Exp. Med. 152, 1036-1047 (1980). However, other growth factor-dependent cells may be used similarly (see, for example, Pierce, JH et al. In Science 239. 628-631 (1988); Shibuya, H. et al. In Cell 70, 57-67 (1992) and Alexander). , WS et al in EMBO J. 10, 3683-3691 (1991)). Recombinant retroviruses were used to express human EGF-R cDNA (see Ullrich, A. et al., Nature 309, 418-425 (1984)) as described by Ruden, T. et al. in EMBO J. 7: 2749-2756 (1988), except that the cDNA of the retroviral vector LXSN was used to express EGF-R (see Miller, AD et al. in BioTechniques 7, 980-990 (1989)) and as envelope cells. cells of the GP + E86 line were used (see Markowitz, D. et al. in J. Virol. 62: 1120-1124 (1988)).

í j

The test was performed as follows: j

F / L-HERc cells were cultured in medium, RPMI / 1640 (BioWhittaker) 1

containing 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng / ml human EGF (Promega) at 37 ° C and 5% CO ₂ . To determine the inhibitory activity of the compounds of the invention, 1.5 10 10 ⁴ cells per well γ three paralleles were cultured in 96-well plates in the indicated medium (200 μΙ), whereby cell proliferation was stimulated with either EGF (20 ng / ml) or mouse IL -3. The culture medium from cell line X63 / 0 m11_-3 was used as the source of IL-3 (see Karasuyama, H. et al., Eur. J. Immunol. 18: 97-104 (1988)). The compounds of the invention were dissolved in 100% dimethylsulfoxide (DMSO) and added to the cultures at various dilutions, with a maximum DMSO concentration of 1%. The cultures were incubated at 37 ° C for 48 hours.

To determine the inhibitory activity of the compounds of the invention, the relative number of cells was determined using a non-radioactive Cell Titer 96 ™ Aqueous (Promega) proliferation assay in optical density units (O.D.). The relative number of cells was calculated as the percentage of control cells (F / L HERc cells without

- 13ínhibítora) is determined and from it the concentration of active substance which inhibits the cell proliferation by 50% (IC _50). The following results were obtained:

compound (example #) Inhibition of EGF-dependent proliferation IC ₅₀ [μΜ] Inhibition of IL-3 dependent proliferation IC ₅₀ [μΜ] 1 0.30 5 2 (1) 0.05 5 1 (11) 0,001 > 10 1 (3) 0.2 > 10 3 0.5 > 10 4 0.25 > 10 1 (2). 0.1 > 1 5 0.06 > 1 1 (15) 0,065 10 5 (1) 0,007 > 1 1 (16) 0.04 > 1 1 (17) 0.02 > 10 1 (20) 0,001 10 1 (21) 0.11 > 1 5 (2). 0.04 > 1 1 (22) 0.15 > 10th 2 0.2 > 10 1 (34) 0.13 > 10

Thus, the compounds of formula (I) of the invention inhibit signal transduction by tyrosine kinases, as shown by the example of the human EGF receptor, and are therefore useful in the treatment of pathophysiological processes that have been induced by excess tyrosine kinase function. For example, benign or malignant tumors,

- 14 especially tumors of epithelial and neuroepithelial origin, metastasis as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

In addition, the compounds of Formula I and their physiologically acceptable salts can be used to treat other diseases caused by aberrant tyrosine kinase function, such as epidermal hyperproliferation (psoriasis), inflammatory processes, immune system diseases, haemopoietic cell hyperproliferation, etc.

Because of their biological properties, the compounds of the invention may be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy by monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors ( such as vinblastine), compounds interacting with nucleic acids (e.g. cisplatin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU, etc.), cytokines (e.g. interferons), antibodies, etc. These combinations may be administered either simultaneously or sequentially.

For pharmaceutical use, the compounds of the invention are generally administered to warm-blooded vertebrates, particularly humans, at a dose of 0.01 to 100 mg / kg body weight, preferably at a dose of 0.1 to 15 mg / kg. They are administered in admixture with one or more conventional inert carriers and / or diluents such as corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, a mixture of water and ethanol, water, and water. glycerin, water and sorbitol, water and polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as solid fat, or suitable mixtures thereof in conventional galenic formulations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories .

The following examples are intended to illustrate the invention in further detail without limiting it.

