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EP1628976A1 - Neue pyridopyrazine und deren verwendung als kinase-inhibitoren - Google Patents
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EP1628976A1 - Neue pyridopyrazine und deren verwendung als kinase-inhibitoren - Google Patents

Neue pyridopyrazine und deren verwendung als kinase-inhibitoren

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Publication number
EP1628976A1
EP1628976A1 EP04733782A EP04733782A EP1628976A1 EP 1628976 A1 EP1628976 A1 EP 1628976A1 EP 04733782 A EP04733782 A EP 04733782A EP 04733782 A EP04733782 A EP 04733782A EP 1628976 A1 EP1628976 A1 EP 1628976A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
heteroaryl
cycloalkyl
heterocyclyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04733782A
Other languages
German (de)
English (en)
French (fr)
Inventor
Eckhard Günther
Eckhard Claus
Irene Seipelt
Ulf-R. Rapp
Ludmilla Wixler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aeterna Zentaris GmbH
Original Assignee
Zentaris AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentaris AG filed Critical Zentaris AG
Publication of EP1628976A1 publication Critical patent/EP1628976A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Definitions

  • the invention relates to kinase inhibitors of the pyrido [2,3-b] pyrazine type, their preparation and use as medicaments in particular for the treatment of malignant and other diseases based on pathological cell proliferation, such as, for. B. restenosis, psoriasis, arteriosclerosis and cirrhosis.
  • protein kinases The activation of protein kinases is a key event in cellular signal transduction processes. Aberrant kinase activation is observed in various disease states. The targeted inhibition of such constitutively active kinases is therefore a fundamental therapeutic goal.
  • the phosphorylation of proteins is generally initiated by extracellular signals and provides a universal mechanism for the control of various cellular events, such as. B. metabolic processes, cell growth, cell migration, cell differentiation, membrane transport and apoptosis.
  • the protein family of kinases is responsible for protein phosphorylation. These enzymes catalyze the phosphate transfer to specific substrate proteins. Based on the substrate specificity, the kinases are divided into two main classes, the tyrosine kinases and the serine / threonine kinases. Both the receptor tyrosine kinases and the cytoplasmic tyrosine and serine / threonine kinases are important proteins in the signal transduction of the cell.
  • Overexpression or degeneration of these proteins plays an important role in diseases based on pathological cell proliferation. These include metabolic diseases, diseases of the connective tissue and blood vessels, as well as malignant and benign tumor diseases. In tumor development and development, they often occur as oncogenes, ie as aberrant, constitutively active kinase proteins. The consequences of this excessive kinase activation are e.g. B. the uncontrolled. Cell growth and reduced cell death. The stimulation of tumor-induced growth factors can also be the cause of overstimulation of kinases. The development of kinase inhibitors is therefore of particular interest for all pathogenic processes that are influenced by kinases.
  • the invention is therefore aimed at creating new compounds which are suitable as inhibitors of such constitutively active kinases, in particular the receptor tyrosine kinases and also the cytoplasmic tyrosine and serine / threonine kinases.
  • Pyrido [2,3-b] pyrazine derivatives substituted in the 6-position are widely used as pharmacologically active compounds and as synthesis building blocks in pharmaceutical chemistry.
  • the patent WO99 / 17759 describes pyrido [2,3-b] pyrazines which carry, inter alia, alkyl, aryl and heteroaryl-substituted carbamates in the 6-position. These compounds are said to be used to modulate the function of serine threonine protein kinases.
  • Amide- and acrylamide-substituted pyrido [2,3-b] pyrazines are described which also contain carbamates as additional substituents and can be used as histone deacetylase inhibitors for the treatment of cell proliferation disorders.
  • Another publication (C. Temple, Jr .; J. Med. Chem. 1990, 3044-3050) describes the synthesis of a 6-ethylcarbamate-substituted pyrido [2,3-b] pyrazine derivative using an example. An anti-tumor effect is neither disclosed nor suggested.
