WO1997032881A1 - 4-amino pyrimidine derivates, medicaments containing these compounds, their use and process for their production - Google Patents

4-amino pyrimidine derivates, medicaments containing these compounds, their use and process for their production Download PDF

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Publication number
WO1997032881A1
WO1997032881A1 PCT/EP1997/001057 EP9701057W WO9732881A1 WO 1997032881 A1 WO1997032881 A1 WO 1997032881A1 EP 9701057 W EP9701057 W EP 9701057W WO 9732881 A1 WO9732881 A1 WO 9732881A1
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WIPO (PCT)
Prior art keywords
group
amino
alkyl
piperidinyl
substituted
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Application number
PCT/EP1997/001057
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German (de)
French (fr)
Inventor
Frank Himmelsbach
Georg Dahmann
Thomas von Rüden
Thomas Metz
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Dr. Karl Thomae Gmbh
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Publication date
Priority claimed from DE1996108631 external-priority patent/DE19608631A1/en
Priority to EE9800277A priority Critical patent/EE9800277A/en
Priority to SK1205-98A priority patent/SK120598A3/en
Priority to NZ331546A priority patent/NZ331546A/en
Priority to IL12540497A priority patent/IL125404A0/en
Priority to AU19251/97A priority patent/AU710274B2/en
Application filed by Dr. Karl Thomae Gmbh filed Critical Dr. Karl Thomae Gmbh
Priority to EP97907066A priority patent/EP0885226A1/en
Priority to JP9531444A priority patent/JP2000506847A/en
Priority to BR9708312A priority patent/BR9708312A/en
Publication of WO1997032881A1 publication Critical patent/WO1997032881A1/en
Priority to BG102708A priority patent/BG102708A/en
Priority to NO984084A priority patent/NO984084D0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to 4-aminopyrimidine derivatives of the general formula
  • R a is a hydrogen atom or a methyl group
  • Rb is a phenyl group substituted by the radicals Rj to R3 or a phenylalkyl group in which the phenyl part is substituted by the radicals R * j to R3, where
  • RI is a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl, trifluoromethyl, ethenyl, ethynyl, alkyloxy, C3_6 cycloalkyl, trifluoromethoxy, cyano, amino, alkylamino , Dialkylamino or nitro group
  • R2 is a hydrogen, fluorine, chlorine or bromine atom or an alkyl group and
  • R3 represent a hydrogen, fluorine, chlorine or bromine atom
  • R c is a morpholine group which is optionally substituted by one or two alkyl groups
  • a 1-Piperaz ⁇ nyl distr in the 4-position by a C3_6-cycloalkyl group, by a 3-tetrahydrofuranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 3-pyrrolidin yl, 1-alkyl-3-pyrrolidinyl, 3rd -P ⁇ peridinyl-, 4-Piper ⁇ dinyl-, 1-alkyl-3-p ⁇ peridinyl or 1-alkyl-4-piper ⁇ d ⁇ nyl group is substituted,
  • R4 is a hydroxy, alkyloxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, N-alkyl-alkylcarbonylamino, 2-oxo-1-pyrrolidinyl, 2-oxo-1-p ⁇ pe ⁇ dinyl, alkyl-oxycarbonylamino -, N-Alkyl-alkyloxycarbonylamino-, alkylsulfonylamino-, N-alkyl-alkylsulfonylamino-, C3_6-cycloalkyl-, tetrahydrofuranyl-, tetrahydropyranyl-, pyrrolidinyl-, 1-alkyl-pyrrolid ⁇ nyl-, piperidinyl-, 1-alkynyl-alkyl -, Morpholino-, 1-piperazyl, 4-alkyl-1-piperazinyl, aminoalkyl, alkylamino
  • a 1 -azet ⁇ d ⁇ nyloli in the 2 hydrogen atoms in the 3-position are replaced by a straight-chain alkylene bridge with 4 or 5 carbon atoms, wherein in the above-mentioned alkylene bridges each a methylene group by an oxygen atom or by an imino or N- Alkyl imino group can be replaced
  • R c represents a (R5NR6) group in which
  • R5 represents a hydrogen atom or an alkyl group
  • Rg is a C5_7-cycloalkyl group substituted by R4, where R4 is defined as mentioned above, a 3-tetrahydrofuranyl group,
  • a 3-Pyrrol ⁇ d ⁇ nyl- or 3- or 4-Piper ⁇ d ⁇ nyixx wherein the ring nitrogen atom of the above-mentioned groups each by an alkyl, alkylcarbonyl, alkyl ⁇ sulfonyl, alkyloxycarbonyl, C3_6-cycloalkyl, 3-tetrahydrofuranyl, 3- or 4-tetra-hydropyranyl, 3-pyrrolidinyl, 1-alkyl-3-pyrrolidinyl, 3- or 4-pipe ⁇ dinyl, 1-alkyl-3-piprodinyl or 1-alkyl-4-piperidnyl group may be substituted ,
  • alkyl parts mentioned above each contain 1 to 4 carbon atoms
  • R a is a hydrogen atom or a methyl group
  • Rb is a phenyl group substituted by the radicals R-j to R3, where
  • R- a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, ethyl, trifluoromethyl, methoxy, cyclopropyl, trifluoromethoxy, cyano, nitro or amino group,
  • R2 is a hydrogen, fluorine, chlorine or bromine atom
  • R3 represent a hydrogen, fluorine, chlorine or bromine atom
  • R c is a morpholine group optionally substituted by one or two methyl groups
  • R4 is an amino, methylamino, dimethylamino, pyrrolidinyl, 1-methylpyrrolidinyl, piperidinyl, 1-methyip ⁇ pe ⁇ dinyl, morpholino, 1-piperazinyl, 4-methyl-1-piperazin ⁇ yl, hydroxy, methoxy -, carboxy, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, or morpholinocarbonyl group,
  • R5 represents a hydrogen atom or a methyl or ethyl group
  • RQ is a cyclopentyl or cyclohexyl group substituted by R4, where R4 is defined as mentioned above,
  • R a is a hydrogen atom
  • Rb is a phenyl group substituted by the radicals R-j to R3, where
  • R-j is a hydrogen, fluorine, chlorine or bromine atom, a methyl or amino group
  • R2 is a hydrogen, fluorine, chlorine or bromine atom
  • R3 represent a hydrogen, fluorine, chlorine or bromine atom
  • R c is a morpholino group
  • R5 is a hydrogen atom or a methyl group
  • Rß is a cyclohexyl group which is substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl, morpholinocarbonyl or hydroxy group,
  • R a and Rb are as defined in the introduction
  • Zj is a leaving group such as a halogen atom, a substituted hydroxyl, mercapto, sulfinyl or sulfonyl group such as a fluorine, chlorine or bromine atom, a methoxy, ethoxy, phenoxy, methylsulfinyl, ethylsulfinyl, methylsulfonyl - Or ethyl sulfonyl group and the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the py ⁇ midine ring, with a compound of the general formula
  • Xt represents one of the radicals mentioned for R c
  • the reaction is advantageously carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, N-methyl-pyrrolid ⁇ n-2-one, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, if appropriate in the presence of an inorganic base, eg sodium carbonate or potassium hydroxide.
  • a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, N-methyl-pyrrolid ⁇ n-2-one, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, if appropriate in the presence of an inorganic base, eg sodium carbonate or potassium hydrox
  • reaction can also be carried out without a solvent or in an excess of the compound of the general formula III used.
  • a reaction accelerator such as a copper salt, a corresponding amino hydrohalide or alkali metal halide at temperatures between 0 and 180 ° C. but preferably carried out at temperatures between 20 and 150 ° C.
  • the reaction can also be carried out without a solvent or in an excess of the compound of the general formula III used.
  • the subsequent alkylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g. with methyl iodide, ethyl bromide.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g. with methyl iodide, ethyl bromide.
  • Dimethyl sulfate or benzyl chloride optionally in the presence of a tertiary organic base or in the presence of an inorganic base, is advantageously carried out at temperatures between 0 and 150X, preferably at temperatures between 0 and 100 ° C.
  • the subsequent reductive alkylation is advantageously carried out with a 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 at a pH of 6-7 and at room temperature or in the presence a hydrogenation catalyst, for example using hydrogen in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar.
  • a complex metal hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride
  • a hydrogenation catalyst for example using hydrogen in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar.
  • 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.
  • the subsequent amidation is carried out by reacting a corresponding reactive carboxylic acid derivative with a corresponding amine, if appropriate in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran or dioxane, it being possible for the amine used to serve simultaneously as a solvent , optionally in the presence of a tertiary organic base or in the presence of an inorganic base or with a corresponding carboxylic acid in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, 2- (1 H-benzotriazole-1 -yl) -1, 1, 3,3-tetramethyl-uronium tetrafluoroborate, N, N ' -dicyctohexylcarbodiimide, N, N '
  • any reactive groups present such as amino or imino groups or carboxy groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert comes as a protective residue for an amino or imino group.
  • the protective radicals for a carboxy group are the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group.
  • Any subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in 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 alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
  • an aqueous solvent e.g. in water, methanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • an alkali base such as sodium hydroxide or
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, for example using hydrogen in the presence of a Catalyst such as palladium / carbon in a suitable solvent such as methanol.
  • Ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • cleavage of a tert-butyl or tert. -Butyloxycarbonylres.es is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • Trifluoracetylrestes are preferably carried out by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C or by treatment with sodium hydroxide solution optionally in the presence of a solvent such Tetrahy ⁇ drofuran at temperatures between 0 and 50 C C
  • a phthalyl radical is preferably cleaved 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.
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
  • the cis / trans mixtures obtained can be chromatographed into their ice and trans isomers, the compounds of the general formula I which occur in racemates and obtained by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, in their Separate diastereomers which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above
  • the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives such as esters or amides, in particular acids and their activated derivatives or alcohols, with the racemic compound and separation of the diastereomeric salt mixture or derivative obtained in this way, for example due to various solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • optically active acids are, for example, the D and L forms of tartaric acid or dibenzoylwemic acid, di-o-tolylwine acid, apple acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or china acid.
  • the optically active alcohol is, for example, (+) - or (-) - menthol and as an optically active acyl radical in amides, for example Either (+) - or (-) - menthyloxycarbonyl into consideration
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • acids used for this are hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, fumaric acid, Succinic acid, lactic acid, citric acid, tartaric acid or maleic acid
  • the compounds of general formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular a specific inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), these for example, by inhibiting ligand binding, receptor diminution or the tyrosine kinase itself. It is also possible for the signal transmission to be blocked on further downward-lying components
  • EGF-R epidermal growth factor receptor
  • the inhibition of the EGF-R mediated signal transmission can e.g. can be detected with cells which express human EGF-R and whose survival and proliferation depends on stimulation by EGF or TGF-alpha.
  • An ⁇ -terleukin-3 (IL-3) -dependent cell line of murine origin was used here, which was genetically modified in such a way that it expresses functional human EGF-R.
  • the proliferation of these cells called F / L-HERc can therefore be stimulated either by murine IL-3 or by EGF (see von Rüden, T. et al. In EMBO J. 7, 2749-2756 (1988) and Pierce. JH et al. In Science 239: 628-631 (1988)).
  • the FDC-Pi cell line the production of which by Dexter, T. M. et al. in J. Exp. Med. 152, 1036-1047 (1980).
  • other growth factor-dependent cells can also be used (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)).
  • human EGF-R cDNA see Ullrich, A. et al.
  • Retrovire ⁇ were used, as in von Rüden, T. et al., EMBO J. 7, 2749 -2756 (1988), with the difference that the retroviral vector LXSN (see Miller, AD et al. In BioTechniques 7, 980-990 (1989)) was used to express the EGF-R cDNA and the line GP as packaging cell + E86 (see Markowitz, D. et al. In J. Virol. 62, 1120-1124 (1988)).
  • F / L-HERc cells were in RPMI / 1640 medium (BioWhittaker), supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (Bio Whittaker), standard antibiotics and 20 ng / ml human EGF (Promega), cultivated at 37 ° C and 5% CO2.
  • FCS fetal bovine serum
  • FCS Boehringer Mannheim
  • FCS 2 mM glutamine
  • standard antibiotics 20 ng / ml human EGF (Promega)
  • 20 ng / ml human EGF Promega
  • 1.5 ⁇ 10 4 cells per well were cultured in triplicates in 96-well plates in the above medium (200 ⁇ l), the proliferation of the cells using either EGF (20 ng / ml) or murine IL-3 was stimulated.
  • the compounds of the general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as has been shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by overfunction of tyrosine kinases.
  • pathophysiological processes which are caused by overfunction of tyrosine kinases.
  • tyrosine kinases are, for example, benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
  • the compounds of general formula I and their physiologically tolerable salts can be used for the treatment of other diseases which are caused by aberrant function of tyrosine kinases, such as epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation hematopoietic Cells etc..
  • diseases which are caused by aberrant function of tyrosine kinases, such as epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation hematopoietic Cells etc.
  • the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitotic inhibitors (e.g. vinblastine), compounds interacting with nucleic acids (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc. ), Cytokines (eg interferons), antibodies etc. These combinations can be administered either simultaneously or sequentially.
  • topoisomerase inhibitors e.g. etoposide
  • mitotic inhibitors e.g. vinblastine
  • compounds interacting with nucleic acids e.g. cis-platinum, cyclophosphamide, adriamycin
  • hormone antagonists e
  • the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg.
  • these are mixed with one or more conventional inert carriers and / or diluents, e.g.
  • 1 coated tablet contains:
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.
  • the dragee cores thus produced are coated with a film which essentially consists of hydroxypropylmethyl cellulose.
  • the finished film coated tablets are polished with beeswax.
  • 1 tablet contains:
  • Active ingredient, milk sugar and starch are mixed and moistened uniformly with an aqueous solution of the polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50X, sieving is carried out again (1.5 mm mesh size) and the lubricant is added. The finished mixture is processed into tablets.
  • Diameter 10 mm, biplane with facet on both sides and partial notch on one side.
  • 1 tablet contains:
  • the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a 1.5 mm mesh size.
  • 1 capsule contains: active ingredient 150.0 mg
  • the active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device.
  • the final mix is filled into size 1 hard gelatin capsules.
  • Capsule shell hard gelatin capsule size 1.
  • 1 suppository contains:
  • Polyethylene glycol 1500 550.0 mg
  • Carboxymethyl cellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
  • the distilled water is heated to 70X.
  • Methyl p-hydroxybenzoate and propyl ester and glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring.
  • the mixture is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously.
  • the sorbitol solution and the Aromas the suspension for evacuation is evacuated under stirring

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-pyrimidin-Derivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung 4-Amino-pyrimidine derivatives, medicaments containing these compounds, their use and process for their preparation
Gegenstand der vorliegenden Erfindung sind 4-Amino-pyrimidin-Derivate der allge¬ meinen FormelThe present invention relates to 4-aminopyrimidine derivatives of the general formula
RR
Figure imgf000003_0001
deren Tautomeren, deren Stereoisomere und deren Salze, insbesonders deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen, welche wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine Hemmwirkung auf die durch Tyrosinkinasen vermittelte Signaltransduktion, de¬ ren Verwendung zur Behandlung von Krankheiten, insbesondere von Tumorerkran¬ kungen, und deren Herstellung.
Figure imgf000003_0001
their tautomers, their stereoisomers and their salts, in particular their physiologically compatible salts with inorganic or organic acids or bases, which have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by tyrosine kinases, their use for the treatment of diseases, in particular tumor cancer ¬ kungen, and their manufacture.