Examples of embodiments of the invention

Example 1

4 - [(3-chloro-4-fluoro-phenyl) amino] -7-fluoro-pyrido [4,3-d] pyrimidine

230 mg of 7-fluoro-4-hydroxy-pyrido [4,3-d] pyrimidine was refluxed in 10 ml of phosphorus trichloride for 3.5 hours. The reaction mixture is reduced, the residue is dissolved in 100 ml of methylene chloride and stirred with 25 ml of saturated sodium carbonate solution for 15 minutes. The organic phase is separated and the aqueous phase is extracted twice with 100 ml of methylene chloride. The combined organic phases are washed with water and dried over magnesium sulphate. To this solution was added 1.26 g of 3-chloro-4-fluoroaniline, 20 mg of 3-chloro-4-fluoroaniline hydrochloride and 5 ml of isopropanol. The methylene chloride was removed in vacuo and the reaction mixture was stirred at room temperature for 1 hour. The mixture is reduced to dryness and the residue is mixed with twice 100 ml of petroleum ether. The residue insoluble in petroleum ether is purified by chromatography on a silica gel column.

Yield: 100 mg (25% of theory),

Melting point: 290-295 ° C (decomposition; crystalline structure changes at approximately 250 ° C),

Rf value: 0.50 (silica gel; cyclohexane / acetic acid ester = 1: 1).

In analogy to Example 1, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-fluoro-pyrido [3,4-d] pyrimidine

Melting point: 264-266 ° C.

_Rf value: 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] pyrimidine

Melting point: 235-237 ° C.

_Rf value: 0.50 (silica gel; petroleum ether / ethyl acetate = 1: 1).

-16Example 2

4 - [(3-chloro-4-fluoro-phenyl) amino] -7- (4-amino-1-piperidinyl) pyrido [4,3-d] pyrimidine

100 mg of 4 - [(3-chloro-4-fluoro-phenyl) amino] -7-fluoro-pyrido [4,3-d] pyrimidine and 202 mg of 4-aminopiperidine are stirred in 3 ml of isopropanol for 4 hours at 90 ° C. , and 18 hours at room temperature. The crude mixture was purified directly in a silica gel column with methylene chloride / methanol / conc. aqueous ammonia (9: 1: 0.1).

Yield: 65 mg (51% of theory),

Melting point: 231-233 ° C.

_Rf value: 0.25 (silica gel; methylene chloride / methanol / ammonia = 4: 1: 0.1)

Mass Spectrum: M ⁺ = 372/4.

In analogy to Example 2, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7 - [(1-methyl-4-piperidinyl) amino] -pyrido [4,3-d] pyrimidine

Melting point: 253-256 ° C.

_Rf value: 0.42 (silica gel; methylene chloride / methanol / ammonia = 4: 1: 0.1)

Mass Spectrum: M ⁺ = 386/8.

(2) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-piperidinyl) piperidin-1-yl] -pyrido [4,3-d] pyrimidine

Melting point: 272-275 ° C.

_Rf value: 0.32 (reversed phase silica gel; methanol / 5% aqueous saline solution = 6: 4).

Mass Spectrum: MH + = 440/2.

(3) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7 - [(1-tert-butoxycarbonyl-4-piperidinyl) amino] pyrido [4,3-d] pyrimidine

Mp: 232-235 ° C,

_Rf value: 0.41 (silica gel, ethyl acetate).

- 17 (4) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7 - [[trans -4- (methoxycarbonyl) cyclohexyl)] - amino] pyrido [4,3-d] pyrimidine

Melting point: 253-254 ° C.

_Rf value: 0.50 (silica gel, ethyl acetate).

(5) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7-morpholino-pyrido [4,3-d] pyrimidine, (6) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [N-methyl-N- (1-methyl-4-piperidinyl) amino] pyrido [4,3-d] pyrimidine, (7) 4 - [(3-chloro-4-fluorophenyl)] amino] -7 - [(trans -4-hydroxycyclohexyl) amino] pyrido [4,3-d] pyrimidine, (8) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [( 2-amino-2-methyl-1-propyl) amino] -pyrido [4,3-d] pyrimidine, (9) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(3) (quinuclidinyl) amino] -pyrido [4,3-d] pyrimidine, (10) 4 - [(3-chloro-4-fluorophenyl) 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 M.p .: 307-309 ° C ( dec)

_Rf value: 0.30 (silica gel; methylene chloride / methanol / conc. 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-hydroxycyclohexyl) amino] -pyrido [3,4-d] pyrimidine,

-18 (14) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - [[trans -4- (methoxycarbonyl) cyclohexyl] amino] pyrido [3,4-d] pyrimidine, (15) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [4- (4-piperidinyl) piperidin-1-yl] -pyrido [3,4-d] pyrimidine

_Rf value: 0.45 (silica gel; methylene chloride / methanol / conc. Aqueous ammonia = 2: 1: 0.15).

(16) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - [(2-amino-2-methyl-1-propyl) amino] -pyrido [3,4-d] pyrimidine

_Rf value: 0.55 (silica gel; methylene chloride / methanol / conc. Aqueous ammonia = 4: 1: 0.1).