  • R1 and R2 can independently:
  • alkyl where the alkyl radical is saturated and can consist of 1 to 8 carbon atoms
  • R3 can:
  • cycloalkyl radical having F, Cl, Br, I, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl , NHS0 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (O) alkyl, OC (O) cycloalkyl,
  • R4 and R5 together mean cycloalkyl or heterocyclyl
  • cycloalkyl radical having F, Cl, Br, I, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (0) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl , NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (O) alkyl, OC (0) cycloalkyl, OC (O) alkyl, OC (0) cycloalkyl, OC (O
  • heterocyclyl radical (iv) unsubstituted or substituted heterocyclyl, it being possible for the heterocyclyl radical to be substituted one or more times, identically or differently, by OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl or aryl,
  • heterocyclyl radical unsubstituted or substituted heterocyclyl, it being possible for the heterocyclyl radical to be substituted one or more times, identically or differently, by OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl or aryl,
  • alkyl for the purposes of this invention acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight chain, having 1 to 8 carbon atoms, that is, ds-alkanyls, C 2 - 8 alkenyls, and C 2 - 8 alkynyls.
  • Alkenyls have at least one CC double bond and alkynyls have at least one CC triple bond
  • cycloalkyl for the purposes of this invention means cyclic hydrocarbons with 3-12 hydrocarbons, which can be saturated or unsaturated.
  • the binding to the compounds of general structure I can take place via any and possible ring member of the cycloalkyl radical.
  • the cycloal - The kyl radical can also be part of a bi- or polycyclic system.
  • heterocyclyl stands for a 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical which contains at least 1, optionally 2, 3, 4 or 5 heteroatoms, the Heteroatoms are the same or different and the cyclic radical is saturated or unsaturated but not aromatic.
  • Binding to the compounds of general structure I can take place via any and possible ring member of the heterocyclic radical.
  • the heterocycle can also be part of a bi- or a polycyclic system.
  • Preferred heteroatoms are nitrogen, oxygen and sulfur. It is preferred that the heterocyclyl radical is selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholine.
  • aryl means aromatic hydrocarbons, including phenyls, naphthyls and anthracenyls.
  • the radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
  • the bond to the compounds of the general structure I can be via any any and possible ring member of the aryl radical take place.
  • heteroaryl stands for a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or different.
  • the bond to the Compounds of the general structure I can be made via any and possible ring member of the heteroaryl radical.
  • the heterocycle can also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur.
  • the Heteroaryl radical is selected from the group consisting of pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl, quinolinyl, isoxinyl Contains quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl.
  • alkyl-cycloalkyl means for the purposes of the present invention that alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl have the meanings defined above and that cycloalkyl, heterocyclyl, aryl and heteroaryl radical is bonded via a C ⁇ -8 alkyl group to the compounds of general structure I.
  • alkyl In connection with “alkyl”, “cycloalkyl”, “heterocyclyl”, “aryl”, “heteroaryl”, “alkylcycloalkyl”, “alkyl heterocyclyl”, “alkyl aryl” and “alkyl heteroaryl” is understood to mean the The term substituted in the sense of this invention, unless explicitly defined above, is the substitution of one or more hydrogen radicals by F, Cl, Br, I, CN, CF 3 , NH 2 , NH-alkyl, NH-aryl, N (alkyl) 2 , NO 2 , SH, S-alkyl, OH, OCF 3 , O-alkyl, O-aryl, CHO, CO 2 H, SO 3 H or alkyl
  • the substituents can be the same or different and the substitution can be any and possible Position of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl radical occur.
  • the multiple substitution can be carried out with the same or different substituents.
  • the compounds of general formula I according to the invention have at least one asymmetry center, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers.
  • the mixtures can be present in any mixing ratio of the stereoisomers.
  • the compounds of general formula I according to the invention which have one or more chiral centers and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se.
  • the separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent elimination of the rest.
  • the compounds according to the invention can be in the form of the tautomers.
  • the compounds of the general formula I according to the invention if they have a sufficiently basic group, such as a primary, secondary or tertiary amine, can be converted into their physiologically tolerable salts with inorganic and organic acids.
  • the pharmaceutically acceptable salts of the compounds according to the invention are preferably in accordance with general structure I with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfoacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, tartaric acid , Malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid.
  • the salts formed include hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, phosphates, methanesulfonates, tosylates, carbonates, hydrogen carbonates, formates, acetates, triflates, sulfoacetates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates , Almondates, fumarates, lactates, citrates, glutaminates and aspartates.
  • the stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
  • the compounds of general formula I according to the invention if they contain a sufficiently acidic group, such as the carboxy group, can be converted into their physiologically tolerable salts with inorganic and organic bases.
  • suitable inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylene diamine and lysine.