In der obigen allgemeinen Formel I bedeutet mit der Maßgabe, daß die Verbindung 4-[(3-Bromphenyl)amino]-6-{1-piperidinyl)-pyrido[3,4-d]pyrimidin vom Schutzumfang ausgeschlossen ist,In the above general formula I, with the proviso that the compound 4 - [(3-bromophenyl) amino] -6- {1-piperidinyl) pyrido [3,4-d] pyrimidine is excluded from the scope of protection,
Ra ein Wasserstoffatom oder eine Methylgruppe,R a is a hydrogen atom or a methyl group,
Rb eine durch die Reste R-j bis R3 substituierte Phenylgruppe oder eine Phenylal- kylgruppe, in der der Phenylteil durch die Reste R*j bis R3 substituiert ist, wobeiRb is a phenyl group substituted by the radicals Rj to R3 or a phenylalkyl group in which the phenyl part is substituted by the radicals R * j to R3, where
R-I ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom, eine Alkyl-, Trifluormethyl-, Ethenyl-, Ethinyl-, Alkyloxy-, C3_6-Cycloalkyl-, Trifluormethoxy-, Cyano-, Amino-, Al¬ kylamino-, Dialkylamino- oder Nitrogruppe, R2 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom oder eine Alkylgruppe undRI is a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl, trifluoromethyl, ethenyl, ethynyl, alkyloxy, C3_6 cycloalkyl, trifluoromethoxy, cyano, amino, alkylamino , Dialkylamino or nitro group, R2 is a hydrogen, fluorine, chlorine or bromine atom or an alkyl group and
R3 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom darstellen,R3 represent a hydrogen, fluorine, chlorine or bromine atom,
A und B zusammen eine Brücke der FormelA and B together form a bridge of the formula
- N = CRC - CH = CH - ,- N = CR C - CH = CH -,
. - CH = N - CRC = CH - ,, - CH = N - CR C = CH -,
- CH = CRC - N = CH - ,- CH = CR C - N = CH -,
- CH = CH - CRC = N - oder- CH = CH - CR C = N - or
- CH = N - CRC = N - bedeuten,- CH = N - CR C = N - mean
wobei jeweils das linke Ende dieser Brücken mit Position 5 und das rechte Ende dieser Brücken mit Position 6 des Pyπmidinπnges verknüpft ist und in denenwhere the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the Pyπmidinπnges and in which
Rc eine gegebenenfalls durch eine oder zwei Alkylgruppen substituierte Morpholi- nogruppe,R c is a morpholine group which is optionally substituted by one or two alkyl groups,
eine gegebenenfalls durch eine oder zwei Alkylgruppen substituierte 1-Piperazinyl- gruppe,a 1-piperazinyl group optionally substituted by one or two alkyl groups,
eine gegebenenfalls durch eine oder zwei Alkylgruppen substituierte 3-Oxo-1 -pipe- razinylgruppe,a 3-oxo-1-piperazinyl group optionally substituted by one or two alkyl groups,
eine 1-Piperazιnylgruppe, die in 4-Stellung durch eine C3_6-Cycloalkylgruppe, durch eine 3-Tetrahydrofuranyl-, 3-Tetrahydropyranyl-, 4-Tetrahydropyranyl-, 3-Pyrrolidin- yl-, 1 -Alkyl-3-pyrrolidinyl-, 3-Pιperidinyl-, 4-Piperιdinyl-, 1 -Alkyl-3-pιperidinyl- oder 1-Alkyl-4-piperιdιnyl-Gruppe substituiert ist,a 1-Piperazιnylgruppe, in the 4-position by a C3_6-cycloalkyl group, by a 3-tetrahydrofuranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 3-pyrrolidin yl, 1-alkyl-3-pyrrolidinyl, 3rd -Pιperidinyl-, 4-Piperιdinyl-, 1-alkyl-3-pιperidinyl or 1-alkyl-4-piperιdιnyl group is substituted,
eine gegebenenfalls durch R4 substituierte 1 -Azetidinyl-, 1-Pyrrolidinyl-, 1 -Piperιdin- yl- oder 1-Azacyclohept-1-yl-Gruppe, wobeian optionally substituted by R4 1 -azetidinyl, 1-pyrrolidinyl, 1-Piperιdin- yl or 1-azacyclohept-1-yl group, wherein
R4 eine Hydroxy-, Alkyloxy-, Amino-, Alkylamino-, Dialkylamino-, Alkylcarbonylami- no-, N-Alkyl-alkylcarbonylamino-, 2-Oxo-1-pyrrolidinyl-, 2-Oxo-l-pιpeπdinyl-, Alkyl- oxycarbonylamino-, N-Alkyl-alkyloxycarbonylamino-, Alkyisulfonylamino-, N-Alkyl- alkylsulfonylamino-, C3_6-Cycloalkyl-, Tetrahydrofuranyl-, Tetrahydropyranyl-, Pyrro- lidinyl-, 1-Alkyl-pyrrolidιnyl-, Piperidinyl-, 1 -Alkyl-piperidinyl-, Morpholino-, 1 -Pipera¬ zinyl-, 4-Alkyl-1 -piperazinyl-, Aminoalkyl-, Alkylaminoalkyl-, Dialkylaminoalkyl-, Carb- oxy-, Alkyloxycarbonyl-, Aminocarbonyl-, Alkylaminocarbonyi-, Dialkylaminocarbo- nyl-, 1-Pyrrolιdιnylcarbonyl-, 1-Pιperιdιnylcarbonyl-, Morpholinocarbonyl-, 1-Pιpera- zinylcarbonyl- 4-Alkyl-1-pιperazιnylcarbonyl- oder Cyanogruppe darstelltR4 is a hydroxy, alkyloxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, N-alkyl-alkylcarbonylamino, 2-oxo-1-pyrrolidinyl, 2-oxo-1-pπpeπdinyl, alkyl-oxycarbonylamino -, N-Alkyl-alkyloxycarbonylamino-, alkylsulfonylamino-, N-alkyl-alkylsulfonylamino-, C3_6-cycloalkyl-, tetrahydrofuranyl-, tetrahydropyranyl-, pyrrolidinyl-, 1-alkyl-pyrrolidιnyl-, piperidinyl-, 1-alkynyl-alkyl -, Morpholino-, 1-piperazyl, 4-alkyl-1-piperazinyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carb oxy-, alkyloxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbon- nyl-, 1-pyrrolidinodylcarbonyl-, 1-pιperιdιnylcarbonyl-, morpholinocarbonyl-, 1-pιpera- zinylcarbonyl- 4-alkyl-1-pιperazιnylcarbonryl- or
eine 1 -Azetιdιnylgruppe in der 2 Wasserstoffatome in 3-Stellung durch eine gerad¬ kettige Alkylenbrucke mit 4 oder 5 Kohlenstoffatomen ersetzt sind, wobei in den vor¬ stehend erwähnten Alkylenbrucken jeweils eine Methylengruppe durch ein Sauer¬ stoffatom oder durch eine Imino- oder N-Alkyl-iminogruppe ersetzt sein kann,a 1 -azetιdιnylgruppe in the 2 hydrogen atoms in the 3-position are replaced by a straight-chain alkylene bridge with 4 or 5 carbon atoms, wherein in the above-mentioned alkylene bridges each a methylene group by an oxygen atom or by an imino or N- Alkyl imino group can be replaced
eine 1-Pyrrolιdιnylgruppe, in der 2 Wasserstoffatome am Kohlenstoffgerust durch eine geradkettige Alkylenbrucke ersetzt sind, wobei diese Brücke 3 bis 5 Kohlen¬ stoffatome enthalt, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden oder 3 oder 4 Kohlenstoffatome enthalt, wenn sich die zwei Wasserstoff¬ atome an benachbarten Kohlenstoffatomen befinden, oder 2 oder 3 Kohlenstoff¬ atome enthalt, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befin¬ den, die durch ein Atom getrennt sind, wobei in den vorstehend erwähnten Alkylen¬ brucken jeweils eine Methylengruppe durch ein Sauerstoffatom oder durch eine Imino- oder N-Alkyl-iminogruppe ersetzt sein kann,a 1-Pyrrolιdιnylgruppe in which 2 hydrogen atoms on the carbon structure are replaced by a straight-chain alkylene bridge, this bridge containing 3 to 5 carbon atoms if the two hydrogen atoms are on the same carbon atom or contains 3 or 4 carbon atoms if the two are hydrogen ¬ are located on adjacent carbon atoms, or contains 2 or 3 carbon atoms if the two hydrogen atoms are on carbon atoms, which are separated by an atom, in the above-mentioned alkylene bridges each having a methylene group through an oxygen atom or through an imino or N-alkylimino group can be replaced,
eine 1-Pιperιdιnylgruppe, in der 2 Wasserstoffatome am Kohlenstoffgerust durch eine geradkettige Alkylenbrucke ersetzt sind, wobei diese Brücke 3 bis 5 Kohlen¬ stoffatome enthalt, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden oder 3 oder 4 Kohlenstoffatome enthalt, wenn sich die zwei Wasserstoff¬ atome an benachbarten Kohlenstoffatomen befinden, oder 2 oder 3 Kohlenstoff¬ atome enthalt, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befin¬ den, die durch ein Atom getrennt sind, oder 1 oder 2 Kohlenstoffatome enthalt, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei in den vorstehend erwähnten Alkylenbrucken jeweils eine Methylengruppe durch ein Sauerstoffatom oder durch eine Imino- oder Alkyl- iminogruppe ersetzt sein kann,a 1-Pιperιdιnylgruppe in which 2 hydrogen atoms on the carbon structure are replaced by a straight-chain alkylene bridge, this bridge containing 3 to 5 carbon atoms if the two hydrogen atoms are on the same carbon atom or contains 3 or 4 carbon atoms if the two are hydrogen ¬ are located on adjacent carbon atoms, or contain 2 or 3 carbon atoms if the two hydrogen atoms are on carbon atoms separated by an atom, or contain 1 or 2 carbon atoms if the two hydrogen atoms are on carbon atoms, which are separated by two atoms, it being possible for one methylene group in the abovementioned alkylene bridges to be replaced by one oxygen atom or by one imino or alkyl imino group,
oder Rc eine (R5NR6)-Gruppe darstellt, in deror R c represents a (R5NR6) group in which
R5 ein Wasserstoffatom oder eine Alkylgruppe, undR5 represents a hydrogen atom or an alkyl group, and
Rg eine durch R4 substituierte C5_7-Cycloalkylgruppe, wobei R4 wie vorstehend er¬ wähnt definiert ist, eme 3-Tetrahydrofuranylgruppe,Rg is a C5_7-cycloalkyl group substituted by R4, where R4 is defined as mentioned above, a 3-tetrahydrofuranyl group,
eine 3- oder 4-Tetrahydropyranylgruppea 3- or 4-tetrahydropyranyl group
eine 3-Pyrrolιdιnyl- oder 3- oder 4-Piperιdιnyigruppe, wobei das Ringstickstoffatom der vorstehend erwähnten Gruppen jeweils durch eine Alkyl-, Alkylcarbonyl-, Alkyl¬ sulfonyl-, Alkyloxycarbonyl-, C3_6-Cycloalkyl-, 3-Tetrahydrofuranyl-, 3- oder 4-Tetra- hydropyranyl-, 3-Pyrrolιdιnyl-, 1 -Alkyl-3-pyrroiιdιnyl-, 3- oder 4-Pipeπdinyl-, 1 -Alkyl- 3-pιpeπdιnyl- oder 1-Alkyl-4-pιperιdιnyl-Gruppe substituiert sein kann,a 3-Pyrrolιdιnyl- or 3- or 4-Piperιdιnyigruppe, wherein the ring nitrogen atom of the above-mentioned groups each by an alkyl, alkylcarbonyl, alkyl¬ sulfonyl, alkyloxycarbonyl, C3_6-cycloalkyl, 3-tetrahydrofuranyl, 3- or 4-tetra-hydropyranyl, 3-pyrrolidinyl, 1-alkyl-3-pyrrolidinyl, 3- or 4-pipeπdinyl, 1-alkyl-3-piprodinyl or 1-alkyl-4-piperidnyl group may be substituted ,
eine durch den Rest R4 substituierte C2-6-Alkylgruppe. wobei R4 wie vorstehend erwähnt definiert ist,a C2-6 alkyl group substituted by the radical R4. where R4 is defined as mentioned above,
eine 3- oder 4-Chιnuclιdιnylgruppe odera 3- or 4-Chιnuclιdιnylgruppe or
eine 3-Tropanyl- oder Desmethyl-3-tropanyigruppe darstellen,represent a 3-tropanyl or desmethyl-3-tropanyi group,
sowie, soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylteile je¬ weils 1 bis 4 Kohlenstoffatome enthaltenand, unless stated otherwise, the alkyl parts mentioned above each contain 1 to 4 carbon atoms
Bevorzugte Verbindungen der obigen allgemeinen Formel I sind jedoch diejenigen, in denenHowever, preferred compounds of the above general formula I are those in which
Ra ein Wasserstoffatom oder eine Methylgruppe,R a is a hydrogen atom or a methyl group,
Rb eine durch die Reste R-j bis R3 substituierte Phenylgruppe, wobeiRb is a phenyl group substituted by the radicals R-j to R3, where
R-| ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom, eine Methyl-, Ethyl-, Tri¬ fluormethyl-, Methoxy-, Cyclopropyl-, Trifluormethoxy-, Cyano-, Nitro- oder Amino¬ gruppe,R- | a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, ethyl, trifluoromethyl, methoxy, cyclopropyl, trifluoromethoxy, cyano, nitro or amino group,
R2 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R2 is a hydrogen, fluorine, chlorine or bromine atom,
R3 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom darstellen,R3 represent a hydrogen, fluorine, chlorine or bromine atom,
A und B zusammen eine Brücke der Formel - N = CRC - CH = CH - , - CH = N - CRC = CH - ,A and B together form a bridge of the formula - N = CR C - CH = CH -, - CH = N - CR C = CH -,
- CH = CRC - N = CH - ,- CH = CR C - N = CH -,
- CH = CH - CRC = N - oder- CH = CH - CR C = N - or
- CH = N - CRC = N - bedeuten,- CH = N - CR C = N - mean
wobei jeweils das linke Ende dieser Brücken mit Position 5 und das rechte Ende dieser Brücken mit Position 6 des Pyrimidinringes verknüpft ist und in denenwhere the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the pyrimidine ring and in which
Rc eine gegebenenfalls durch eine oder zwei Methylgruppen substituierte Morpho- linogruppe,R c is a morpholine group optionally substituted by one or two methyl groups,
eine gegebenenfalls durch eine oder zwei Methyigruppen substituierte 1-Piperazin- ylgruppe,a 1-piperazinyl group optionally substituted by one or two methyl groups,
eine 1 -Piperazinylgruppe, die in 4-Stellung durch eine 4-Piperidinyl- oder 1-Alkyl- 4-piperidinyl-Gruppe substituiert ist,a 1-piperazinyl group which is substituted in the 4-position by a 4-piperidinyl or 1-alkyl-4-piperidinyl group,
eine in 3-Steilung durch R4 substituierte 1-Pyrrolidinylgruppe oder eine in 3- oder 4-Stellung durch R4 substituierte 1-Piperidinylgruppe, wobeia 1-pyrrolidinyl group substituted by R4 in 3-position or a 1-piperidinyl group substituted by R4 in 3- or 4-position, where
R4 eine Amino-, Methylamino-, Dimethylamino-, Pyrrolidinyl-, 1-Methylpyrrolidinyl-, Piperidinyl-, 1-Methyipιpeπdinyl-, Morpholino-, 1 -Piperazinyl-, 4-Methyl-1 -piperazin¬ yl-, Hydroxy-, Methoxy-, Carboxy-, Methoxycarbonyl-, Ethoxycarbonyl-, Dimethyl- aminocarbonyl-, 1-Pyrrolidinylcarbonyl-, 1-Piperidinylcarbonyl-, oder Morpholino- carbonylgruppe darstellt,R4 is an amino, methylamino, dimethylamino, pyrrolidinyl, 1-methylpyrrolidinyl, piperidinyl, 1-methyipιpeπdinyl, morpholino, 1-piperazinyl, 4-methyl-1-piperazin¬ yl, hydroxy, methoxy -, carboxy, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, or morpholinocarbonyl group,
oder eine (R5NRg)-Gruppe, in deror a (R5NRg) group in which
R5 ein Wasserstoffatom oder eine Methyl- oder Ethylgruppe undR5 represents a hydrogen atom or a methyl or ethyl group and
RQ eine durch R4 substituierte Cyclopentyl- oder Cyclohexylgruppe, wobei R4 wie vorstehend erwähnt definiert ist,RQ is a cyclopentyl or cyclohexyl group substituted by R4, where R4 is defined as mentioned above,
eine 3-Pyrrolidinyl- oder 3- oder 4-Piperidinylgruppe, wobei das Ringstickstoffatom der vorstehend erwähnten Gruppen jeweils durch eine Methyl-, Ethyl-, C*j ^-Alkyl¬ oxycarbonyl-, Acetyl- oder Methylsulfonylgruppe substituiert sein kann, eine durch den Rest R4 substituierte C2-4-Alkylgruppe, wobei R4 wie vorstehend erwähnt definiert ist,a 3-pyrrolidinyl or 3- or 4-piperidinyl group, it being possible for the ring nitrogen atom of the above-mentioned groups to be substituted in each case by a methyl, ethyl, C * j ^ -alkyloxycarbonyl, acetyl or methylsulfonyl group, a C2-4 alkyl group substituted by the radical R4, where R4 is defined as mentioned above,
eine 3- oder 4-Chιnuclιdιnylgruppe odera 3- or 4-Chιnuclιdιnylgruppe or
eine 3-Tropanylgruppe darstellen,represent a 3-tropanyl group,
deren Tautomere, deren Stereoisomere und deren Salzetheir tautomers, their stereoisomers and their salts
Besonders bevorzugte Verbindungen der obigen allgemeinen Formel I sind jedoch diejenigen, in denenHowever, particularly preferred compounds of the above general formula I are those in which
Ra ein WasserstoffatomR a is a hydrogen atom
Rb eine durch die Reste R-j bis R3 substituierte Phenylgruppe, wobeiRb is a phenyl group substituted by the radicals R-j to R3, where
R-j ein Wasserstoff-, Fluor-, Chlor- oder Bromatom, eine Methyl- oder Aminogruppe,R-j is a hydrogen, fluorine, chlorine or bromine atom, a methyl or amino group,
R2 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R2 is a hydrogen, fluorine, chlorine or bromine atom,
R3 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom darstellen,R3 represent a hydrogen, fluorine, chlorine or bromine atom,
A und B zusammen eine Brücke der FormelA and B together form a bridge of the formula
- N = CRC - CH = CH - , - CH = N - CRC = CH - ,- N = CR C - CH = CH -, - CH = N - CR C = CH -,
- CH = CRC - N = CH - ,- CH = CR C - N = CH -,
- CH = CH - CRC = N - oder- CH = CH - CR C = N - or
- CH = N - CRC = N - bedeuten,- CH = N - CR C = N - mean
wobei jeweils das linke Ende dieser Brücken mit Position 5 und das rechte Ende dieser Brücken mit Position 6 des Pyπmidinπnges verknüpft ist und in denenwhere the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the Pyπmidinπnges and in which
Rc eine Morpholinogruppe,R c is a morpholino group,
eine 1-Pιpeπdιnylgruppe, die in 3- oder 4-Stellung durch eine Amino-, Pipendinyl- oder 1-Methylpιpendιnylgruppe substituiert ist, oder eine (R5NR5)-Gruppe, wobeia 1-Pιpeπdιnylgruppe which is substituted in the 3- or 4-position by an amino, pipendinyl or 1-methylpιpendιnyl group, or a (R5NR5) group, where
R5 ein Wasserstoffatom oder eine Methylgruppe undR5 is a hydrogen atom or a methyl group and
Rß eine Cyclohexylgruppe, die durch eine Carboxy-, Methoxycarbonyl-, Ethoxycar¬ bonyl-, Morpholinocarbonyl- oder Hydroxygruppe substituiert ist,Rß is a cyclohexyl group which is substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl, morpholinocarbonyl or hydroxy group,
eine 3- oder 4- Pipendinylgruppe, wobei das Ringstickstoffatom jeweils durch eine Methyl-, Ethyl- oder C*|^-Alkyl-oxycarbonylgruppe substituiert sein kann,a 3- or 4-pipendinyl group, where the ring nitrogen atom can in each case be substituted by a methyl, ethyl or C * | ^ -alkyl-oxycarbonyl group,
eine durch eine Aminogruppe substituierte C2-4-Alkylgruppe,a C2-4 alkyl group substituted by an amino group,
eine 3-Tropanyl- oder eine 3-Chιnuclιdιnylgruppe darstellen.represent a 3-tropanyl or a 3-chιnuclιdιnylgruppe.
deren Tautomere, deren Stereoisomere und deren Salze.their tautomers, their stereoisomers and their salts.