(17) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - [(3-quinuclidinyl) amino] -pyrido [3,4-d] pyrimidine R _f value: 0.34 (silica gel; methylene chloride / methanol / conc. ammonia = 6: 1: 0.1).

(18) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - [[1- (tert-butyloxycarbonyl) -4-piperidinyl] amino] -pyrido [3,4-d] pyrimidine, ( 19) 4 - [(4-amino-3,5-dibromo-phenyl) amino] -6 - [(1-methyl-4-piperidinyl) amino] -pyrido [3,4-d] pyrimidine, (20) 4 - [(4-amino-3,5-dibromo-phenyl) amino] -6 - [(trans-4-hydroxycyclohexyl) amino] pyrido [3,4-d] pyrimidine

Melting point: 170 ° C (decomposition),

_Rf value: 0.40 (silica gel; petroleum ether / ethyl acetate / methanol = 10: 10: 3) MS: M ⁺ = 506/508/510 (2 Br).

(21) 4 - [(4-Amino-3,5-dibromo-phenyl) -amino] -6- [4- (4-piperidinyl) -piperidin-1-yl] -pyrido [3,4-d] pyrimidine

R _f value: 0.27 (silica gel; methylene chloride / methanol / conc. Ammonia = 2: 1: 0.1), mass spectrum: M ⁺ = 559/561/563 (2 Br).

19 (22) 4 - [(4-amino-3,5-dibromo-phenyl) amino] -6 - [(2-amino-2-methyl-1-propyl) amino] pyrido [3,4- d] pyrimidine

R _f value: 0.23 (silica gel; methylene chloride / methanol / conc. Ammonia = 6: 1: 0.1), mass spectrum: M ⁺ = 479/481/483 (2 Br).

(23) 4 - [(3-chlorophenyl) amino] -6-morpholino-pyrido [3,2-d] pyrimidine, (24) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (4-amino-1-piperidinyl) -pyrido [3,2-d] pyrimidine, (2S) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [[trans -4- (methoxycarbonyl) (cyclohexyl) amino] pyrido [3,2-d] pyrimidine, (2S) 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; 4-Fluoro-phenyl) amino] -7 - [(trans -4-hydroxycyclohexyl) amino] -pyrido [2,3-d] pyrimidine, (2 S) 4 - [(3-bromophenyl) amino] -7-morpholino -pyrimido [4,5-d] pyrimidine, (3 S) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [N -methyl-N- (1-methyl-4-piperidinyl) - amino] -pyrimido [4,5-d] pyrimidine, (3 S) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(1-methyl-4-piperidinyl) amino] -pyrimido [4,5-d] pyrimidine, (32) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [[trans -4- (methoxycarbonyl) cyclohexyl] amino] pyrimido [4,5- d] pyrimidine;

-20 (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-tropnayl) amino] -pyrido [3,4-d] pyrimidine

Melting point: sintered from 150 ° C, decomposed from 170 ° C,

R f value: 0.17 (silica gel; methylene chloride / methanol / conc. Ammonia = 6: 1: 0.1), mass spectrum: M ⁺ = 531/533/535 (2 Br).

(35) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4-aminocyclohexylamino] -pyrido [4,3-d] pyrimidine, (36) 4 - [(3- chloro-4-fluoro-phenyl) amino] -7- [4-methylaminocyclohexylamino] -pyrido [4,3-d] pyrimidine, (37) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4-dimethylaminocyclohexylamino] -pyrido [4,3-d] pyrimidine, (38) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [4-aminocyclohexylamino] pyrido [3,4-d] pyrimidine, (39) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4-methylaminocyclohexylamino] -pyrido [3,4-d] (40) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [4-dimethylaminocyclohexylamino] -pyrido [3,4-d] pyrimidine, (41) 4 - [( 3-chloro-4-fluoro-phenyl) amino] -7- [4-aminocyclohexylamino] -pyrido [2,3-d] pyrimidine, (42) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4-methylaminocyclohexyl-amino] -pyrido [2,3-d] pyrimidine;

-21 (43) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4-dimethylaminocyclohexylamino] -pyrido [2,3-d] pyrimidine, (44) 4 - [( 3-chloro-4-fluoro-phenyl) amino] -7- [4-amino-cyclohexyl-amino] pyrimido [4,5-d] pyrimidine,

(45) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4-methylaminocyclohexylamino] -pyrimido [4,5-d] pyrimidine, (46) 4 - [(3- chloro-4-fluoro-phenyl) amino] -7- [4-dimethylaminocyclohexylamino] -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-methylaminocyclohexylamino] (49) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [4-dimethylaminocyclohexylamino] -pyrido [3,2-d] pyrimidine .

