Classifications

• • 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

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