Als besonders bevorzugte Verbindungen seien beispielsweise folgende erwähnt:The following may be mentioned as particularly preferred compounds:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amιno]-7-(4-amιno-1-pιpehdinyl)-pyπdo[4,3-d]py- rimidin,(1) 4 - [(3-chloro-4-fluorophenyl) amino] -7- (4-amino-1-pyridinyl) -pyπdo [4,3-d] pyrimidine,
(2) 4-[(3-Chlor-4-fluor-phenyl)amιno]-7-[(1 -methyl-4-piperidinyl)amιno]-pyrιdo[4,3-d]- pyπmidin,(2) 4 - [(3-chloro-4-fluorophenyl) amιno] -7 - [(1-methyl-4-piperidinyl) amιno] -pyrιdo [4,3-d] - pyπmidin,
(3) 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-(4-amιno-1-pιperidinyl)-pyrιdo[3,4-d]pyrιmi- din,(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (4-amino-1-piperidinyl) pyrido [3,4-d] pyrimidine,
(4) 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-[(3-chιnuclidinyl)amιno]-pyhdo[3,4-d]pyrι- midin,(4) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(3-chloronuclidinyl) amino] -pyhdo [3,4-d] pyridimine,
(5) 4-[(4-Amino-3,5-dibrom-phenyl)amιno]-6-[(trans-4-hydroxycyciohexyl)amιno]- pyrido[3,4-d]pyhmidin,(5) 4 - [(4-amino-3,5-dibromo-phenyl) amino] -6 - [(trans-4-hydroxycyciohexyl) amino] -pyrido [3,4-d] pyhmidine,
(6) 4-[(3-Chlor-4-fIuor-phenyl)amino]-6-[4-(1 -methyl-4-pipeπdιnyl)pipeπdin-1 -yl]-py- rido[3,4-d]pyrimidin(6) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [4- (1-methyl-4-pipeπdιnyl) pipeπdin-1 -yl] -pyrido [3,4-d ] pyrimidine
und deren Salze. Die Verbindungen der allgemeinen Formel I lassen sich beispielsweise nach folgen¬ den Verfahren herstellenand their salts. The compounds of the general formula I can be prepared, for example, by the following processes
Umsetzung einer Verbindung der allgemeinen FormelImplementation of a compound of the general formula
Ra und Rb wie eingangs definiert sind,R a and Rb are as defined in the introduction,
A und B' zusammen eine Brücke der FormelA and B 'together form a bridge of the formula
- N = CZ-j - CH = CH - ,- N = CZ-j - CH = CH -,
- CH = N - CZ-j = CH - ,- CH = N - CZ-j = CH -,
- CH = CZ-| - N = CH - ,- CH = CZ- | - N = CH -,
- CH = CH - CZ-j = N - oder- CH = CH - CZ-j = N - or
- CH = N - CZ-i = N - bedeuten,- CH = N - CZ-i = N - mean
in denenin which
Z-j eine Austrittsgruppe wie ein Halogenatom, eine substituierte Hydroxy-, Mercap¬ to-, Sulfinyl- oder Sulfonylgruppe wie ein Fluor-, Chlor- oder Bromatom, eine Meth¬ oxy-, Ethoxy-, Phenoxy-, Methylsulfinyl-, Ethylsulfinyl-, Methylsulfonyl- oder Ethyl- sulfonylgruppe darstellt und jeweils das linke Ende dieser Brücken mit Position 5 und das rechte Ende dieser Brücken mit Position 6 des Pyπmidinπnges verknüpft ist, mit einer Verbindung der allgemeinen FormelZj is a leaving group such as a halogen atom, a substituted hydroxyl, mercapto, sulfinyl or sulfonyl group such as a fluorine, chlorine or bromine atom, a methoxy, ethoxy, phenoxy, methylsulfinyl, ethylsulfinyl, methylsulfonyl - Or ethyl sulfonyl group and the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the pyπmidine ring, with a compound of the general formula
X1 - H , (lll)X1 - H, (lll)
m derm the
Xt einen der für Rc eingangs erwähnten Reste darstelltXt represents one of the radicals mentioned for R c
Die Umsetzung wird zweckmaßigerweise in einem Losungsmittel wie Isopropanol, Butanol, Tetrahydrofuran, Dioxan, Toluol, Chlorbenzol, Dimethylformamid, N-Methyl- pyrrolidιn-2-on, Dimethylsulfoxid, Ethylenglycolmonomethylether, Ethylenglycoldi- ethyiether oder Sulfolan gegebenenfalls in Gegenwart einer anorganischen Base, z.B. Natriumcarbonat oder Kaliumhydroxid. oder einer tertiären organischen Base, z.B. Triethylamin oder Pyπdin, wobei letztere gleichzeitig auch als Losungsmittel dienen können, und gegebenenfalls in Gegenwart eines Reaktionsbeschleunigers wie eines Kupfersalzes, eines entsprechenden Amiπ-hydrohalogenids oder Alkali- halogenids bei Temperaturen zwischen 0 und 180°C. vorzugsweise jedoch bei Tem¬ peraturen zwischen 20 und 150°C, durchgeführt. Die Umsetzung kann jedoch auch ohne Lösungsmittel oder in einem Überschuß der eingesetzten Verbindung der all¬ gemeinen Formel III durchgeführt werden.The reaction is advantageously carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, N-methyl-pyrrolidιn-2-one, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, if appropriate in the presence of an inorganic base, eg sodium carbonate or potassium hydroxide. or a tertiary organic base, for example triethylamine or pyridine, the latter also serving as solvents at the same time, and optionally in the presence of a reaction accelerator such as a copper salt, a corresponding amino hydrohalide or alkali metal halide at temperatures between 0 and 180 ° C. but preferably carried out at temperatures between 20 and 150 ° C. However, the reaction can also be carried out without a solvent or in an excess of the compound of the general formula III used.
Erhält man erfindungsgemäß eine Verbindung der allgemeinen Formel I, die eine Amino- oder Iminogruppe enthält, so kann diese mittels Alkylierung oder reduktiver Alkylierung in eine entsprechende Alkylverbindung der allgemeinen Formel I überge¬ führt werden oderIf, according to the invention, a compound of the general formula I is obtained which contains an amino or imino group, this can be converted into a corresponding alkyl compound of the general formula I by means of alkylation or reductive alkylation or
eine Verbindung der allgemeinen Formel I, die eine Carboxy- oder Estergruppe ent¬ hält, so kann diese mittels Amidierung in ein entsprechendes Amid der Formel I übergeführt werden.a compound of the general formula I which contains a carboxy or ester group, this can be converted into a corresponding amide of the formula I by amidation.
Die nachträgliche Alkylierung wird gegebenenfalls in einem Lösungsmittel oder Lö- sungsmittelgemisch wie Methylenchlond, Dimethylformamid, Benzol, Toluol, Chlor¬ benzol, Tetrahydrofuran, Benzol/Tetrahydrofuran oder Dioxan mit einem Alkylie- rungsmittel wie einem entsprechenden Halogenid oder Sulfonsäureester, z.B. mit Methyljodid, Ethylbromid. Dimethylsulfat oder Benzylchlorid, gegebenenfalls in Ge¬ genwart einer tertiären organischen Base oder in Gegenwart einer anorganischen Base zweckmäßigerweise bei Temperaturen zwischen 0 und 150X, vorzugsweise bei Temperaturen zwischen 0 und 100°C, durchgeführt.The subsequent alkylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g. with methyl iodide, ethyl bromide. Dimethyl sulfate or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, is advantageously carried out at temperatures between 0 and 150X, preferably at temperatures between 0 and 100 ° C.
Die nachträgliche reduktive Alkylierung wird mit einer entsprechenden Carbonylver- bindung wie Formaldehyd, Acetaldehyd, Propionaldehyd oder Aceton in Gegenwart eines komplexen Metallhydrids wie Natriumborhydrid, Lithiumborhydrid oder Na¬ triumcyanoborhydrid zweckmäßigerweise bei einem pH-Wert von 6-7 und bei Raum¬ temperatur oder in Gegenwart eines Hydrierungskatalysators, z.B. mit Wasserstoff in Gegenwart von Palladium/Kohle, bei einem Wasserstoffdruck von 1 bis 5 bar durchgeführt. Die Methylierung kann jedoch auch in Gegenwart von Ameisensäure als Reduktionsmittel bei erhöhten Temperaturen, z.B. bei Temperaturen zwischen 60 und 120°C, durchgeführt werden. Die nachträgliche Amidierung wird durch Umsetzung eines entsprechenden reak¬ tionsfähigen Carbonsäurederivates mit einem entsprechenden Amin gegebenenfalls in einem Lösungsmittel oder Lösungsmittelgemisch wie Methylenchlorid, Dimethyl¬ formamid, Benzol, Toluol, Chlorbenzol, Tetrahydrofuran oder Dioxan, wobei das ein¬ gesetzte Amin gleichzeitig als Lösungsmittel dienen kann, gegebenenfalls in Gegen¬ wart einer tertiären organischen Base oder in Gegenwart einer anorganischen Base oder mit einer entsprechenden Carbonsäure in Gegenwart eines wasserentziehen¬ den Mittels, z.B. in Gegenwart von Chlorameisensäureisobutylester, Thionylchlorid, Trimethylchlorsilan, Phosphortrichlorid, 2-(1 H-Benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyl- uronium-tetrafluorborat, N,N'-Dicyctohexylcarbodiimid, N,N'-Dicyclohexylcarbodi- imid/N-Hydroxysuccinimid oder 1 -Hydroxy benztriazol und gegebenfalls in Gegen¬ wart von 4-Dimethylaminopyridin, N,N'-Carbonyldiimidazol oder Triphenylphos- phin/Tetrachlorkohlenstoff, zweckmäßigerweise bei Temperaturen zwischen 0 und 150°C, vorzugsweise bei Temperaturen zwischen 0 und 80°C, durchgeführt.The subsequent reductive alkylation is advantageously carried out with a 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 at a pH of 6-7 and at room temperature or in the presence a hydrogenation catalyst, for example using hydrogen in the presence of palladium / carbon, at a hydrogen pressure of 1 to 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. The subsequent amidation is carried out by reacting a corresponding reactive carboxylic acid derivative with a corresponding amine, if appropriate in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran or dioxane, it being possible for the amine used to serve simultaneously as a solvent , optionally in the presence of a tertiary organic base or in the presence of an inorganic base or with a corresponding carboxylic acid in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, 2- (1 H-benzotriazole-1 -yl) -1, 1, 3,3-tetramethyl-uronium tetrafluoroborate, N, N ' -dicyctohexylcarbodiimide, N, N ' -dicyclohexylcarbodimide / N-hydroxysuccinimide or 1-hydroxybenztriazole and optionally in the presence of 4 -Dimethylaminopyridine, N, N ' -carbonyldiimidazole or triphenylphosphine / tetr Achlorkohlenstoff, expediently carried out at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C.
Bei den vorstehend beschriebenen Umsetzungen können gegebenenfalls vorhande¬ ne reaktive Gruppen wie Amino- oder Iminogruppen oder Carboxygruppen während der Umsetzung durch übliche Schutzgruppen geschützt werden, welche nach der Umsetzung wieder abgespalten werden.In the reactions described above, any reactive groups present, such as amino or imino groups or carboxy groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
Beispielsweise kommt als Schutzrest für eine Amino- oder Iminogruppe die Formyl-, Acetyl-, Trifluoracetyl-, Ethoxycarbonyl-, tert. -Butoxycarbonyl-, Benzyloxycarbonyl-, Benzyl-, Methoxybenzyl- oder 2,4-Dimethoxybenzylgruppe und für die Aminogruppe zusätzlich die Phthalylgruppe,For example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert comes as a protective residue for an amino or imino group. Butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group additionally the phthalyl group,
als Schutzreste für eine Carboxygruppe die Trimethylsilyl-, Methyl-, Ethyl-, tert.Bu- tyl-, Benzyl- oder Tetrahydropyranylgruppe in Betracht.the protective radicals for a carboxy group are the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group.
Die gegebenenfalls anschließende Abspaltung eines verwendeten Schutzrestes er¬ folgt beispielsweise hydrolytisch in einem wässrigen Lösungsmittel, z.B. in Wasser, Methanol/Wasser, Essigsäure/Wasser, Tetrahydrofuran/Wasser oder Dioxan/Was- ser, in Gegenwart einer Säure wie Trifluoressigsaure, Salzsäure oder Schwefelsäure oder in Gegenwart einer Alkalibase wie Natriumhydroxid oder Kaliumhydroxid oder aprotisch, z.B. in Gegenwart von Jodtrimethylsilan, bei Temperaturen zwischen 0 und 120°C, vorzugsweise bei Temperaturen zwischen 10 und 100°C.Any subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in 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 alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
Die Abspaltung eines Benzyl-, Methoxybenzyl- oder Benzyloxycarbonylrestes erfolgt jedoch beispielsweise hydrogenolytisch, z.B. mit Wasserstoff in Gegenwart eines Katalysators wie Palladium/Kohle in einem geeigneten Losungsmittel wie Methanol. Ethanol, Essigsaureethylester oder Eisessig gegebenenfalls unter Zusatz einer Säure wie Salzsäure bei Temperaturen zwischen 0 und 100°C, vorzugsweise jedoch bei Temperaturen zwischen 20 und 60°C, und bei einem Wasserstoffdruck von 1 bis 7 bar, vorzugsweise jedoch von 3 bis 5 bar. Die Abspaltung eines 2.4-Dimeth- oxybenzylrestes erfolgt jedoch vorzugsweise in Trifluoressigsaure in Gegenwart von Anisol.However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, for example using hydrogen in the presence of a Catalyst such as palladium / carbon in a suitable solvent such as methanol. Ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
Die Abspaltung eines tert.-Butyl- oder tert. -Butyloxycarbonylres.es erfolgt vorzugs¬ weise durch Behandlung mit einer Säure wie Trifluoressigsaure oder Salzsäure oder durch Behandlung mit Jodtrimethylsilan gegebenenfalls unter Verwendung eines Lö¬ sungsmittels wie Methylenchlond, Dioxan, Methanol oder Diethylether.The cleavage of a tert-butyl or tert. -Butyloxycarbonylres.es is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
Die Abspaltung eines Trifluoracetylrestes erfolgt vorzugsweise durch Behandlung mit einer Säure wie Salzsaure gegebenenfalls in Gegenwart eines Lösungsmittels wie Essigsaure bei Temperaturen zwischen 50 und 120°C oder durch Behandlung mit Natronlauge gegebenenfalls in Gegenwart eines Lösungsmittels wie Tetrahy¬ drofuran bei Temperaturen zwischen 0 und 50CCThe elimination of a Trifluoracetylrestes is preferably carried out by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C or by treatment with sodium hydroxide solution optionally in the presence of a solvent such Tetrahy¬ drofuran at temperatures between 0 and 50 C C
Die Abspaltung eines Phthalylrestes erfolgt vorzugsweise in Gegenwart von Hydra¬ zin oder eines primären Amins wie Methylamin, Ethylamin oder n-Butylamiπ in einem Lösungsmittel wie Methanol, Ethanol, Isopropanol. Toluol/Wasser oder Dioxan bei Temperaturen zwischen 20 und 50°C.A phthalyl radical is preferably cleaved 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.