Example 3

4 - [(3-chloro-4-fluoro-phenyl) amino] -7 - [(4-piperidinyl) amino] pyrido [4,3-d] pyrimidine

186 mg of 4 - [(3-chloro-4-fluoro-phenyl) amino] -7 - [(1-tert-butoxycarbonyl-4-piperidinyl) amino] -pyrido [4,3-d] pyrimidine, 2 ml of methylene chloride and 2 ml of trifluoroacetic acid is stirred for 1 hour at room temperature. It is reduced to dryness, stirred in 5 ml of water and made alkaline with 1 N sodium hydroxide solution. After stirring at room temperature for 30 minutes, the precipitate is filtered off with suction, washed with water and dried under vacuum at 70 ° C.

Yield: 115 mg (78% of theory);

-22 Melting point: 265-267 ° C

Rf value: 0.50 (reverse phase silica gel; acetonitrile / water 1: 1) + 1% trifluoroacetic acid.

In analogy to Example 3, the following compounds are obtained:

(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-piperidinyl] -pyrido [4,3-d] pyrimidine, (3) 4 - [(3-chloro-4- Fluoro-phenyl) amino] -7- [4- (4-piperidinyl) -1-piperazinyl] -pyrido [4,3-d] pyrimidine, (4) 4 - [(3-chloro-4-fluoro-phenyl)] amino] -6- [4- (1-piperazinyl) -1-piperidinyl] -pyrido [3,4-d] pyrimidine, (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [4- (4-piperidinyl) -1-piperazinyl] -pyrido [3,4-d] pyrimidine, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (1-piperazinyl) -1-piperidinyl] -pyrido [2,3-d] pyrimidine, (7) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-piperidinyl) 11-piperazinyl-pyrido [2,3-d] pyrimidine, (8) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (1-piperazinyl) -1- piperidinyl] -pyrimido [4,5-d] pyrimidine, (9) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (4-piperidinyl) -1-piperazinyl] -pyrimido [4,5-d] pyrimidine,

-23 (10) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [4- (1-piperazinyl) -1-piperidinyl] -pyrido [3,2-d] pyrimidine, (11) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [4- (4-piperidinyl) -1-piperazinyl] -pyrido [3,2-d] pyrimidine,

Example 4

4 - [(3-chloro-4-fluoro-phenyl) amino] -7 - [(trans-4-carboxycyclohexyl) amino] pyrido [4,3-d] pyrimidine

210 mg of 4 - [(3-chloro-4-fluoro-phenyl) amino] -7 - [[trans-4- (methoxycarbonyl) cyclohexyl] amino] -pyrido [4,3-d] pyrimidine in 2 ml of methanol were mixed with 2 ml of 1N sodium hydroxide solution and stirred at room temperature for 2 hours. 2.1 ml of 1N hydrochloric acid are added and the methanol is removed in vacuo. After addition of 5 ml of water, it is stirred for 30 minutes in an ice bath, the precipitate is filtered off with suction, washed with ice water and dried.

Yield: 170 mg (84% of theory),

Melting point: 306-310 ° C,

Rf value: 0.10 (silica gel; acetic acid ester).

In analogy to Example 4, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - [(trans-4-carboxycyclohexyl) amino] -pyrido [3,4-d] pyrimidine, (2) 4 - [(3- chloro-4-fluoro-phenyl) amino] -6 - [(trans-4-carboxycyclohexyl) amino] -pyrido [3,2-d] pyrimidine, (3) 4 - [(3-chloro-4-fluoro-phenyl) amino] ] -7 - [(trans-4-carboxycyclohexyl) amino] pyrimido [4,5-d] pyrimidine,

-24Example 5

4 - [(3-chloro-4-fluoro-phenyl) amino] -7 - [[trans-4- (morpholinocarbonyl) cyclohexyl]] - amino] pyrido [4,3-d] pyrimidine

To a solution of 140 mg of 4 - [(3-chloro-4-fluoro-phenyl) amino] -7 - [(trans-4-carboxycyclohexyl) amino] -pyrido [4,3-d] pyrimidine in 1 mL of dimethylformamide is added 135 mg of 2 (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 0.19 ml of triethylamine and 0.06 ml of morpholine and stirred for 1.5 hours at room temperature. Add 10 mL of water and stir for 20 minutes. The precipitate is filtered off with suction, washed with water and dried under vacuum at 60 ° C.

Yield: 130 mg (82% of theory),

Melting point: 278-283 ° C.

R f value: 0.54 (silica gel; methylene chloride / methanol = 6: 1).

In analogy to Example 5, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - [[trans -4- (morpholinocarbonyl) cyclohexyl] amino] pyrido [3,4-d] pyrimidine, (2) 4- [(3-chloro-4-fluoro-phenyl) amino] -6 - [[trans -4- (morpholinocarbonyl) cyclohexyl] amino] pyrido [3,2-d] pyrimidine, (3) 4 - [(3-chloro) 4-fluoro-phenyl) amino] -7 - [[trans-4- (morpholinocarbonyl) cyclohexyl] amino] pyrimido [4,5-d] pyrimidine,

Example 6

4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (1-methyl-4-piperidinyl) piperidin-1-yl] pyrido [4,3-pyrimidine

To a suspension of 365 mg of 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-piperidinyl) piperidin-1-yl] -pyrido [4,3-d] pyrimidine in 30 ml of methanol and 0.07 ml of a 37% formalin solution and 57 mg of sodium cyanoborohydride are added. After stirring for 30 minutes at

10 ml of methylene chloride are added at room temperature and stirred for 3 hours. It is then reduced to dryness, 15 ml of water are added and stirred for 30 minutes. The residue is filtered off with suction and purified by chromatography over a silica gel column with methylene chloride / methanol / conc. aqueous ammonia (9: 1: 0.1).

Yield: 196 mg (52% of theory),

Mp .: 291-292 ° C,

_Rf value: 0.50 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia = 6: 1: 0.1)

In analogy to Example 6, the following compounds are obtained:

(1) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [4- (1-methyl-4-piperidinyl) piperidin-1-yl] -pyrido [3,4-d] pyrimidine

Melting point: 180 to 185 ° C (decomposition, sintering from 168 ° C),

_Rf value: 0.43 (silica gel; methylene chloride / methanol / conc. Ammonia = 6: 1: 0.1).

(2) 4 - [(4-amino-3,5-dibromophenyl) amino] -6- [4- (1-methyl-4-piperidinyl) piperidin-1 - yl] pyrido [3,4-d] pyrimidine

Melting point: 220-222 ° C,

R _f value: 0.24 (silica gel; methylene chloride / methanol / conc. Ammonia = 10: 1: 0.1), mass spectrum: M ⁺ = 573/575/577 (2 Br).

(3) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-methyl-1-piperazinyl) -1-piperidinyl] -py [α] 4,3-d] pyrimidine, (4) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (1-methyl-4-piperidinyl) -1-piperazinyl] -pyrido [4,3-d] pyrimidine, (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (4-methyl-1-piperazinyl) -1] -piperidinyl] -pyrido [3,4-d] pyrimidine, (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (1-methyl-4-) piperidinyl) -1-piperazinyl] -pyrido [3,4-d] pyrimidine,

-26 (7) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-methyl-1-piperazinyl) -1-piperidinyl] -pyrido [2,3-d] pyrimidine, (8) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (1-methyl-4-piperidinyl) -1-piperidine] perazinyl] -pyrido [2,3-d] pyrimidine, (9) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4) -methyl-1-piperazinyl-1-piperidinyl] pyrimidine [4,5-d] pyrimidine, (10) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (1-methyl-4-piperidinyl) -1-piperazinyl] pyrimidine [4,5-d] pyrimidine, (11) 4 - [(3-chloro-4-fluoro-) phenyl) amino] -6- [4- (4-methyl-1-piperazinyl) -1-piperidinyl] -pyrido [3,2-d] pyrimidine, (12) 4 - [(3-chloro-4-fluoro- phenyl) amino] -6- [4- (1-methyl-4-piperidinyl) -1-piperazinyl] -pyrido [3,2-d] pyrimidine,

Example 7

Dragee with 75 mg of the active substance

Dragee core 1 contains:

Active Substance 75.0 mg

Calcium phosphate 93.0 mg

Corn starch 35,5 mg

Polyvinylpyrrolidone 10.0 mg

Hydroxypropylmethylcellulose 15.0 mg

Magnesium stearate 1.5 mg

230.0 mg

-27Príprava

The active ingredient is mixed with calcium phosphate, maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the indicated amount of magnesium stearate. Moldings with a diameter of approximately 13 mm are pressed on a tabletting machine, which are passed through a sieve with a 1.5 mm aperture in a suitable machine and mixed with the remaining amount of magnesium stearate. This granulate is compressed into tablets of the desired shape in a tabletting machine.

Dragee core weight: 230 mg

Stamp: 9 mm, domed

The prepared dragees are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished coated dragees are polished with beeswax.

Weight dragees: 245 mg

Example 8

Tablets of 100 mg of the active substance

composition 1 tablet contains: Active substance 100.0 mg Milk sugar 80.0 mg Maize starch 34.0 mg polyvinylpyrrolidone 4.0 mg Magnesium stearate 2,0 mq

220.0 mg

Method of preparation:

The active ingredient, milk sugar and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After extruding the wet mass (aperture size 2.0 mm) and drying the oven in a drying oven at 50 ° C, press it again (aperture size 1.5 mm) and mix the lubricant. The mixture thus prepared for compression

-28 Processes into pills.