Ferner können die erhaltenen Verbindungen der allgemeinen Formel I, wie bereits eingangs erwähnt wurde, in ihre Enantiomeren und/oder Diastereomeren aufge¬ trennt werden. So können beispielsweise cis-/trans-Gemιsche in ihre eis- und trans-lsomere, und Verbindungen mit mindestens einem optisch aktiven Kohlen¬ stoffatom in ihre Enantiomeren aufgetrennt werden.Furthermore, the compounds of general formula I obtained, as already mentioned at the beginning, can be separated into their enantiomers and / or diastereomers. For example, cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
So lassen sich beispielsweise die erhaltenen cis-/trans-Gemιsche durch Chro¬ matographie in ihre eis- und trans-lsomeren, die erhaltenen Verbindungen der allgemeinen Formel I, welche in Racematen auftreten, nach an sich bekannten Methoden (siehe Allinger N. L. und Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 )) in ihre optischen Antipoden und Verbindungen der allgemeinen Formel I mit mindestens 2 asymmetrischen Kohlenstoffatomen auf Grund ihrer physikalisch-chemischen Unterschiede nach an sich bekannten Me¬ thoden, z.B. durch Chromatographie und/oder fraktionierte Kristallisation, in ihre Diastereomeren auftrennen, die, falls sie in racemischer Form anfallen, anschlie¬ ßend wie oben erwähnt in die Enantiomeren getrennt werden könnenFor example, the cis / trans mixtures obtained can be chromatographed into their ice and trans isomers, the compounds of the general formula I which occur in racemates and obtained by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, in their Separate diastereomers which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above
Die Enantiomerentrennung erfolgt vorzugsweise durch Saulentrennung an chiralen Phasen oder durch Umkristallisieren aus einem optisch aktiven Losungsmittel oder durch Umsetzen mit einer, mit der racemischen Verbindung Salze oder Derivate wie z B Ester oder Amide bildenden optisch aktiven Substanz, insbesondere Sauren und ihre aktivierten Derivate oder Alkohole, und Trennen des auf diese Weise er¬ haltenen diastereomeren Salzgemisches oder Derivates, z B auf Grund von ver¬ schiedenen Loslichkeiten, wobei aus den reinen diastereomeren Salzen oder Deri¬ vaten die freien Antipoden durch Einwirkung geeigneter Mittel freigesetzt werden können Besonders gebräuchliche, optisch aktive Sauren sind z B die D- und L-Formen von Weinsaure oder Dibenzoylwemsaure, Dι-o-Tolylweιnsaure, Apfel- saure, Mandelsaure, Camphersulfonsaure, Glutaminsäure, Asparaginsaure oder Chinasaure Als optisch aktiver Alkohol kommt beispielsweise (+)- oder (-)-Menthol und als optisch aktiver Acylrest in Amiden beispielsweise (+)-oder (-)-Menthyloxy- carbonyl in BetrachtThe enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives such as esters or amides, in particular acids and their activated derivatives or alcohols, with the racemic compound and separation of the diastereomeric salt mixture or derivative obtained in this way, for example due to various solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are, for example, the D and L forms of tartaric acid or dibenzoylwemic acid, di-o-tolylwine acid, apple acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or china acid. The optically active alcohol is, for example, (+) - or (-) - menthol and as an optically active acyl radical in amides, for example Either (+) - or (-) - menthyloxycarbonyl into consideration
Desweiteren können die erhaltenen Verbindungen der Formel I in ihre Salze, insbe¬ sondere für die pharmazeutische Anwendung in ihre physiologisch vertraglichen Salze mit anorganischen oder organischen Säuren, übergeführt werden Als Säuren kommen hierfür beispielsweise Salzsaure, Bromwasserstoffsaure, Methansulfon¬ säure Schwefelsaure, Phosphorsaure, Fumarsaure, Bernsteinsaure, Milchsäure, Zitronensaure, Weinsaure oder Maleinsäure in BetrachtFurthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of acids used for this are hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, fumaric acid, Succinic acid, lactic acid, citric acid, tartaric acid or maleic acid
Die als Ausgangsstoffe verwendeten Verbindungen der allgemeinen Formeln II und III sind teilweise hteraturbekannt oder man erhalt diese nach an sich literaturbekann- ten Verfahren (siehe beispielsweise WO 95/19774)Some of the compounds of the general formulas II and III used as starting materials are known in terms of temperature or can be obtained by processes known per se from the literature (see for example WO 95/19774)
Wie bereits eingangs erwähnt, weisen die erfindungsgemaßen Verbindungen der allgemeinen Formel I und ihre physiologisch vertraglichen Salze wertvolle pharma¬ kologische Eigenschaften auf, insbesondere eine spezifische Hemmwirkung auf die durch den Epidermal Growth Factor-Rezeptor (EGF-R) vermittelte Signaltrans¬ duktion, wobei diese beispielsweise durch eine Inhibition der Ligandenbindung, der Rezeptordimeπsierung oder der Tyrosmkinase selbst bewirkt werden kann Außer¬ dem ist es möglich, daß die Signalubertragung an weiter abwärts hegenden Kom¬ ponenten blockiert wird Die biologischen Eigenscπaften der neuen Verbindungen wurden wie folgt geprüft:As already mentioned at the beginning, the compounds of general formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular a specific inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), these for example, by inhibiting ligand binding, receptor diminution or the tyrosine kinase itself. It is also possible for the signal transmission to be blocked on further downward-lying components The biological properties of the new compounds were tested as follows:
Die Hemmung der EGF-R vermittelten Signaiύbertragung kann z.B. mit Zellen nach¬ gewiesen werden, die humanen EGF-R exprimieren und deren Überleben und Proli¬ feration von Stimulierung durch EGF bzw. TGF-alpha abhängt. Hier wurde eine Iπ- terleukin-3- (IL-3) abhängige Zellinie murinen Ursprungs verwendet, die derart gene¬ tisch verändert wurde, daß sie funktionellen humanen EGF-R exprimiert. Die Proli¬ feration dieser F/L-HERc genannten Zellen kann daher entweder durch murines IL-3 oder durch EGF stimuliert werden (siehe von Rüden, T. et al. in EMBO J. 7, 2749- 2756 (1988) und Pierce. J. H. et al. in Science 239, 628-631 (1988)).The inhibition of the EGF-R mediated signal transmission can e.g. can be detected with cells which express human EGF-R and whose survival and proliferation depends on stimulation by EGF or TGF-alpha. An π-terleukin-3 (IL-3) -dependent cell line of murine origin was used here, which was genetically modified in such a way that it expresses functional human EGF-R. The proliferation of these cells called F / L-HERc can therefore be stimulated either by murine IL-3 or by EGF (see von Rüden, T. et al. In EMBO J. 7, 2749-2756 (1988) and Pierce. JH et al. In Science 239: 628-631 (1988)).
Als Ausgangsmaterial für die F/L-HERc Zellen diente die Zelllinie FDC-Pi , deren Herstellung von Dexter, T. M. et al. in J. Exp. Med. 152, 1036-1047 (1980) beschrie¬ ben wurde. Alternativ können aber auch andere Wachstumsfaktor-abhängige Zellen verwendet werden (siehe beispielsweise Pierce, J. H. et al. in Science 239. 628-631 (1988), Shibuya, H. et al. in Cell 70, 57-67 (1992) und Alexander, W. S. et al. in EMBO J. 10, 3683-3691 (1991 )). Zur Expression der humanen EGF-R cDNA (siehe Ullrich, A. et al. in Nature 309, 418-425 (1984)) wurden rekombinante Retrovireπ verwendet, wie in von Rüden, T. et al., EMBO J. 7, 2749-2756 (1988) beschrieben, mit dem Unterschied, daß zur Expression der EGF-R cDNA der retrovirale Vektor LXSN (siehe Miller, A. D. et al. in BioTechniques 7, 980-990 (1989)) eingesetzt wurde und als Verpackungszelle die Linie GP+E86 (siehe Markowitz, D. et al. in J. Virol. 62, 1120-1124 (1988)) diente.The FDC-Pi cell line, the production of which by Dexter, T. M. et al. in J. Exp. Med. 152, 1036-1047 (1980). Alternatively, other growth factor-dependent cells can also be used (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)). For the expression of the human EGF-R cDNA (see Ullrich, A. et al. In Nature 309, 418-425 (1984)), recombinant Retrovireπ were used, as in von Rüden, T. et al., EMBO J. 7, 2749 -2756 (1988), with the difference that the retroviral vector LXSN (see Miller, AD et al. In BioTechniques 7, 980-990 (1989)) was used to express the EGF-R cDNA and the line GP as packaging cell + E86 (see Markowitz, D. et al. In J. Virol. 62, 1120-1124 (1988)).
Der Test wurde wie folgt durchgeführt:The test was carried out as follows:
F/L-HERc Zellen wurden in RPMI/1640 Medium (BioWhittaker), supplementiert mit 10 % foetalem Rinderserum (FCS, Boehringer Mannheim), 2 mM Glutamin (Bio¬ Whittaker), Standardantibiotika und 20 ng/ml humanem EGF (Promega), bei 37°C und 5% CO2 kultiviert. Zur Untersuchung der inhibitorischen Aktivität der erfin¬ dungsgemäßen Verbindungen wurden 1 ,5 x 104 Zellen pro Vertiefung in Triplikaten in 96-Loch-Platten in obigem Medium (200μl) kultiviert, wobei die Proliferation der Zellen entweder mit EGF (20 ng/ml) oder murinem IL-3 stimuliert wurde. Als Quelle für IL-3 dienten Kulturüberstände der Zellinie X63/0 mlL-3 (siehe Karasuyama, H. et al.in Eur. J. Immunol. 1J3, 97-104 (1988)). Die erfindungsgemäßen Verbindungen wurden in 100% Dimethylsulfoxid (DMSO) gelöst und in verschiedenen Verdün¬ nungen den Kulturen zugefügt, wobei die maximale DMSO Konzentration 1 % betrug. Die Kulturen wurden für 48 Stunden bei 37°C inkubiert. Zur Bestimmung der inhibitorischen Aktivität der erfindungsgemäßen Verbindungen wurde die relative Zellzahl mit dem Cell Titer 96™ AQueous Non-Radioactive Cell Proliferation Assay (Promega) in O.D. Einheiten gemessen. Die relative Zellzahl wurde in Prozent der Kontrolle (F/LHERc Zellen ohne Inhibitor) berechnet und die Wirkstoffkonzentration, die die Proliferation der Zellen zu 50% hemmt (ICso), ab¬ geleitet. Hierbei wurden folgende Ergebnisse erhalten:F / L-HERc cells were in RPMI / 1640 medium (BioWhittaker), supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (Bio Whittaker), standard antibiotics and 20 ng / ml human EGF (Promega), cultivated at 37 ° C and 5% CO2. To investigate the inhibitory activity of the compounds according to the invention, 1.5 × 10 4 cells per well were cultured in triplicates in 96-well plates in the above medium (200 μl), the proliferation of the cells using either EGF (20 ng / ml) or murine IL-3 was stimulated. Culture supernatants from cell line X63 / 0 ml L-3 served as the source for IL-3 (see Karasuyama, H. et al. In Eur. J. Immunol. 1J3, 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated at 37 ° C for 48 hours. To determine the inhibitory activity of the compounds according to the invention the relative cell number was measured using the Cell Titer 96 ™ AQ u eous Non-Radioactive Cell Proliferation Assay (Promega) in OD units. The relative cell number was calculated as a percentage of the control (F / LHERc cells without inhibitor) and the active ingredient concentration which inhibits the proliferation of the cells by 50% (IC 50) was derived. The following results were obtained:
Figure imgf000016_0001
Figure imgf000016_0001
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I hemmen somit die Signaltransduktion durch Tyrosinkinasen, wie am Beispiel des humanen EGF-Re- zeptors gezeigt wurde, und sind daher nützlich zur Behandlung pathophysiolo- gischer Prozesse, die durch Überfunktion von Tyrosinkinasen hervorgerufen wer¬ den. Das sind z.B. benigne oder maligne Tumoren, insbesondere Tumoren epithe- lialen und neuroepithelialen Ursprungs, Metastasierung sowie die abnorme Proli¬ feration vaskulärer Endothelzellen (Neoangiogenese). Außerdem können die Verbindungen der allgemeinen Formel I und deren physiolo¬ gisch verträglichen Salze zur Behandlung anderer Krankheiten verwendet werden, die durch aberrante Funktion von Tyrosinkinasen verursacht werden, wie z.B. epi¬ dermaler Hyperproliferation (Psoriasis), inflammatorischer Prozesse, Erkrankungen des Immunsystems, Hyperproliferation hämatopoetischer Zellen etc. .The compounds of the general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as has been shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by overfunction of tyrosine kinases. These are, for example, benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis). In addition, the compounds of general formula I and their physiologically tolerable salts can be used for the treatment of other diseases which are caused by aberrant function of tyrosine kinases, such as epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation hematopoietic Cells etc..
Auf Grund ihrer biologischen Eigenschaften können die erfindungsgemäßen Verbin¬ dungen allein oder in Kombination mit anderen pharmakologisch wirksamen Verbin¬ dungen angewendet werden, beispielsweise in der Tumortherapie in Moπotherapie oder in Kombination mit anderen Anti-Tumor Therapeutika, beispielsweise in Kom¬ bination mit Topoisomerase-Inhibitoren (z.B. Etoposide), Mitoseinhibitoren (z.B. Vin- blastin), mit Nukleinsäuren interagierenden Verbindungen (z.B. cis-Platin, Cyclo- phosphamid, Adriamycin), Hormon-Antagonisten (z.B. Tamoxifen), Inhibitoren meta- bolischer Prozesse (z.B. 5-FU etc.), Zytokinen (z.B. Interferonen), Antikörpern etc. Diese Kombinationen können entweder simultan oder sequentiell verabreicht wer¬ den.Because of their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitotic inhibitors (e.g. vinblastine), compounds interacting with nucleic acids (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc. ), Cytokines (eg interferons), antibodies etc. These combinations can be administered either simultaneously or sequentially.
Bei der pharmazeutischen Anwendung werden die erfindungsgemäßen Verbin¬ dungen in der Regel bei warmblütigen Wirbeltieren, insbesondere beim Menschen, in Dosierungen von 0,01-100 mg/kg Körpergewicht, vorzugsweise bei 0,1 -15 mg/kg verwendet. Zur Verabreichung werden diese mit einem oder mehreren üblichen in¬ erten Trägerstoffen und/oder Verdünnungsmitteln, z.B. mit Maisstärke, Milchzucker, Rohrzucker, mikrokristalliner Zellulose, Magnesiumstearat, Polyvinylpyrrolidon, Zi¬ tronensäure, Weinsäure, Wasser, Wasser/Äthanol, Wasser/Glycerin, Wasser/Sor¬ bit, Wasser/Polyäthylenglykol, Propylenglykol, Stearylalkohol, Carboxymethylcel- lulose oder fetthaltigen Substanze wie Hartfett oder deren geeigneten Gemischen in übliche galenische Zubereitungen wie Tabletten, Dragees, Kapseln, Pulver, Suspen¬ sionen, Lösungen, Sprays oder Zäpfchen eingearbeitet.In pharmaceutical use, the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg. For administration, these are mixed with one or more conventional inert carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty acid such as hard fat or their suitable mixtures incorporated into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.