Tablet weight: 220 mg

Diameter: 10 mm, flat on both sides with double faced veneer and split groove on one side

Example 9

Tablets of 150 mg of the active substance

The composition of the tablet contains

Active Substance 150.0 mg

Milk sugar powder 89.0 mg

Corn starch 40.0 mg

Colloidal silicic acid 10.0 mg

Polyvinylpyrrolidone 10.0 mg

Magnesium stearate 1.0 mg

300.0 mg

preparation

The active ingredient mixed with milk sugar, corn starch and silicic acid is moistened with a 20% aqueous solution of polyvinylpyrrolidone and passed through a 1.5 mm sieve.

The granulate dried at 45 ° C is passed through the same sieve once more and mixed with the indicated amount of magnesium stearate. Tablets are compressed from the mixture.

Tablet weight: 300 mg

Stamp: 10 mm, flat

Example 10

Hard gelatine capsules with 150 mg of the active substance

-291 capsule contains: Active ingredient Corn starch Milk sugar powder Magnesium stearate

150.0 mg about 180.0 mg about 87.0 mg

3.0 mg about 420.0 mg

preparation

The active substance is mixed with excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable machine. The final blend is filled into hard gelatin size 1 capsules.

Capsule content: about 320 mg

Capsule shell: hard gelatin capsules, size 1.

Example 11

Suppositories of 150 mg of the active ingredient suppositories contain:

Active Substance 150.0 mg

Polyethylene glycol 1500 550.0 mg

Polyethylene glycol 6000 460.0 mg

Polyoxyethylene sorbitan monostearate 840.0 mg

2000.0 mg

Preparation:

After melting the suppository mass, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds.

Example 12

Suspension with 50 mg of the active substance

100 ml of suspension contains:

Active Substance 1.00 g

Carboxymethylcellulose, sodium salt 0,10 g p-Methyl hydroxybenzoate 0,05 g p-hydroxybenzoic acid propyl ester 0,01 g

Cane sugar 10,00 g

Glycerin 5.00 g

Sorbitol solution, 70% 20.00 g

Aroma 0,30 g

Water, distilled ad 100 ml

preparation

The distilled water is heated to 70 ° C. The pmethyl ester and the p-propyl ester of hydroxybenzoic acid as well as glycerin and sodium carboxymethylcellulose are dissolved therein with stirring. It is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously therein. After addition and dissolution of the sugar, sorbitol solution and flavor, the suspension is evacuated with stirring to remove air. 5 ml of suspension contains 50 mg of active substance.

Claims (7)