Die nachfolgenden Beispiele sollen die vorliegende Erfindung näher erläutern ohne diese zu beschränken: Beispiel IThe following examples are intended to illustrate the present invention without restricting it: Example I
4-[(3-Chlor-4-fluor-phenyl)amino]-7-fluor-pyrido[4,3-d]pyrimidin4 - [(3-chloro-4-fluorophenyl) amino] -7-fluoropyrido [4,3-d] pyrimidine
230 mg 7-Fluor-4-hydroxy-pyrido[4,3-d]pyrimidin werden in 10 ml Phosphoroxy- chlorid 3.5 Stunden am Rückfluß erhitzt. Das Reaktionsgemisch wird eingeengt, der Rückstand in 100 ml Methylenchlorid gelöst und mit 25 ml gesättigter Natriumcar- bonat-Lösung 15 Minuten gerührt.Die organische Phase wird abgetrennt und die wäßrige Phase zweimal mit je 100 ml Methylenchlorid extrahiert. Die vereinigten organischen Phasen werden mit Wasser gewaschen und über Magnesiumsulfat getrocknet. Zu dieser Lösung werden 1.26 g 3-Chlor-4-fluoranilin, 20 mg 3-Chlor- 4-fluoranilin-hydrochlorid und 5 ml Isopropanol zugegeben. Das Methylenchlorid wird im Vakuum entfernt und das Reaktionsgemisch eine Stunde bei Raumtem¬ peratur gerührt. Das Gemisch wird zur Trockne eingeengt und der Rückstand zwei¬ mal mit je 100 ml Petrolether gerührt. Der im Petrolether unlösliche Rückstand wird durch Chromatographie über eine Kieselgelsäule gereinigt. Ausbeute: 100 mg (25% der Theorie),230 mg of 7-fluoro-4-hydroxy-pyrido [4,3-d] pyrimidine are refluxed in 10 ml of phosphorus oxychloride for 3.5 hours. The reaction mixture is concentrated, 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 off and the aqueous phase is extracted twice with 100 ml of methylene chloride each time. The combined organic phases are washed with water and dried over magnesium sulfate. 1.26 g of 3-chloro-4-fluoroaniline, 20 mg of 3-chloro-4-fluoroaniline hydrochloride and 5 ml of isopropanol are added to this solution. The methylene chloride is removed in vacuo and the reaction mixture is stirred for one hour at room temperature. The mixture is evaporated to dryness and the residue is stirred twice with 100 ml of petroleum ether. The residue, which is insoluble in petroleum ether, is purified by chromatography on a silica gel column. Yield: 100 mg (25% of theory),
Schmelzpunkt: 290-295X (Zersetzung; bei ca. 250 X tritt Veränderung der Kristall¬ struktur ein) Rf-Wert: 0.50 (Kieselgel; Cyclohexan/Essigester = 1 :1 )Melting point: 290-295X (decomposition; the crystal structure changes at approx. 250 X) Rf value: 0.50 (silica gel; cyclohexane / ethyl acetate = 1: 1)
Analog Beispiel I werden folgende Verbindungen erhalten:The following compounds are obtained analogously to Example I:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-fluor-pyhdo[3,4-d]pyrimidin(1) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-fluoro-pyhdo [3,4-d] pyrimidine
Schmelzpunkt: 264-266XMelting point: 264-266X
Rf-Wert: 0.58 (Kieselgel; Petrolether/Essigester = 1 :1 )Rf value: 0.58 (silica gel; petroleum ether / ethyl acetate = 1: 1)
(2) 4-[(4-Amino-3,5-dibrom-phenyl)amino]-6-fluor-pyhdo[3,4-d]pyrimidin(2) 4 - [(4-Amino-3,5-dibromo-phenyl) amino] -6-fluoro-pyhdo [3,4-d] pyrimidine
Schmelzpunkt: 235-237XMelting point: 235-237X
Rf-Wert: 0.50 (Kieselgel; Petrolether/Essigester = 1 :1 )Rf value: 0.50 (silica gel; petroleum ether / ethyl acetate = 1: 1)
Beispiel 1example 1
4-[(3-Chlor-4-fluor-phenyl)amino]-7-(4-amino-1-piperidinyl)-pyrido[4,3-d]pyrimidin4 - [(3-chloro-4-fluorophenyl) amino] -7- (4-amino-1-piperidinyl) pyrido [4,3-d] pyrimidine
100 mg 4-[(3-Chlor-4-fluor-phenyl)amino]-7-fluor-pyrido[4,3-d]pyrimidin und 202 mg 4-Aminopiperidin werden in 3 ml Isopropanol 4 Stunden bei 90 X und 18 Stunden bei Raumtemperatur gerührt. Das Rohgemisch wird direkt auf einer Kieselgelsäule mit Methylenchlorid/Methanol/konz. wäßriges Ammoniak (9:1 :0.1 ) gereinigt. Ausbeute: 65 mg (51 % der Theorie),100 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -7-fluoropyrido [4,3-d] pyrimidine and 202 mg of 4-aminopiperidine are added in 3 ml of isopropanol at 90 X and 18 for 4 hours Stirred for hours at room temperature. The crude mixture is directly on a silica gel column with methylene chloride / methanol / conc. aqueous ammonia (9: 1: 0.1) cleaned. Yield: 65 mg (51% of theory),
Schmelzpunkt: 231-233XMelting point: 231-233X
Rf-Wert: 0.25 (Kieselgel; Methylenchlorid/Methanol/Ammoniak = 4:1 :0.1 )Rf value: 0.25 (silica gel; methylene chloride / methanol / ammonia = 4: 1: 0.1)
Massenspektrum: M+ = 372/4Mass spectrum: M + = 372/4
Analog Beispiel 1 werden folgende Verbindungen erhalten:The following compounds are obtained analogously to Example 1:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[(1-methyl-4-piperidinyl)amino]-pyhdo[4,3-d]- pyrimidin(1) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(1-methyl-4-piperidinyl) amino] pyhdo [4,3-d] pyrimidine
Schmelzpunkt: 253-256XMelting point: 253-256X
Rf-Wert: 0.42 (Kieselgel; Methylenchlorid/Methanol/Ammoniak = 4:1 :0.1 )Rf value: 0.42 (silica gel; methylene chloride / methanol / ammonia = 4: 1: 0.1)
Massenspektrum: M+ = 386/8Mass spectrum: M + = 386/8
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(4-piperidinyl)piperidin-1 -yl]-pyrido[4,3-d]- pyrimidin(2) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [4- (4-piperidinyl) piperidin-1-yl] pyrido [4,3-d] pyrimidine
Schmelzpunkt: 272-275XMelting point: 272-275X
Rf-Wert: 0.32 (Reversed-Phase-Kieselgel; Methanol/5%-ige wäßrige Kochsalz¬ lösung = 6:4) Massenspektrum: M+ = 440/2Rf value: 0.32 (reversed-phase silica gel; methanol / 5% aqueous sodium chloride solution = 6: 4) mass spectrum: M + = 440/2
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[(1-tert.butyloxycarbonyl-4-piperidinyl)amino]- pyrido[4,3-d]pyrimidiπ(3) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(1-tert-butyloxycarbonyl-4-piperidinyl) amino] - pyrido [4,3-d] pyrimidiπ
Schmelzpunkt: 232-235XMelting point: 232-235X
Rf-Wert: 0.41 (Kieselgel; Essigester)Rf value: 0.41 (silica gel; ethyl acetate)
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[[trans-4-(methoxycarbonyl)cyclohexyl)]-ami- no]-pyhdo[4,3-d]pyrimidin(4) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [[trans-4- (methoxycarbonyl) cyclohexyl)] - amino] -pyhdo [4,3-d] pyrimidine
Schmelzpunkt: 253-254XMelting point: 253-254X
Rf-Wert: 0.50 (Kieselgel; Essigester)Rf value: 0.50 (silica gel; ethyl acetate)
(5) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-morpholino-pyrido[4,3-d]pyrimidin(5) 4 - [(3-chloro-4-fluorophenyl) amino] -7-morpholino-pyrido [4,3-d] pyrimidine
(6) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[N-methyl-N-(1-methyl-4-piperidinyl)-amino]- pyrido[4,3-d]pyrimidin(6) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [N-methyl-N- (1-methyl-4-piperidinyl) amino] - pyrido [4,3-d] pyrimidine
(7) 4-[(3-Chlor-4-fluor-phenyl)aminö]-7-[(trans-4-hydroxycyclohexyl)amino]-pyrido- [4,3-d]pyrimidin (8) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[(2-amino-2-methyl-1-propyl)amino]-pyrido- [4,3-d]pyrimidin(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-Chlor-4-fluor-phenyl)amino]-7-[(3-chinuclidinyi)amino]-pyrido[4,3-d]pyrimi- din(9) 4 - [(3-Chloro-4-fluorophenyl) amino] -7 - [(3-quinuclidinyi) amino] pyrido [4,3-d] pyrimidine
(10) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-morpholino-pyrido[3,4-d]pyrimidin(10) 4 - [(3-chloro-4-fluorophenyl) amino] -6-morpholino-pyrido [3,4-d] pyrimidine
(11 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(4-amino-1 -piperidinyl)-pyrido[3,4-d]pyri- midin(11) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (4-amino-1-piperidinyl) pyrido [3,4-d] pyrimidine
Schmelzpunkt: 307-309X (Zers.)Melting point: 307-309X (dec.)
Rf-Wert: 0.30 (Kieselgel; Methylenchlorid/Methanol/konz. wäßriges Ammoniak = 4: 1 :0,1 )Rf value: 0.30 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 4: 1: 0.1)
(12) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(1-methyl-4-piperidinyl)amino]-pyrido- [3,4-d]pyrimidin(12) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [(1-methyl-4-piperidinyl) amino] pyrido- [3,4-d] pyrimidine
(13) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(trans-4-hydroxycyclohexyl)amino]-pyrido- [3,4-d]pyrimidin(13) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(trans-4-hydroxycyclohexyl) amino] pyrido- [3,4-d] pyrimidine
(14) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[[trans-4-(methoxycarbonyl)cyclohexyl]- amino]-pyrido[3,4-d]pyrimidin(14) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [[trans-4- (methoxycarbonyl) cyclohexyl] amino] pyrido [3,4-d] pyrimidine
(15) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-(4-piperidinyl)piperidin-1-yl]-pyhdo- [3,4-d]pyrimidin(15) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [4- (4-piperidinyl) piperidin-1-yl] pyhdo- [3,4-d] pyrimidine
Rf-Wert: 0.45 (Kieselgel; Methylenchlorid/Methanol/konz. wäßriges Ammoniak = 2:1 :0,15)Rf value: 0.45 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 2: 1: 0.15)
(16) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(2-amino-2-methyl-1-propyl)amino]-pyrido- [3,4-d]pyrimidin(16) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(2-amino-2-methyl-1-propyl) amino] pyrido- [3,4-d] pyrimidine
Rf-Wert: 0.55 (Kieselgel; Methylenchlorid/Methanol/konz. wäßriges Ammoniak = 4:1 :0,1 )Rf value: 0.55 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 4: 1: 0.1)
(17) 4-[(3-Chlor-4-fluor-ρhenyl)amino]-6-[(3-chinuclidinyl)amino]-pyrido[3,4-d]pyri- midin(17) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [(3-quinuclidinyl) amino] pyrido [3,4-d] pyrimidine
Rf-Wert: 0,34 (Kieselgel; Methylenchlorid/Methanol/konz. Ammoniak = 6:1 :0,1 ) (18) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[[1 -(tert.butyloxycarbonyl)-4-piperidinyl]ami- no]-pyrido[3,4-d]pyrimidinRf value: 0.34 (silica gel; methylene chloride / methanol / concentrated ammonia = 6: 1: 0.1) (18) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [[1 - (tert.butyloxycarbonyl) -4-piperidinyl] amino] pyrido [3,4-d] pyrimidine
(19) 4-[(4-Amino-3,5-dibrom-pheπyl)amino]-6-[(1 -methyl-4-piperidinyl)amino]-pyri- do[3,4-d]pyrimidin(19) 4 - [(4-Amino-3,5-dibromophenyl) amino] -6 - [(1-methyl-4-piperidinyl) amino] pyrido [3,4-d] pyrimidine
(20) 4-[(4-Amino-3,5-dibrom-phenyl)amino]-6-[(trans-4-hydroxycyclohexyl)amino]- pyrido[3,4-d]pyrimidin(20) 4 - [(4-Amino-3,5-dibromophenyl) amino] -6 - [(trans-4-hydroxycyclohexyl) amino] pyrido [3,4-d] pyrimidine
Schmelzpunkt: 170X (Zersetzung)Melting point: 170X (decomposition)
Rf-Wert: 0,40 (Kieselgel; Petrolether/Essigester/Methanol = 10:10:3)Rf value: 0.40 (silica gel; petroleum ether / ethyl acetate / methanol = 10: 10: 3)
Massenspektrum: M+ = 506/508/510 (2 Br)Mass spectrum: M + = 506/508/510 (2 Br)
(21 ) 4-[(4-Amino-3,5-dibrom-phenyl)amino]-6-[4-(4-piperidinyl)piperidin-1 -yl]-pyrido- [3,4-d)pyrimidin(21) 4 - [(4-Amino-3,5-dibromo-phenyl) amino] -6- [4- (4-piperidinyl) piperidin-1-yl] pyrido- [3,4-d) pyrimidine
Rf-Wert: 0,27 (Kieselgel; Methylenchlorid/Methanol/konz. Ammoniak = 2:1:0,1) Massenspektrum: M+ = 559/561/563 (2 Br)Rf value: 0.27 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.1) mass spectrum: M + = 559/561/563 (2 Br)
(22) 4-[(4-Amino-3,5-dibrom-phenyl)amino]-6-[(2-amino-2-methyl-1-propyl)amino]- pyrido[3,4-d]pyrimidin(22) 4 - [(4-Amino-3,5-dibromophenyl) amino] -6 - [(2-amino-2-methyl-1-propyl) amino] pyrido [3,4-d] pyrimidine
Rf-Wert: 0,23 (Kieseigel; Methylenchlorid/Methanol/konz. Ammoniak = 6:1:0,1 ) Massenspektrum: M+ = 479/481/483 (2 Br)Rf value: 0.23 (gravels; methylene chloride / methanol / concentrated ammonia = 6: 1: 0.1) mass spectrum: M + = 479/481/483 (2 Br)
(23) 4-[(3-Chlorphenyl)amino]-6-morpholino-pyrido[3,2-d]pyrimidin(23) 4 - [(3-chlorophenyl) amino] -6-morpholino-pyrido [3,2-d] pyrimidine
(24) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(4-amiπo-1-piperidinyl)-pyrido[3,2-d]pyrimi- din(24) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (4-amino-1-piperidinyl) pyrido [3,2-d] pyrimidine
(25) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[[trans-4-(methoxycarbonyl)cyclohexyl]ami- no]-pyrido[3,2-d]pyrimidin(25) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - [[trans-4- (methoxycarbonyl) cyclohexyl] amino] pyrido [3,2-d] pyrimidine
(26) 4-[(3-Methylphenyl)amino]-7-morpholino-pyrido[2,3-d]pyrimidin(26) 4 - [(3-Methylphenyl) amino] -7-morpholino-pyrido [2,3-d] pyrimidine
(27) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[(1-methyl-4-piperidinyl)amino]-pyrido- [2,3-d]pyrimidin(27) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(1-methyl-4-piperidinyl) amino] pyrido- [2,3-d] pyrimidine
(28) 4-[(3-Chlor-4-fluor-phenyl)amiho]-7-[(trans-4-hydroxycyclohexyl)amino]-pyrido- [2,3-d]pyrimidin (29) 4-[(3-Bromphenyl)amιno]-7-morpholιno-pyrιmιdo[4,5-d]pyrimιdin(28) 4 - [(3-chloro-4-fluorophenyl) amiho] -7 - [(trans-4-hydroxycyclohexyl) amino] pyrido- [2,3-d] pyrimidine (29) 4 - [(3-bromophenyl) amιno] -7-morpholιno-pyrιmιdo [4,5-d] pyrimιdin
(30) 4-[(3-Chlor-4-fluor-phenyl)amιno]-7-[N-methyl-N-(1 -methyl-4-pιperidιnyl)-amιno]- pyπmιdo[4,5-d]pyrιmιdin(30) 4 - [(3-chloro-4-fluorophenyl) amιno] -7- [N-methyl-N- (1-methyl-4-pιperidιnyl) -amιno] - pyπmιdo [4,5-d] pyrιmιdin
(31 ) 4-[(3-Chlor-4-fluor-phenyl)amιno]-7-[(1-methyl-4-pιperιdιnyl)amιno]-pyrimιdo- [4,5-d]pyrιmidin(31) 4 - [(3-chloro-4-fluorophenyl) amιno] -7 - [(1-methyl-4-pιperιdιnyl) amιno] -pyrimιdo- [4,5-d] pyrιmidin
(32) 4-[(3-Chlor-4-fluor-phenyl)amιno]-7-[[trans-4-(methoxycarbonyl)cyclohexyl]- amιno]-pyrιmido[4,5-d]pyrimidin(32) 4 - [(3-chloro-4-fluorophenyl) amιno] -7 - [[trans-4- (methoxycarbonyl) cyclohexyl] - amιno] -pyrιmido [4,5-d] pyrimidine
(33) 4-[(3-Chlor-4-fluor-phenyl)amιno]-7-[(3-tropaπyl)amιno]-pyrιdo[4,3-d]pyπmidιn(33) 4 - [(3-chloro-4-fluorophenyl) amιno] -7 - [(3-tropaπyl) amιno] -pyrιdo [4,3-d] pyπmidιn
(34) 4-[(4-Amιno-3,5-dibrom-phenyl)amino]-6-[(3-tropanyl)amιno]-pyrιdo[3,4-d]- pynmidin(34) 4 - [(4-Amιno-3,5-dibromo-phenyl) amino] -6 - [(3-tropanyl) amιno] -pyrιdo [3,4-d] - pynmidine
Schmelzpunkt: sintert ab 150X, ab 170X ZersetzungMelting point: sinters from 150X, from 170X decomposition
Rf-Wert: 0,17 (Kieselgel; Methylenchlorid/Methanol/konz. Ammoniak = 6 1 :0,1 )Rf value: 0.17 (silica gel; methylene chloride / methanol / concentrated ammonia = 6 1: 0.1)
Massenspektrum: M+ = 531/533/535 (2 Br)Mass spectrum: M + = 531/533/535 (2 Br)
(35) 4-[(3-Chlor-4-fluor-phenyl)amιno]-7-[4-aminocyclohexyl-amιno]-pyrido[4,3-d]- pyrimidin(35) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4-aminocyclohexyl amino] pyrido [4,3-d] pyrimidine
(36) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-methylaminocyclohexyl-amιno]-pyrιdo- [4,3-d]pyπmidin(36) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4-methylaminocyclohexylamino] -pyrιdo- [4,3-d] pyπmidine
(37) 4-[(3-Chlor-4-fluor-phenyl)amιno]-7-[4-dιmethylaminocyclohexyl-amιno]-pyrido- [4,3-d]pyrimιdιn(37) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4-dimethylaminocyclohexyl amino] pyrido [4,3-d] pyrimidine
(38) 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-[4-aminocyclohexyl-amino]-pyrιdo[3,4-d]- pyrimidin(38) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4-aminocyclohexylamino] pyrido [3,4-d] pyrimidine
(39) 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-[4-methylamιnocyciohexyl-amιno]-pyrιdo- [3,4-d]pyπmidin(39) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4-methylaminocyciohexyl amino] pyridine - [3,4-d] pyπmidine
(40) 4-[(3-Chlor-4-fluor-ρhenyl)amιno]-6-[4-dιmethylamιnocyclohexyl-amino]-pyrido- [3,4-d]pyhmidin (41 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-aminocyclohexyl-amino]-pyrido[2,3-d]- pyrimidin(40) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4-dimethylaminocyclohexylamino] pyrido [3,4-d] pyhmidine (41) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4-aminocyclohexylamino] pyrido [2,3-d] pyrimidine
(42) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-methylaminocyclohexyl-amino]-pyrido- [2,3-d]pyrimidin(42) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4-methylaminocyclohexylamino] pyrido- [2,3-d] pyrimidine
(43) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-dimethylaminocyclohexyl-amino]-pyrido- [2,3-d]pyrimidin(43) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4-dimethylaminocyclohexylamino] pyrido- [2,3-d] pyrimidine
(44) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-aminocyclohexyl-amino]-pyrimido[4,5-d]- pyrimidin(44) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4-aminocyclohexylamino] pyrimido [4,5-d] pyrimidine
(45) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-methylaminocyclohexyl-amino]-pyrimido- [4,5-d]pyrimidin(45) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4-methylaminocyclohexylamino] pyrimido [4,5-d] pyrimidine
(46) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-dimethylaminocyclohexyl-amino]-pyrimi- do[4,5-d]pyrimidin(46) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [4-dimethylaminocyclohexylamino] pyrimido [4,5-d] pyrimidine