1,4-Amino-pyrimidine derivatives of formula I except 4 - [(3-bromophenyl) amino] -6- (1-piperidinyl) -pyrido [3,4-d] pyrimidine, in which: R ^a is a hydrogen atom or a methyl group, R ^b is a phenyl group substituted with R ¹ to R ³ or a phenylalkyl group wherein the phenyl moiety is substituted with R ¹ to R ³ wherein R ¹ is hydrogen, fluoro, chloro, bromo or iodo, alkyl-, trifluoromethyl-, ethenyl, ethynyl, alkyloxy, _C3 _6-cycloalkyl, trifluoromethoxy, cyano, amino, alkylamino, dialkylamino, or nitro, R ² is H, F, Cl, Br or alkyl, and R ³ is a hydrogen, fluorine, chlorine or bromine atom, A and B together represent 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 the left end of the bridge is connected to the 5-position and the right end of the bridge is connected to the 6-position of the pyrimidine ring, wherein R ^c is v in this case, a morpholino group substituted with one or two alkyl groups, A 1-piperazinyl group in this case substituted by one or two alkyl groups, -323-oxo-1-piperazinyl in this case substituted by one or two alkyl groups, 1-piperazinyl group which in position 4 is substituted by C _{3. 6-} cycloalkyl, 3-tetrahydrofuranyl-, 3-tetrahydropyranyl-, 4-tetrahydropyranyl-, 3-pyrrolidinyl-, 1-alkyl-3-pyrrolidinyl-, 3-piperidinyl-, 4-piperidinyl-, 1-alkyl-3-piperidinyl or 1- alkyl-4-piperidinyl, 1-azetidinyl-, 1-pyrrolidinyl-, 1-piperidinyl- or 1-azacyclohept-1-yl in this case substituted by R ⁴ , wherein: R ⁴ is hydroxy-, alkyloxy-, amino-, alkylamino-, dialkylamino-, alkylcarbonylamino-, Nalkyl-alkylcarbonylamino-, 2-oxo-1-pyrrolidinyl-, 2-oxo-1-piperidinyl-, alkyl-oxycarbonylamino-, N alkyl-alkyloxykarbonylamino-, alkylsulfonylamino, N-alkylalkylsulfonylamino-, C _{3. 6-} cycloalkyl-, tetrahydrofuranyl-, tetrahydropyranyl-, pyrrolidinyl-, 1-alkyl-pyrrolidinyl-, piperidinyl-, 1-alkyl-piperidinyl-, morpholino-, 1-piperazinyl-, 4-alkyl-1-piperazinyl-, aminoalkyl-, alkylaminoalkyl dialkylaminoalkyl-, carboxy-, alkyloxycarbonyl-, aminocarbonyl-, alkylaminocrabonyl-, dialkylaminocarbonyl-, 1-pyrrolidinylcarbonyl-, 1-piperidinylcarbonyl-, morpholinocarbonyl-, 1-piperazinylcarbonyl-, 4-alkyl-1-piperazinylcarbonyl- or 1-piperazinylcarbonyl- an azetidinyl group in which the 2 hydrogen atoms in the 3-position are replaced by an unbranched alkylene bridge having 4 or 5 carbon atoms, wherein in the above alkylene bridges the methylene group may be replaced by an oxygen atom or an imino- or N-alkyl-imino group, A 1-pyrrolidinyl group in which 2 hydrogen atoms on the carbon skeleton are replaced by an unbranched alkylene bridge, said bridge containing 3 to 5 carbon atoms if the two hydrogen atoms are on the same carbon atom or contain 3 or 4 carbon atoms, if the two hydrogen atoms are on adjacent carbon atoms or contain 2 or 3 carbon atoms, if the two hydrogen atoms are on carbon atoms separated by one atom, the methylene group in the above alkylene bridges may be replaced an oxygen atom or an imino- or Nalkyl-imino group, A 1-piperidinyl group in which 2 hydrogen atoms on the carbon backbone are replaced -33 non-branched alkylene bridge, said bridge containing 3 to 5 carbon atoms if the two hydrogen atoms are on the same carbon atom, or contain 3 or 4 carbon atoms if the two carbon atoms are on adjacent carbon atoms, or contain 2 or 3 carbon atoms if the two hydrogen atoms are on carbon atoms separated by one atom or contain 1 or 2 carbon atoms if the two hydrogen atoms are on carbon atoms separated by two atoms, in which of the above alkylene bridges the methylene group may be replaced by an oxygen atom or an imino- or alkylimino group, or R ^c is a (R ⁵ NR ⁶ ) group in which R ⁵ is a hydrogen atom or an alkyl group; and R ⁶ is C ₅ . ₇ cycloalkyl group substituted by the radical R ^{2 * 4,} wherein R ⁴ is as defined above, 3-tetrahydrofuranyl, 3- or 4-tetrahydropyranyl, 3-pyrrolidinyl or 3- or 4-piperidinyl group, wherein the ring nitrogen of said groups may be substituted by alkyl, alkylcarbonyl, alkylsulfonyl, alkyloxy, C _{3. 6-} cycloalkyl-, 3-tetrahydrofuranyl-, 3- or 4-tetrahydropyranyl-, 3-pyrrolidinyl-, 1-alkyl-3-pyrrolidinyl-, 3- or 4-piperidinyl-, 1-alkyl-3-piperidinyl- or 1-alkyl -4-piperidinyl, C ₂ . _{A 6-} alkyl group substituted with an R ⁴ radical, wherein R ⁴ is as defined above, a 3- or 4-quinuclidinyl group or a 3-tropanyl or desmethyl-3-tropanyl group, and, unless otherwise mentioned, said alkyl portions always contain 1-4 carbon atoms, tautomers, stereoisomers and salts thereof. The 4-amino-pyrimidine derivatives of the general formula I according to claim 1, with the exception of 4 - [(3-bromophenyl) amino] -6- (1-piperidinyl) -pyrido [3,4-d] pyrimidine, in which: R ^a is a hydrogen atom or a methyl group, -34R ^b is a phenyl group substituted with R ¹ -R ³ , wherein R ¹ is H, F, Cl, Br, I, methyl, ethyl, trifluoromethyl, methoxy, cyclopropyl, trifluoromethoxy, cyano, nitro or amino, R ² is H, F, Cl, Br, R ³ is a hydrogen, fluorine, chlorine or bromine atom, A and B together represent 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, the left end of the bridge being linked to the 5-position and the right end of the bridge being linked to the 6-position of the pyrimidine ring, wherein R ^c in this case is morpholino substituted with one or two methyl groups; 1-piperazinyl in the present case substituted by one or two methyl groups, A 1-piperazinyl group which is substituted at the 4-position with a 4-piperidinyl or 1alkyl-4-piperidinyl group, 1-pyrrolidinyl substituted at the 3-position by R ⁴ or 1-piperidinyl at the 3-position or 4 substituted by R ⁴ , wherein R ⁴ is amino-, methylamino-, dimethylamino-, pyrrolidinyl-, 1-methylpyrrolidinyl-, piperidinyl-, 1-methylpiperidinyl-, morpholino-, 1-piperazinyl-, 4-methyl-1-piperazinyl-, hydroxy-, methoxy-, carboxy-, methoxycarbonyl-, ethoxycarbonyl-, dimethylaminocarbonyl-, 1-pyrrolidinylcarbonyl-, 1-piperidinylcarbonyl- or a morpholinocarbonyl group, or a (R ⁵ NR ⁶ ) group in which R ⁵ is hydrogen or methyl or ethyl; and R ⁶ is a cyclopentyl or cyclohexyl group substituted with an R ⁴ radical, wherein R ⁴ is as defined above, 3-pyrrolidinyl- or 3- or 4-piperidinyl, wherein the ring nitrogen atom -35 said groups may be substituted by a methyl-, ethyl-, C 1-4 -alkyloxycarbonyl-, acetyl- or methylsulfonyl group, C ₂ . _{A 4-} alkyl group substituted with the radical R ⁴ , wherein R ⁴ is as defined above, a 3- or 4-quinuclidinyl group or a 3-tropanyl group, their tautomers, stereoisomers and salts thereof. The 4-amino-pyrimidine derivatives of formula 1 according to claim 1, with the exception of 4 - [(bromophenyl) amino] -6- (1-piperidinyl) -pyrido [3,4-d] pyrimidine, wherein: R ^a is a hydrogen atom, R ^b is a phenyl group substituted with R ¹ to R ³ , wherein R ¹ is H, F, Cl, Br, methyl or amino, R ² is H, F, Cl, Br, R ³ is a hydrogen, fluorine, chlorine or bromine atom, A and B together represent a bridge of the formula - N = ^C CR - CH = CH -, -CH = N-CR ^C = CH-, -CH = CR ^C -N = CH-, -CH = CH-CR ^C = N- or -CH = N -CR ^C = N, wherein the left-hand end of the bridge is joined to the 5-position and the right-hand end of the bridge is joined to the 6-position of the pyrimidine ring, wherein R ^c is morpholino, A 1-piperidinyl group which at the 3 or 4 position is substituted with an amino, piperidinyl or 1-methylpiperidinyl group, or a (R ⁵ NR ⁶ ) group wherein: R ⁵ is a hydrogen atom or a methyl group; and R ⁶ is a cyclohexyl group which is substituted by carboxy, methoxycarbonyl, ethoxycarbonyl, morpholinocarbonyl or hydroxy, 3- or 4-piperidinyl, wherein the ring nitrogen atom may be -36-substituted methyl-, ethyl- or C1-6-alkyl-oxycarbonyl, C ₂ . _4- amino-substituted alkyl, 3-tropanyl- or 3-quinuclidinyl, their tautomers, stereoisomers and salts thereof. 4. A compound according to claim 1 selected from the group consisting of: (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, (S) 4 - [(4-amino-3,5-dibromophenyl) amino] -6 - [(trans-4) (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (1-methyl-4-pi) -hydroxycyclohexyl) amino] -pyrido [3,4-d] pyrimidine peridinyl 1) piperidin-1-yl] -pyrido [3,4-d] pyrimidine, and salts thereof. Physiologically acceptable salts of 4-amino-pyrimidine derivatives according to at least one of claims 1 to 4 with inorganic or organic acids or bases. Process for the preparation of 4-amino-pyrimidine derivatives of the general formula I according to claims 1 to 5, characterized in that: a) to a compound of formula II R (II) -37 in which R ^a and R ^b are as defined in claims 1 to 4, 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 in which Z ¹ is a starting group and the left end of this bridge is linked to the 5-position and the right end of this bridge is linked to the 6-position of the pyrimidine ring is treated with a compound of formula III X ¹ -H (III) wherein X ¹ is one of the radicals listed in claims 1 to 4 for R ^c , and if desired, the subsequently obtained compound of the formula I containing an amino or imino group is transformed into the corresponding alkyl compound of the formula I by alkylation or reductive alkylation, and / or the thus obtained compound of the formula I which contains a carboxy- or ester group is converted by means of amidation to the corresponding amide of the formula I and / or, if necessary, the protective group used in the above reactions is cleaved again and / or the compound of formula (I) thus obtained is separated into its stereoisomers, and / or the compound of formula (I) thus obtained is transformed into salts, in particular to physiologically acceptable salts for pharmaceutical use. 387. A pharmaceutical composition comprising a 4-aminopyrimidine derivative according to at least one of claims 1 to 4, or a physiologically acceptable salt according to claim 5, in addition to one or more inert carriers and / or diluents. Use of a compound according to at least one of claims 1 to 5 for the preparation of a medicament for the treatment of benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastases, as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).