(47) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-aminocyclohexyl-amino]-pyrido[3,2-d]- pyrimidin(47) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4-aminocyclohexylamino] pyrido [3,2-d] pyrimidine
(48) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-methylaminocyclohexyl-amino]-pyrido- [3,2-d]pyrimidin(48) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4-methylaminocyclohexylamino] pyrido- [3,2-d] pyrimidine
(49) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-dimethylaminocyclohexyl-amino]-pyrido- [3,2-d]pyrimidin(49) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4-dimethylaminocyclohexylamino] pyrido- [3,2-d] pyrimidine
Beispiel 2Example 2
4-[(3-Chlor-4-fluor-phenyl)amino]-7-[(4-piperidinyl)amino]-pyrido[4,3-d]pyrimidin4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(4-piperidinyl) amino] pyrido [4,3-d] pyrimidine
186 mg 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[(1-tert.butyloxycarbonyl-4-piperidinyl)- amino]-pyrido[4,3-d]pyrimidin, 2 ml Methylenchlorid und 2 ml Trifluoressigsaure werden 1 Stunde bei Raumtemperatur gerührt. Es wird zur Trockne eingeengt, in 5 ml Wasser aufgenommen und mit 1 N Natronlauge alkalisch gestellt. Nach 30 Mi¬ nuten Rühren bei Raumtemperatur wird der Niederschlag abgesaugt, mit Wasser gewaschen und bei 70X im Vakuum getrocknet. Ausbeute: 115 mg (78 % der Theorie), Schmelzpunkt: 265-267X186 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(1-tert-butyloxycarbonyl-4-piperidinyl) amino] pyrido [4,3-d] pyrimidine, 2 ml of methylene chloride and 2 ml of trifluoroacetic acid are stirred at room temperature for 1 hour. It is evaporated to dryness, taken up in 5 ml of water and made alkaline with 1 N sodium hydroxide solution. After stirring for 30 minutes at room temperature, the precipitate is filtered off, washed with water and dried at 70X in vacuo. Yield: 115 mg (78% of theory), Melting point: 265-267X
Rf-Wert: 0.50 (Reversed Phase Kieselgel; Aceton itril/Waser (1 :1 ) + 1 % Trifluor¬ essigsaure)Rf value: 0.50 (reversed phase silica gel; acetone itril / water (1: 1) + 1% trifluoroacetic acid)
Analog Beispiel 2 werden folgende Verbindungen erhalten:The following compounds are obtained analogously to Example 2:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-pipehdinyl)amino]-pyrido[3,4-d]pyrimidin(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4-pipehdinyl) amino] pyrido [3,4-d] pyrimidine
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(1-piperazinyl)-1 -piperidinyl]-pyhdo[4,3-d]- pyrimidin(2) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [4- (1-piperazinyl) -1 -piperidinyl] pyhdo [4,3-d] pyrimidine
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(4-piperidinyl)-1-piperazinyl]-pyrido[4,3-d]- pyrimidin(3) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (4-piperidinyl) -1-piperazinyl] pyrido [4,3-d] pyrimidine
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-(1 -piperazinyl)-1-piperidinyl]-pyhdo[3,4-d]- pyrimidin(4) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (1-piperazinyl) -1-piperidinyl] pyhdo [3,4-d] pyrimidine
(5) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-(4-piperidinyl)-1-piperazinyl]-pyrido[3,4-d)- pyrimidin(5) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [4- (4-piperidinyl) -1-piperazinyl] pyrido [3,4-d) pyrimidine
(6) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(1-piperazinyl)-1-piperidinyl]-pyrido[2,3-d]- pyrimidin(6) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [4- (1-piperazinyl) -1-piperidinyl] pyrido [2,3-d] pyrimidine
(7) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(4-piperidinyl)-1-piperazinyl]-pyrido[2,3-d]- pyrimidin(7) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [4- (4-piperidinyl) -1-piperazinyl] pyrido [2,3-d] pyrimidine
(8) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-{4-(1 -piperazinyl )-1 -piperidinylj-pyrimido- [4,5-d]pyrimidin(8) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- {4- (1-piperazinyl) -1 -piperidinylj-pyrimido- [4,5-d] pyrimidine
(9) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(4-piperidinyl)-1-piperazinyl]-pyrimido- [4,5-d]pyrimidin(9) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [4- (4-piperidinyl) -1-piperazinyl] pyrimido- [4,5-d] pyrimidine
(10) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-(1-piperazinyl)-1-pipehdinyl]-pyhdo- [3,2-d]pyrimidin(10) 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [4- (1-piperazinyl) -1-pipehdinyl] -pyhdo- [3,2-d] pyrimidine
(11 ) 4-[(3-Chlor-4-fluor-phenyl)amirio]-6-[4-(4-pipehdinyl)-1-piperazinyl]-pyrido- [3,2-d]pyrimidin Beispiel 3(11) 4 - [(3-Chloro-4-fluorophenyl) amirio] -6- [4- (4-pipehdinyl) -1-piperazinyl] pyrido- [3,2-d] pyrimidine Example 3
4-[(3-Chlor-4-fiuor-phenyl)amino]-7-[(trans-4-carboxycyclohexyl)amino]-pyrido- [4,3-d]pyrimidin4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(trans-4-carboxycyclohexyl) amino] pyrido- [4,3-d] pyrimidine
210 mg 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[[trans-4-(methoxycarbonyl)cyclohexyl]- amino]-pyrido[4,3-d]pyrimidin in 2 ml Methanol werden mit 2 ml 1 N Natronlauge versetzt und 2 Stunden bei Raumtemperatur gerührt. Es werden 2.1 ml 1 N Salz¬ säure zugegeben und das Methanol im Vakuum abgezogen. Nach Zugabe von 5 ml Wasser wird 30 Minuten im Eisbad gerührt, der Niederschlag wird abgesaugt, mit Eiswasser gewaschen und getrocknet. Ausbeute: 170 mg (84% der Theorie), Schmelzpunkt: 306-31 OX Rf-Wert: 0.10 (Kieselgel; Essigester)210 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [[trans-4- (methoxycarbonyl) cyclohexyl] amino] pyrido [4,3-d] pyrimidine in 2 ml of methanol mixed with 2 ml of 1 N sodium hydroxide solution and stirred for 2 hours at room temperature. 2.1 ml of 1 N hydrochloric acid are added and the methanol is stripped off in vacuo. After adding 5 ml of water, the mixture is stirred in an ice bath for 30 minutes, the precipitate is filtered off, washed with ice water and dried. Yield: 170 mg (84% of theory), melting point: 306-31 OX Rf value: 0.10 (silica gel; ethyl acetate)
Analog Beispiel 3 werden folgende Verbindungen erhalten:The following compounds are obtained analogously to Example 3:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(trans-4-carboxycyclohexyl)amino]-pyrido- [3,4-d]pyhmidin(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(trans-4-carboxycyclohexyl) amino] pyrido- [3,4-d] pyhmidine
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(trans-4-carboxycyclohexyl)amino]-pyrido- [3,2-d]pyrimidin(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(trans-4-carboxycyclohexyl) amino] pyrido- [3,2-d] pyrimidine
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[(trans-4-carboxycyclohexyl)amino]-pyrimido- [4,5-d]pyrimidin(3) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(trans-4-carboxycyclohexyl) amino] pyrimido [4,5-d] pyrimidine
Beispiel 4Example 4
4-[(3-Chlor-4-fluor-phenyl)amino]-7-[[trans-4-(morpholinocarbonyl)cyclohexyl]]-ami- no]-pyrido[4,3-d]pyrimidin4 - [(3-Chloro-4-fluorophenyl) amino] -7 - [[trans-4- (morpholinocarbonyl) cyclohexyl]] - amino] pyrido [4,3-d] pyrimidine
Zu einer Lösung von 140 mg 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[(trans-4-carb- oxycyclohexyl)amino]-pyrido[4,3-d]pyrimidin in 1 ml Dimethylformamid werden 135 mg 2-(1 H-Benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium-tetrafluorborat, 0,19 ml Triethylamin und 0.06 ml Morpholin zugegeben und 1 ,5 Stunden bei Raumtempera¬ tur gerührt. Es werden 10 ml Wasser zugesetzt und 20 Minuten gerührt. Der Nieder¬ schlag wird abgesaugt, mit Wasser gewaschen und bei 60X im Vakuum getrocknet. Ausbeute: 130 mg (82% der Theorie), Schmelzpunkt: 278-283X Rf-Wert: 0.54 (Kieselgel; Methylenchlorid/Methanol = 6:1 )To a solution of 140 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(trans-4-carboxycyclohexyl) amino] pyrido [4,3-d] pyrimidine in 1 ml Dimethylformamide, 135 mg of 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate, 0.19 ml triethylamine and 0.06 ml morpholine are added and the mixture is stirred for 1.5 hours at room temperature. 10 ml of water are added and the mixture is stirred for 20 minutes. The precipitate is filtered off, washed with water and dried at 60X in vacuo. Yield: 130 mg (82% of theory), melting point: 278-283X Rf value: 0.54 (silica gel; methylene chloride / methanol = 6: 1)
Analog Beispiel 4 werden folgende Verbindungen erhalten:The following compounds are obtained analogously to Example 4:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[[trans-4-(morpholinocarbonyl)cyclohexyi]- amino]-pyrido[3,4-d]pyrimidin(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [[trans-4- (morpholinocarbonyl) cyclohexyi] amino] pyrido [3,4-d] pyrimidine
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[[trans-4-(morpholinocarbonyl)cyclohexyl]- amino]-pyrido[3,2-d]pyhmidin(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [[trans-4- (morpholinocarbonyl) cyclohexyl] amino] pyrido [3,2-d] pyhmidine
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[[trans-4-(morpholinocarbonyl)cyclohexyl]- aminoj-pyrimido[4,5-d]pyrimidin(3) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [[trans-4- (morpholinocarbonyl) cyclohexyl] - aminoj-pyrimido [4,5-d] pyrimidine
Beispiel 5Example 5
4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(1-methyl-4-piperidinyl)piperidin-1-yl]-pyhdo- [4,3-d]pyrimidin4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (1-methyl-4-piperidinyl) piperidin-1-yl] pyhdo- [4,3-d] pyrimidine
Zu einer Suspension von 365 mg 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(4-piperi- dinyl)piperidin-1-yl]-pyrido[4,3-d]pyhmidin in 30 ml Methanol werden 0.07 ml 37%ige Formalinlösung und 57 mg Natriumcyanborhydrid zugegeben. Nach 30 Minuten Rühren bei Raumtemperatur werden 10 ml Methylenchlorid zugesetzt und 3 Stunden gerührt. Danach wird zur Trockene eingeengt, 15 ml Wasser zugesetzt und 30 Minu¬ ten gerührt. Der Rückstand wird abgesaugt und durch Chromatographie über eine Kieselgelsäule mit Methylenchlorid/Methanol/konz. wäßriges Ammoniak (9:1 :0,1 ) gereinigt.To a suspension of 365 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (4-piperidinyl) piperidin-1-yl] pyrido [4,3-d] pyhmidine in 30 ml of methanol, 0.07 ml of 37% formalin solution and 57 mg of sodium cyanoborohydride are added. After stirring for 30 minutes at room temperature, 10 ml of methylene chloride are added and the mixture is stirred for 3 hours. The mixture is then evaporated to dryness, 15 ml of water are added and the mixture is stirred for 30 minutes. The residue is filtered off and by chromatography on a silica gel column with methylene chloride / methanol / conc. aqueous ammonia (9: 1: 0.1) cleaned.
Ausbeute: 196 mg (52% der Theorie), Schmelzpunkt: 291-292XYield: 196 mg (52% of theory), melting point: 291-292X
Rf-Wert: 0.50 (Kieselgel; Methylenchlorid/Methanol/konz. wäßriges Ammoniak = 6:1 :0,1 )Rf value: 0.50 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 6: 1: 0.1)
Analog Beispiel 5 werden folgende Verbindungen erhaltenThe following compounds are obtained analogously to Example 5
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-(1 -methyl-4-piperidinyl)piperidin-1-yl]-py- hdo[3,4-d]pyrimidin(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (1-methyl-4-piperidinyl) piperidin-1-yl] pyhdo [3,4-d ] pyrimidine
Schmelzpunkt: 180-185X (Zersetzung, sintert ab 168X)Melting point: 180-185X (decomposition, sinters from 168X)
Rf-Wert: 0,43 (Kieselgel; Methylenchlorid/Methanol/konz. Ammoniak = 6:1 :0,1 ) (2) 4-[(4-Amino-3,5-dibrom-phenyl)amino]-6-[4-(1-methyl-4-piperidinyl)piperidin- 1 -yl]-pyrido[3,4-d]pyrimidinRf value: 0.43 (silica gel; methylene chloride / methanol / concentrated 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
Schmelzpunkt: 220 - 222XMelting point: 220-222X
Rf-Wert: 0,24 (Kieselgel; Methylenchlorid/Methanol/konz. Ammoniak = 10:1:0,1 )Rf value: 0.24 (silica gel; methylene chloride / methanol / concentrated ammonia = 10: 1: 0.1)
Massenspektrum: M+ = 573/575/577 (2 Br)Mass spectrum: M + = 573/575/577 (2 Br)
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(4-methyl-1 -piperazinyl)-1 -piperidinylj-pyri- do[4,3-d]pyrimidin(3) 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4- (4-methyl-1-piperazinyl) -1 -piperidinylj-pyrido [4,3-d] pyrimidine
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(1-methyl-4-piperidinyl)-1 -piperazinyl]-pyri- do[4,3-d]pyrimidin(4) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (1-methyl-4-piperidinyl) -1 -piperazinyl] pyrido [4,3-d] pyrimidine
(5) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-(4-methyl-1 -piperazinyl)-1 -piperidinyl]-ρyri- do[3,4-d]pyrimidin(5) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (4-methyl-1-piperazinyl) -1 -piperidinyl] -ρyrido [3,4-d] pyrimidine
(6) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-(1-methyl-4-pipehdinyl)-1 -piperazinyl]-pyri- do[3,4-d]pyrimidin(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (1-methyl-4-pipehdinyl) -1 -piperazinyl] pyrido [3,4-d] pyrimidine
(7) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(4-methyl-1 -piperazinyl)-1 -piperidinyl]-pyri- do[2,3-d]pyrimidin(7) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (4-methyl-1-piperazinyl) -1 -piperidinyl] pyrido [2,3-d] pyrimidine
(8) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(1 -methyl-4-pipehdinyl)-1 -piperazinyl]-pyri- do[2,3-d]pyrimidin(8) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (1-methyl-4-pipehdinyl) -1 -piperazinyl] pyrido [2,3-d] pyrimidine
(9) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(4-methyl-1 -piperazinyl)-1 -piperidinylj-pyri- mido[4,5-d]pyhmidin(9) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [4- (4-methyl-1-piperazinyl) -1 -piperidinylj-pyrimido [4,5-d] pyhmidine
(10) 4-[(3-Chlor-4-fiuor-phenyl)amino]-7-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-py- rimido[4,5-d]pyrimidin(10) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (1-methyl-4-piperidinyl) -1-piperazinyl] pyyrido [4,5-d] pyrimidine
(11) 4-[(3-Chior-4-fluor-phenyl)amino]-6-[4-(4-methyl-1 -piperazinyl)-1 -piperidinyl]-py- rido[3,2-d]pyhmidin(11) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (4-methyl-1-piperazinyl) -1 -piperidinyl] -pyrido [3,2-d] pyhmidine
(12) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-(1-methyl-4-piperidinyl)-1-piperazinyl]-py- hdo[3,2-d]pyhmidin Beispiel 6(12) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (1-methyl-4-piperidinyl) -1-piperazinyl] -py-hdo [3,2-d] pyhmidine Example 6
Dragees mit 75 mg WirksubstanzDragees with 75 mg of active substance
1 Drageekern enthält:1 coated tablet contains:
Wirksubstanz 75,0 mgActive substance 75.0 mg
Calciumphosphat 93,0 mgCalcium phosphate 93.0 mg
Maisstärke 35,5 mgCorn starch 35.5 mg
Polyvinylpyrrolidon 10,0 mgPolyvinyl pyrrolidone 10.0 mg
Hydroxypropylmethylcellulose 15,0 mgHydroxypropylmethyl cellulose 15.0 mg
Magnesiumstearat 1 ,5 mαMagnesium stearate 1.5 mα
230,0 mg230.0 mg
Herstellung:Manufacturing:
Die Wirksubstanz wird mit Calciumphosphat, Maisstärke, Polyvinylpyrrolidon, Hy¬ droxypropylmethylcellulose und der Hälfte der angegebenen Menge Magnesium¬ stearat gemischt. Auf einer Tablettiermaschine werden Preßlinge mit einem Durch¬ messer von ca. 13 mm hergestellt, diese werden auf einer geeigneten Maschine durch ein Sieb mit 1 ,5 mm-Maschenweite gerieben und mit der restlichen Menge Magnesiumstearat vermischt. Dieses Granulat wird auf einer Tablettiermaschine zu Tabletten mit der gewünschten Form gepreßt.The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.
Kerngewicht: 230 mgCore weight: 230 mg
Stempel: 9 mm, gewölbtStamp: 9 mm, domed
Die so hergestellten Drageekerne werden mit einem Film überzogen, der im wesent¬ lichen aus Hydroxypropylmethylcellulose besteht. Die fertigen Filmdragees werden mit Bienenwachs geglänzt.The dragee cores thus produced are coated with a film which essentially consists of hydroxypropylmethyl cellulose. The finished film coated tablets are polished with beeswax.
Drageegewicht: 245 mg.Drage weight: 245 mg.
Beispiel 7Example 7
Tablette'n mit 100 mg WirksubstanzTablet 'n with 100 mg of active substance
Zusammensetzung:Composition:
1 Tablette enthält:1 tablet contains:
Wirksubstanz 100,0 mgActive substance 100.0 mg
Milchzucker 80,0 mgMilk sugar 80.0 mg
Maisstärke 34,0 mg Polyvinylpyrrolidon 4,0 mgCorn starch 34.0 mg Polyvinyl pyrrolidone 4.0 mg
Magnesiumstearat 2.0 mgMagnesium stearate 2.0 mg
220,0 mg220.0 mg
Herstellungverfahren:Manufacturing process:
Wirkstoff, Milchzucker und Stärke werden gemischt und mit einer wäßrigen Lösung des Polyvinylpyrrolidons gleichmäßig befeuchtet. Nach Siebung der feuchten Masse (2,0 mm-Maschenweite) und Trocknen im Hordentrockenschrank bei 50X wird er¬ neut gesiebt (1 ,5 mm-Maschenweite) und das Schmiermittel zugemischt. Die pre߬ fertige Mischung wird zu Tabletten verarbeitet.Active ingredient, milk sugar and starch are mixed and moistened uniformly with an aqueous solution of the polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50X, sieving is carried out again (1.5 mm mesh size) and the lubricant is added. The finished mixture is processed into tablets.
Tablettengewicht: 220 mgTablet weight: 220 mg
Durchmesser: 10 mm, biplan mit beidseitiger Facette und einseitiger Teilkerbe.Diameter: 10 mm, biplane with facet on both sides and partial notch on one side.
Beispiel 8Example 8
Tabletten mit 150 mg WirksubstanzTablets with 150 mg of active substance
Zusammensetzung:Composition:
1 Tablette enthält:1 tablet contains:
Wirksubstanz 150,0 mgActive substance 150.0 mg
Milchzucker pulv. 89,0 mgMilk sugar powder 89.0 mg
Maisstärke 40,0 mgCorn starch 40.0 mg
Kolloide Kieselgelsäure 10,0 mgColloidal silica 10.0 mg
Polyvinylpyrrolidon 10,0 mgPolyvinyl pyrrolidone 10.0 mg
Magnesiumstearat 1.0 mgMagnesium stearate 1.0 mg
300,0 mg300.0 mg
Herstellung:Manufacturing:
Die mit Milchzucker, Maisstärke und Kieselsäure gemischte Wirksubstanz wird mit einer 20%igen wäßrigen Polyvinylpyrrolidonlösung befeuchtet und durch ein Sieb mit 1 ,5 mm-Maschenweite geschlagen.The active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a 1.5 mm mesh size.
Das bei 45X getrocknete Granulat wird nochmals durch dasselbe Sieb gerieben und mit der angegebenen Menge Magnesiumstearat gemischt. Aus der Mischung werden Tabletten gepreßt. Tablettengewicht: 300 mg Stempel: 10 mm, flachThe granules dried at 45X are rubbed through the same sieve again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Tablet weight: 300 mg stamp: 10 mm, flat
Beispiel 9Example 9
Hartgelatine-Kapseln mit 150 mg WirksubstanzHard gelatin capsules with 150 mg of active substance
1 Kapsel enthält: Wirkstoff 150,0 mg1 capsule contains: active ingredient 150.0 mg
Maisstärke getr. ca. 180,0 mgCornstarch dr. approximately 180.0 mg
Milchzucker pulv. ca. 87,0 mgMilk sugar powder approx. 87.0 mg
Magnesiumstearat 3.0 mg ca. 420,0 mgMagnesium stearate 3.0 mg approx.420.0 mg
Herstellung:Manufacturing:
Der Wirkstoff wird mit den Hilfsstoffen vermengt, durch ein Sieb von 0,75 mm-Ma¬ schenweite gegeben und in einem geeigneten Gerät homogen gemischt. Die Endmischung wird in Hartgelatine-Kapseln der Größe 1 abgefüllt.The active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device. The final mix is filled into size 1 hard gelatin capsules.
Kapselfüllung: ca. 320 mgCapsule filling: approx. 320 mg
Kapselhülle: Hartgelatine-Kapsel Größe 1.Capsule shell: hard gelatin capsule size 1.
Beispiel 10Example 10
Suppositohen mit 150 mg WirksubstanzSuppositohen with 150 mg of active substance
1 Zäpfchen enthält:1 suppository contains:
Wirkstoff 150,0 mgActive ingredient 150.0 mg
Polyäthylenglykol 1500 550,0 mgPolyethylene glycol 1500 550.0 mg
Polyäthylenglykol 6000 460,0 mgPolyethylene glycol 6000 460.0 mg
Polyoxyäthylensorbitanmonostearat 840.0 mgPolyoxyethylene sorbitan monostearate 840.0 mg
2 000,0 mg2,000.0 mg
Herstellung:Manufacturing:
Nach dem Aufschmelzen der Suppositorienmasse wird der Wirkstoff darin homogen verteilt und die Schmelze in vorgekühlte Formen gegossen Beispiel 11After the suppository mass has melted, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds Example 11
Suspension mit 50 mg WirksubstanzSuspension with 50 mg of active substance
100 ml Suspension enthalten100 ml suspension included
Wirkstoff 1 ,00 gActive ingredient 1.00 g
Carboxymethylcellulose-Na-Salz 0,10 g p-Hydroxybenzoesauremethylester 0,05 g p-Hydroxybenzoesaurepropylester 0,01 gCarboxymethyl cellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
Rohrzucker 10,00 gCane sugar 10.00 g
Glycerin 5,00 gGlycerin 5.00 g
Sorbitlosung 70%ιg 20,00 gSorbitol solution 70% ιg 20.00 g
Aroma 0,30 gAroma 0.30 g
Wasser dest ad 100 mlWater least ad 100 ml
HerstellungManufacturing
Dest Wasser wird auf 70X erhitzt Hierin wird unter Ruhren p-Hydroxybenzoe- sauremethylester und -propylester sowie Glycerin und Carboxymethylcellulose- Natnumsalz gelost Es wird auf Raumtemperatur abgekühlt und unter Rühren der Wirkstoff zugegeben und homogen dispergiert Nach Zugabe und Losen des Zuckers, der Sorbitlosung und des Aromas wird die Suspension zur Entlüftung unter Ruhren evakuiertThe distilled water is heated to 70X. Methyl p-hydroxybenzoate and propyl ester and glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring. The mixture is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. After adding and dissolving the sugar, the sorbitol solution and the Aromas the suspension for evacuation is evacuated under stirring
5 ml Suspension enthalten 50 mg Wirkstoff 5 ml of suspension contain 50 mg of active ingredient

Claims

Patentansprüche claims
1. 4-Amino-pyrimidin-Derivate der allgemeinen Formel1. 4-aminopyrimidine derivatives of the general formula
Figure imgf000032_0001
in der mit der Maßgabe, daß die Verbindung 4-[(3-Bromphenyl)amino]-6-(1-pipe- ridinyl)-pyrido[3,4-d]pyrimidin vom Schutzumfang ausgeschlossen ist,
Figure imgf000032_0001
with the proviso that the compound 4 - [(3-bromophenyl) amino] -6- (1-pipe-ridinyl) pyrido [3,4-d] pyrimidine is excluded from the scope of protection,
Ra ein Wasserstoffatom oder eine Methylgruppe,R a is a hydrogen atom or a methyl group,
Rb eine durch die Reste R-j bis R3 substituierte Phenylgruppe oder eine Phenylal- kylgruppe, in der der Phenylteil durch die Reste R-| bis R3 substituiert ist, wobeiRb is a phenyl group substituted by the radicals R-j to R3 or a phenylalkyl group in which the phenyl part is substituted by the radicals R- | to R3 is substituted, wherein
R-j ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom, eine Alkyl-, Trifluormethyl-, Ethenyl-, Ethinyl-, Alkyloxy-, C3_6-Cycloalkyl-, Trifluormethoxy-, Cyano-, Amino-, Al¬ kylamino-, Dialkylamino- oder Nitrogruppe,Rj is a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl, trifluoromethyl, ethenyl, ethynyl, alkyloxy, C3_6-cycloalkyl, trifluoromethoxy, cyano, amino, alkylamino , Dialkylamino or nitro group,
R2 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom oder eine Alkylgruppe undR2 is a hydrogen, fluorine, chlorine or bromine atom or an alkyl group and
R3 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom darstellen,R3 represent a hydrogen, fluorine, chlorine or bromine atom,
A und B zusammen eine Brücke der FormelA and B together form a bridge of the formula
- N = CRC - CH = CH - , - CH = N - CRC = CH - , - CH = CRC - N = CH - ,- N = CR C - CH = CH -, - CH = N - CR C = CH -, - CH = CR C - N = CH -,
- CH = CH - CRC = N - oder- CH = CH - CR C = N - or
- CH = N - CRC = N - bedeuten,- CH = N - CR C = N - mean
wobei jeweils das linke Ende dieser Brücken mit Position 5 und das rechte Ende dieser Brücken mit Position 6 des Pyrimidinringes verknüpft ist und in denen Rc eine gegebenenfalls durch eine oder zwei Alkylgruppen substituierte Morpholino- gruppe,where the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the pyrimidine ring and in which R c is a morpholino group which is optionally substituted by one or two alkyl groups,
eine gegebenenfalls durch eine oder zwei Alkylgruppen substituierte 1-Piperazinyl- gruppe,a 1-piperazinyl group optionally substituted by one or two alkyl groups,
eine gegebenenfalls durch eine oder zwei Alkylgruppen substituierte 3-Oxo-1 -pipe- razinylgruppe,a 3-oxo-1-piperazinyl group optionally substituted by one or two alkyl groups,
eine 1-Piperazinylgruppe, die in 4-Stellung durch eine C3_6-Cycloalkylgruppe, durch eine 3-Tetrahydrofuranyl-, 3-Tetrahydropyranyl-, 4-Tetrahydropyranyl-, 3-Pyrrolidin- yl-, 1 -Alkyl-3-pyrrolidinyl-, 3-Piperidinyl-, 4-Piperidinyl-, 1 -Alkyl-3-piperidinyl- oder 1-Alkyl-4-piperidinyl-Gruppe substituiert ist,a 1-piperazinyl group which is in the 4-position by a C3_6-cycloalkyl group, by a 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 group is substituted,
eine gegebenenfalls durch R4 substituierte 1-Azetidinyl-, 1 -Pyrrolidinyl-, 1 -Piperidin¬ yl- oder 1-Azacyclohept-1-yl-Gruppe, wobeian 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyll or 1-azacyclohept-1-yl group which is optionally substituted by R4, where
R4 eine Hydroxy-, Alkyloxy-, Amino-, Alkylamino-, Dialkylamino-, Alkylcarbonytami- no-, N-Alkyl-alkylcarbonylamino-, 2-Oxo-1-pyrrolidinyl-, 2-Oxo-1 -piperidinyl-, Alkyl- oxycarbonylamino-, N-Alkyl-alkyloxycarbonylamino-, Alkyisulfonylamino-, N-Alkyl- alkylsulfonylamino-, C3_6-Cycloalkyl-, Tetrahydrofuranyl-, Tetrahydropyranyl-, Pyrro- lidinyl-, 1-Alkyl-pyrrolidinyl-, Piperidinyl-, 1-Alkyl-pipehdiπyl-, Morpholino-, 1 -Pipera¬ zinyl-, 4-Alkyl-1 -piperazinyl-, Aminoalkyl-, Alkylaminoalkyl-, Dialkylaminoalkyl-, Carb¬ oxy-, Alkyloxycarbonyl-, Aminocarbonyl-, Alkylaminocarbonyl-, Dialkylaminocarbo- nyl-, 1-Pyrrolidinylcarbonyl-, 1-Piperidinylcarbonyl-, Morpholinocarbonyl-, 1 -Pipera- zinylcarbonyl-, 4-Alkyl-1-piperazinylcarbonyl- oder Cyanogruppe darstellt,R4 is a hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, N-alkylalkylcarbonylamino, 2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl, alkyloxycarbonylamino -, N-Alkyl-alkyloxycarbonylamino-, alkylsulfonylamino-, N-alkyl-alkylsulfonylamino-, C3_6-cycloalkyl-, tetrahydrofuranyl-, tetrahydropyranyl-, pyrrolidinyl-, 1-alkyl-pyrrolidinyl-, piperidinyl-, 1-alkyl-pipehdi -, Morpholino-, 1-piperazinyl, 4-alkyl-1-piperazinyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, 1 Represents pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, morpholinocarbonyl, 1 -piperazinylcarbonyl, 4-alkyl-1-piperazinylcarbonyl or cyano group,
eine 1-Azetidinylgruppe, in der 2 Wasserstoffatome in 3-Stellung durch eine gerad¬ kettige Alkylenbrucke mit 4 oder 5 Kohlenstoffatomen ersetzt sind, wobei in den vor¬ stehend erwähnten Alkylenbrucken jeweils eine Methylengruppe durch ein Sauer¬ stoffatom oder durch eine Imino- oder N-Alkyl-iminogruppe ersetzt sein kann,a 1-azetidinyl group in which 2 hydrogen atoms in the 3-position are replaced by a straight-chain alkylene bridge with 4 or 5 carbon atoms, in the above-mentioned alkylene bridges each a methylene group by an oxygen atom or by an imino or N Alkyl imino group can be replaced,
eine 1-Pyrrolidinylgruppe, in der 2 Wasserstoffatome am Kohlenstoffgerust durch eine geradkettige Alkylenbrucke ersetzt sind, wobei diese Brücke 3 bis 5 Kohlen¬ stoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 3 oder 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoff¬ atome an benachbarten Kohlenstoffatomen befinden, oder 2 oder 3 Kohlenstoff- atome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befin¬ den, die durch ein Atom getrennt sind, wobei in den vorstehend erwähnten Alkylen¬ brucken jeweils eine Methylengruppe durch ein Sauerstoffatom oder durch eine Imino- oder N-Alkyl-iminogruppe ersetzt sein kann,a 1-pyrrolidinyl group in which 2 hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 3 to 5 carbon atoms if the two hydrogen atoms are on the same carbon atom, or 3 or 4 carbon atoms if the two Hydrogen atoms are located on adjacent carbon atoms, or 2 or 3 carbon atoms contains atoms if the two hydrogen atoms are on carbon atoms which are separated by an atom, it being possible for one methylene group in the abovementioned alkylene bridges to be replaced by one oxygen atom or by an imino or N-alkylimino group,
eine 1 -Pipendinylgruppe, in der 2 Wasserstoffatome am Kohlenstoffgerust durch eine geradkettige Alkylenbrucke ersetzt sind, wobei diese Brücke 3 bis 5 Kohlen¬ stoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoff atom befinden, oder 3 oder 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoff¬ atome an benachbarten Kohlenstoffatomen befinden, oder 2 oder 3 Kohlenstoff¬ atome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoff atomen befin¬ den, die durch ein Atom getrennt sind, oder 1 oder 2 Kohlenstoff atome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei in den vorstehend erwähnten Alkylenbrucken jeweils eine Methylengruppe durch ein Sauerstoffatom oder durch eine Imino- oder Alkyl- iminogruppe ersetzt sein kann,a 1 -pipendinyl group in which 2 hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 3 to 5 carbon atoms if the two hydrogen atoms are on the same carbon atom, or contains 3 or 4 carbon atoms if the two hydrogen atoms are located on adjacent carbon atoms, or contains 2 or 3 carbon atoms if the two hydrogen atoms are on carbon atoms which are separated by an atom, or contains 1 or 2 carbon atoms if the two hydrogen atoms are are on carbon atoms which are separated by two atoms, it being possible for one methylene group in the abovementioned alkylene bridges to be replaced by an oxygen atom or by an imino or alkylimino group,
oder Rc eine (RsNRßJ-Gruppe darstellt, in deror R c represents a (RsNRßJ group in which
R5 ein Wasserstoffatom oder eine Alkylgruppe, undR5 represents a hydrogen atom or an alkyl group, and
Rg eine durch R4 substituierte C5_7-Cycloalkylgruppe, wobei R4 wie vorstehend er¬ wähnt definiert ist,Rg is a C5_7-cycloalkyl group substituted by R4, where R4 is defined as mentioned above,
eine 3-Tetrahydrofuranylgruppe,a 3-tetrahydrofuranyl group,
eine 3- oder 4-Tetrahydropyranylgruppe,a 3- or 4-tetrahydropyranyl group,
eine 3-Pyrrolidinyl- oder 3- oder 4-Piperidinylgruppe, wobei das Ringstickstoffatom der vorstehend erwähnten Gruppen jeweils durch eine Alkyl-, Alkylcarbonyl-, Alkyl¬ sulfonyl-, Alkyloxycarbonyl-, C3_6-Cycloalkyl-, 3-Tetrahydrofuranyl-, 3- oder 4-Tetra- hydropyranyl-, 3-Pyrrolidinyl-, 1-Alkyl-3-pyrrolidinyl-, 3- oder 4-Piperidinyl-, 1-Alkyl- 3-piperidinyl- oder 1-Alkyl-4-piperidinyl-Gruppe substituiert sein kann,a 3-pyrrolidinyl or 3- or 4-piperidinyl group, the ring nitrogen atom of the groups mentioned above in each case by an alkyl, alkylcarbonyl, alkyl sulfonyl, alkyloxycarbonyl, C3_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 group can be substituted ,
eine durch den Rest R4 substituierte C2-6-Alkylgnjppe, wobei R4 wie vorstehend er¬ wähnt definiert ist,a radical R4-substituted by C 2-6 lkylgnjppe A, wherein R4 is as above defined imagines er¬,
eine 3- oder 4-Chinuclidinylgruppe oder eine 3-Tropanyl- oder Desmethyl-3-tropanylgruppe darstellen,a 3- or 4-quinuclidinyl group or represent a 3-tropanyl or desmethyl-3-tropanyl group,
sowie, soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylteile je¬ weils 1 bis 4 Kohleπstoffatome enthalten,and, unless stated otherwise, the alkyl parts mentioned above each contain 1 to 4 carbon atoms,
deren Tautomeren, deren Stereoisomere und deren Salze.their tautomers, their stereoisomers and their salts.
2. 4-Amino-pyrimidin-Derivate der allgemeinen Formel I gemäß Anspruch 1 , in der mit der Maßgabe, daß die Verbindung 4-[(3-Bromphenyl)amino]-6-(1-piperidinyl)- pyrido[3,4-d]pyrimidin vom Schutzumfang ausgeschlossen ist,2. 4-aminopyrimidine derivatives of the general formula I according to claim 1, with the proviso that the compound 4 - [(3-bromophenyl) amino] -6- (1-piperidinyl) pyrido [3,4 -d] pyrimidine is excluded from the scope,
Ra ein Wasserstoffatom oder eine Methyigruppe,R a is a hydrogen atom or a methyl group,
Rb eine durch die Reste R-j bis R3 substituierte Phenylgruppe, wobeiRb is a phenyl group substituted by the radicals R-j to R3, where
R-j ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom, eine Methyl-, Ethyl-, Tri¬ fluormethyl-, Methoxy-, Cyclopropyl-, Trifluormethoxy-, Cyano-, Nitro- oder Amino¬ gruppe,R-j is a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, ethyl, trifluoromethyl, methoxy, cyclopropyl, trifluoromethoxy, cyano, nitro or amino group,
R2 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R2 is a hydrogen, fluorine, chlorine or bromine atom,
R3 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom darstellen,R3 represent a hydrogen, fluorine, chlorine or bromine atom,
A und B zusammen eine Brücke der FormelA and B together form a bridge of the formula
- N = CRC - CH = CH - , - CH = N - CRC = CH - , - CH = CRC - N = CH - ,- N = CR C - CH = CH -, - CH = N - CR C = CH -, - CH = CR C - N = CH -,
- CH = CH - CRC = N - oder- CH = CH - CR C = N - or
- CH = N - CRC = N - bedeuten,- CH = N - CR C = N - mean
wobei jeweils das linke Ende dieser Brücken mit Position 5 und das rechte Ende dieser Brücken mit Position 6 des Pyrimidinringes verknüpft ist und in denenwhere the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the pyrimidine ring and in which
Rc eine gegebenenfalls durch eine oder zwei Methylgruppen substituierte Morpho- linogruppe, eine gegebenenfalls durch eine oder zwei Methylgruppen substituierte 1 -Piperazin- ylgruppe,R c is a morpholine group optionally substituted by one or two methyl groups, a 1-piperazin-yl group optionally substituted by one or two methyl groups,
eine 1 -Piperazinylgruppe, die in 4-Stellung durch eine 4-Piperidinyl- oder 1 -Alkyl- 4-piperidinyl-Gruppe substituiert ist,a 1 -piperazinyl group which is substituted in the 4-position by a 4-piperidinyl or 1-alkyl- 4-piperidinyl group,
eine in 3-Stellung durch R4 substituierte 1-Pyrrolidinylgruppe oder eine in 3- oder 4-Stellung durch R4 substituierte 1-Piperidinylgruppe, wobeia 1-pyrrolidinyl group substituted in the 3-position by R4 or a 1-piperidinyl group substituted in the 3- or 4-position by R4, where
R4 eine Amino-, Methylamino-, Dimethylamino-, Pyrrolidinyl-, 1-Methylpyrrolidinyl-, Piperidinyl-, 1 -Methylpiperidinyl-, Morpholino-, 1 -Piperazinyl-, 4-Methyl-1 -piperazin¬ yl-, Hydroxy-, Methoxy-, Carboxy-, Methoxycarbonyl-, Ethoxycarbonyl-, Dimethyl- aminocarbonyl-, 1-Pyrrolidinylcarbonyl-, 1-Piperidinylcarbonyl-, oder Morpholino- carbonylgruppe darstellt,R4 is an amino, methylamino, dimethylamino, pyrrolidinyl, 1-methylpyrrolidinyl, piperidinyl, 1-methylpiperidinyl, morpholino, 1-piperazinyl, 4-methyl-1-piperazin¬ yl, hydroxy, methoxy -, carboxy, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, or morpholinocarbonyl group,
oder eine (RsNRgJ-Gruppe, in deror an (RsNRgJ group in which
R5 ein Wasserstoffatom oder eine Methyl- oder Ethylgruppe undR5 represents a hydrogen atom or a methyl or ethyl group and
RQ eine durch R4 substituierte Cyclopentyl- oder Cyclohexylgruppe, wobei R4 wie vorstehend erwähnt definiert ist,RQ is a cyclopentyl or cyclohexyl group substituted by R4, where R4 is defined as mentioned above,
eine 3-Pyrrolidinyl- oder 3- oder 4-Piperidiπylgruppe, wobei das Ringstickstoffatom der vorstehend erwähnten Gruppen jeweils durch eine Methyl-, Ethyl-, C-j ^-Alkyl¬ oxycarbonyl-, Acetyl- oder Methylsulfonylgruppe substituiert sein kann,a 3-pyrrolidinyl or 3- or 4-piperidyl group, it being possible for the ring nitrogen atom of the groups mentioned above to be substituted in each case by a methyl, ethyl, C 1-4 alkylalkyloxycarbonyl, acetyl or methylsulfonyl group,
eine durch den Rest R4 substituierte C2-4-Alkylgruppe, wobei R4 wie vorstehend erwähnt definiert ist,a C2-4 alkyl group substituted by the radical R4, where R4 is defined as mentioned above,
eine 3- oder 4-Chinuclidinylgruppe odera 3- or 4-quinuclidinyl group or
eine 3-Tropanylgruppe darstellen,represent a 3-tropanyl group,
deren Tautomeren, deren Stereoisomere und deren Salze.their tautomers, their stereoisomers and their salts.
3. 4-Amino-pyrimidin-Derivate der allgemeinen Formel I gemäß Anspruch 1 , in der mit der Maßgabe, daß die Verbindung 4-[(3-Bromphenyl)amino]-6-(1 -piperidinyl)- pyrido[3,4-d]pyrimidin vom Schutzumfang ausgeschlossen ist, Ra ein Wasserstoff atom,3. 4-aminopyrimidine derivatives of the general formula I according to claim 1, with the proviso that the compound 4 - [(3-bromophenyl) amino] -6- (1-piperidinyl) pyrido [3,4 -d] pyrimidine is excluded from the scope, R a is a hydrogen atom,
Rb eine durch die Reste R-j bis R3 substituierte Phenylgruppe, wobeiRb is a phenyl group substituted by the radicals R-j to R3, where
R-j ein Wasserstoff-, Fluor-, Chlor- oder Bromatom, eine Methyl- oder Aminogruppe,R-j is a hydrogen, fluorine, chlorine or bromine atom, a methyl or amino group,
R2 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R2 is a hydrogen, fluorine, chlorine or bromine atom,
R3 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom darstellen,R3 represent a hydrogen, fluorine, chlorine or bromine atom,
A und B zusammen eine Brücke der FormelA and B together form a bridge of the formula
- N = CRC - CH = CH - , - CH = N - CRC = CH - , - CH = CRC - N = CH - ,- N = CR C - CH = CH -, - CH = N - CR C = CH -, - CH = CR C - N = CH -,
- CH = CH - CRC = N - oder- CH = CH - CR C = N - or
- CH = N - CRC = N - bedeuten,- CH = N - CR C = N - mean
wobei jeweils das linke Ende dieser Brücken mit Position 5 und das rechte Ende dieser Brücken mit Position 6 des Pyrimidinringes verknüpft ist und in denenwhere the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the pyrimidine ring and in which
Rc eine Morpholinogruppe,R c is a morpholino group,
eine 1 -Pipendinylgruppe, die in 3- oder 4-Stellung durch eine Amino-, Piperidinyl- oder 1-Methylpipehdinylgruppe substituiert ist,a 1 -pipendinyl group which is substituted in the 3- or 4-position by an amino, piperidinyl or 1-methylpipehdinyl group,
oder eine (RsNRßJ-Gruppe, wobeior a (RsNRßJ group, where
R5 ein Wasserstoffatom oder eine Methylgruppe undR5 is a hydrogen atom or a methyl group and
R5 eine Cyclohexylgruppe, die durch eine Carboxy-, Methoxycarbonyl-, Ethoxycar¬ bonyl-, Morpholinocarbonyl- oder Hydroxygruppe substituiert ist,R5 is a cyclohexyl group which is substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl, morpholinocarbonyl or hydroxy group,
eine 3- oder 4- Pipendinylgruppe, wobei das Ringstickstoffatom jeweils durch eine Methyl-, Ethyl- oder C-ι_4-Alkyl-oxycarbonylgruppe substituiert sein kann,a 3- or 4-pipendinyl group, where the ring nitrogen atom can in each case be substituted by a methyl, ethyl or C 1-4 alkyloxycarbonyl group,
eine durch eine Aminogruppe substituierte C2-4-Alkyigruppe, eine 3-Tropanyl- oder 3-Chinuclidinylgruppe darstellen,a C2-4-alkyl group substituted by an amino group, represent a 3-tropanyl or 3-quinuclidinyl group,
deren Tautomeren, deren Stereoisomere und deren Salze.their tautomers, their stereoisomers and their salts.
4. Folgende 4-Amino-pyrimidindehvate der allgemeinen Formel I gemäß Anspruch 1:4. The following 4-aminopyrimidine dehvates of the general formula I according to claim 1:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-(4-amino-1-piperidinyl)-pyhdo[4,3-d]pyrimi- din,(1) 4 - [(3-chloro-4-fluorophenyl) amino] -7- (4-amino-1-piperidinyl) pyhdo [4,3-d] pyrimidine,
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[(1-methyl-4-piperidinyl)amino]-pyrido[4,3-d]- pyrimidin,(2) 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(1-methyl-4-piperidinyl) amino] pyrido [4,3-d] pyrimidine,
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(4-amino-1-piperidinyl)-pyhdo[3,4-d]pyhmi- din,(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (4-amino-1-piperidinyl) pyhdo [3,4-d] pyhmidine,
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(3-chinuclidinyl)amino]-pyrido[3,4-d]pyri- midin,(4) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(3-quinuclidinyl) amino] pyrido [3,4-d] pyrimidine,
(5) 4-[(4-Amino-3,5-dibrom-phenyl)amino]-6-[(trans-4-hydroxycyclohexyl)aminoj- pyrido[3,4-d]pyrimidin,(5) 4 - [(4-amino-3,5-dibromophenyl) amino] -6 - [(trans-4-hydroxycyclohexyl) aminoj-pyrido [3,4-d] pyrimidine,
(6) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[4-(1 -methyl-4-piperidinyl)piperidin-1 -yl]-py- rido[3,4-d]pyrimidin(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (1-methyl-4-piperidinyl) piperidin-1-yl] pyrido [3,4-d ] pyrimidine
und deren Salze.and their salts.
5. Physiologisch verträgliche Salze der Verbindungen nach mindestens einem der Ansprüche 1 bis 4 mit anorganischen oder organischen Säuren oder Basen.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. Arzneimittel, enthaltend eine Verbindung nach mindestens einem der Ansprüche 1 bis 4 oder ein physiologisch verträgliches Salz gemäß Anspruch 5 neben gegebe¬ nenfalls einem oder mehreren inerten Trägerstoffen und/oder Verdünnungsmitteln.6. Medicament containing a compound 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, if appropriate.
7. Verwendung einer Verbindung nach mindestens einem der AnOsprüche 1 bis 5 zur Herstellung eines Arzneimittels, das zur Behandlung von benignen oder malig¬ nen Tumoren, insbesondere Tumoren epithelialen und neuroepithelialen Ursprungs, der Metastasierung sowie der abnormen Proliferation vaskulärer Endothelzellen (Neoangiogenese), geeignet ist.7. Use of a compound according to at least one of Claims 1 to 5 for the manufacture of a medicament which is used to treat benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and abnormal proliferation of vascular endothelial cells (neoangiogenesis).
8. Verfahren zur Herstellung eines Arzneimittels gemäß Anspruch 6, dadurch ge¬ kennzeichnet, daß auf nichtchemischem Wege eine Verbindung nach mindestens einem der Ansprüche 1 bis 5 in einen oder mehrere inerte Trägerstoffe und/oder Verdünnungsmit-tel eingearbeitet wird.8. A method for producing a medicament according to claim 6, characterized ge indicates that a compound according to at least one of claims 1 to 5 is incorporated in one or more inert carriers and / or diluents by a non-chemical route.
9. Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I gemäß den Ansprüchen 1 bis 5, dadurch gekennzeichnet, daß9. A process for the preparation of the compounds of general formula I according to claims 1 to 5, characterized in that
a) eine Verbindung der allgemeinen Formela) a compound of the general formula
Figure imgf000039_0001
in der
Figure imgf000039_0001
in the
Ra und Rb wie in den Ansprüchen 1 bis 4 definiert sind,R a and Rb are as defined in claims 1 to 4,
A und B' zusammen eine Brücke der FormelA and B 'together form a bridge of the formula
- N = CZ-j - CH = CH - , - CH = N - CZ-j = CH - ,- N = CZ-j - CH = CH -, - CH = N - CZ-j = CH -,
- CH = CZ-j - N = CH - ,- CH = CZ-j - N = CH -,
- CH = CH - CZ-j = N - oder- CH = CH - CZ-j = N - or
- CH = N - CZ-i = N - bedeuten,- CH = N - CZ-i = N - mean
in denenin which
Z-j eine Austrittsgruppe darstellt und jeweils das linke Ende dieser Brücken mit Posi¬ tion 5 und das rechte Ende dieser Brücken mit Position 6 des Pyrimidinringes ver¬ knüpft ist, mit einer Verbindung der allgemeinen FormelZ-j represents a leaving group and the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the pyrimidine ring, with a compound of the general formula
Xl - H , (lll) in derXl - H, (lll) in the
X-j einen der für Rc in den Ansprüchen 1 bis 4 erwähnten Reste darstellt, umgesetzt wird undXj represents one of the radicals mentioned for R c in claims 1 to 4, is reacted and
gewünschtenfalls anschließend eine so erhaltene Verbindung der allgemeinen For¬ mel I, die eine Amino- oder Iminogruppe enthält, mittels Alkylierung oder reduktiver Alkylierung in eine entsprechende Alkylverbindung der allgemeinen Formel I überge¬ führt wird und/oderif desired, a compound of the general formula I thus obtained, which contains an amino or imino group, is subsequently converted into an appropriate alkyl compound of the general formula I by means of alkylation or reductive alkylation and / or
eine so erhaltene Verbindung der aligemeinen Formel I, die eine Carboxy- oder Estergruppe enthält, mittels Amidierung in ein entsprechendes Amid der allgemeinen Formel I übergeführt wird und/odera compound of the general formula I thus obtained, which contains a carboxy or ester group, is converted into a corresponding amide of the general formula I by amidation and / or
erforderlichenfalls ein bei den vorstehend beschriebenen Umsetzungen verwendeter Schutzrest wieder abgespalten wird und/oderif necessary, a protective residue used in the reactions described above is split off again and / or
gewünschtenfalls eine so erhaltene Verbindung der allgemeinen Formel I in ihre Stereoisomere aufgetrennt wird und/oderif desired, a compound of the general formula I thus obtained is separated into its stereoisomers and / or
eine so erhaltene Verbindung der allgemeinen Formel I in ihre Salze, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträgliche Salze über¬ geführt wird. a compound of the general formula I thus obtained is converted into its salts, in particular for its pharmaceutical use into its physiologically tolerable salts.
PCT/EP1997/001057 1996-03-06 1997-03-03 4-amino pyrimidine derivates, medicaments containing these compounds, their use and process for their production WO1997032881A1 (en)

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BR9708312A BR9708312A (en) 1996-03-06 1997-03-03 Derivatives of 4-amino-pyrimidine drugs containing these compounds their application and process for their manufacture
SK1205-98A SK120598A3 (en) 1996-03-06 1997-03-03 4-amino pyrimidine derivates, medicaments containing these compounds, their use and process for their production
NZ331546A NZ331546A (en) 1996-03-06 1997-03-03 4-phenylamino pyridopyrimidine derivatives, medicaments containing these compounds, their use and process for their production
IL12540497A IL125404A0 (en) 1996-03-06 1997-03-03 4-amino-pyrimidine derivatives medicaments containing these compounds their use and process for their production
AU19251/97A AU710274B2 (en) 1996-03-06 1997-03-03 4-amino-pyrimidine derivates, medicaments containing these compounds, their use and process for their production
EE9800277A EE9800277A (en) 1996-03-06 1997-03-03 4-Aminopyrimidine derivatives, drugs containing these compounds, their use and a process for their preparation
EP97907066A EP0885226A1 (en) 1996-03-06 1997-03-03 4-amino pyrimidine derivates, medicaments containing these compounds, their use and process for their production
JP9531444A JP2000506847A (en) 1996-03-06 1997-03-03 4-Amino-pyrimidine derivatives, pharmaceuticals containing these compounds, their use and production
BG102708A BG102708A (en) 1996-03-06 1998-08-20 4-aminopyrimidine derivatives, medicamentous preparations containing them, their application and method for their preparation
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DE1996108631 DE19608631A1 (en) 1996-03-06 1996-03-06 New (heterocyclyl- pyrimidino or -pyrido)fused pyrimidine derivatives
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DE19629652A DE19629652A1 (en) 1996-03-06 1996-07-23 4-Amino-pyrimidine derivatives, medicaments containing these compounds, their use and processes for their preparation
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TR199801749T2 (en) 1998-12-21
NO984084L (en) 1998-09-04
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IL125404A0 (en) 1999-03-12
CZ281798A3 (en) 1999-02-17
AU710274B2 (en) 1999-09-16
KR19990087550A (en) 1999-12-27
JP2000506847A (en) 2000-06-06
NO984084D0 (en) 1998-09-04
SK120598A3 (en) 1999-06-11
HUP9901820A3 (en) 2001-10-29
PL328771A1 (en) 1999-02-15
BG102708A (en) 1999-09-30
NZ331546A (en) 2000-03-27
AU1925197A (en) 1997-09-22
CN1212695A (en) 1999-03-31
EP0885226A1 (en) 1998-12-23
EE9800277A (en) 1999-02-15
HUP9901820A2 (en) 1999-09-28

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