  • the stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
  • Solvates and in particular hydrates of the compounds according to the invention which, for. B. can be obtained by crystallization from a solvent or from aqueous solution.
  • One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • chemical substances form solids which are in various states of order, which are referred to as polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds of general formula I according to the invention can exist in various polymorphic forms, certain modifications being metastable.
  • the starting compounds are either commercially available or can be prepared by processes known per se.
  • the starting materials 1 and 4 are valuable intermediates for the preparation of the pyridopyrazines of the general formula I according to the invention.
  • 2,6-diamino-3-nitropyridine is dissolved in a polar, organic solvent, such as, for example, methanol, ethanol, dimethylformamide or dioxane, alone or in combination of two of these solvents.
  • a polar, organic solvent such as, for example, methanol, ethanol, dimethylformamide or dioxane, alone or in combination of two of these solvents.
  • a catalyst for example Raney nickel, palladium on carbon or platinum (IV) dioxide
  • the reaction mixture is placed under a hydrogen atmosphere, a pressure between 1 and 5 bar being set.
  • the reaction mixture is allowed to react for several hours, for example 1-16 hours, in a temperature range between 20 ° C. and 60 ° C.
  • the insoluble residues are filtered off, the filter medium being able to consist, for example, of silica gel, Celite or commercially available glass fiber filters, and washing is carried out with the appropriate solvent.
  • the crude product, in solution, is used for the next reaction without further purification.
  • the 1,2-dione derivative is placed in an organic solvent, for example methanol, ethanol, dioxane, toluene or dimethylformamide.
  • 2,3,6-triaminopyridine is added directly after the reduction as a solution of its crude product in one of the abovementioned solvents to the 1,2-dione, optionally with the addition of an acid, such as, for. B. acetic acid or a base, for example potassium hydroxide.
  • the reaction mixture is allowed to react in a temperature range from 20 ° C. to 80 ° C. for some time, for example 20 minutes to 40 hours.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo.
  • dimethylformamide the reaction mixture is stirred into a large amount of water and the precipitate which has precipitated is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo.
  • the remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • the products obtained by the basic process can be converted into secondary products according to the formula I according to the invention in a procedure known to the person skilled in the art.
  • reaction product 4 with a corresponding isocyanate and optionally a suitable base, preferably sodium hydride, potassium hexamethyldisilazide, triethylamine or potassium carbonate, in a suitable, inert solvent, such as dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane or dioxane.
  • a suitable, inert solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane or dioxane.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. If dimethylformamide is used, the reaction mixture is stirred into a large amount of water and the precipitate which has separated out is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or toluene, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • a suitable solvent for example ethanol or toluene
  • reaction product 4 with phosgene or carbonyldiimidazole and a corresponding amine in a suitable inert solvent, such as, for example, tetrahydrofuran, toluene, dichloromethane or acetonitrile be implemented.
  • a suitable base preferably pyridine, sodium hydrogen carbonate, triethylamine, N-methylmorpholine or sodium acetate, is used.
  • the reaction mixture is allowed to react for a time, for example 15 minutes to 24 hours, in a temperature range between 0 and 60 ° C.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo.
  • dimethylformamide the reaction mixture is stirred into a large amount of water and the precipitate is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo.
  • the remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or ethyl acetate, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • reaction product 4 with a corresponding isothiocyanate and optionally a suitable base, preferably sodium hydride, triethylamine or pyridine, in a suitable, inert solvent, such as, for example Dimethylformamide, tetrahydrofuran, acetone or toluene can be implemented.
  • a suitable, inert solvent such as, for example Dimethylformamide, tetrahydrofuran, acetone or toluene
  • the reaction mixture is allowed to react for a time, for example 30 minutes to 90 hours, in a temperature range between 0 and 115 ° C.
  • the Filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. If dimethylformamide is used, the reaction mixture is stirred into a large amount of water and the precipitate which has separated out is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or ethyl acetate, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • a suitable solvent for example ethanol or ethyl acetate
  • reaction product 4 with thiophosgene or thiocarbonyldiimidazole and a corresponding amine in a suitable inert solvent such as, for example, tetrahydrofuran, toluene, dichloromethane
  • a suitable inert solvent such as, for example, tetrahydrofuran, toluene, dichloromethane
  • Ethanol or acetonitrile are implemented.
  • a suitable base preferably pyridine, sodium hydrogen carbonate, potassium carbonate, triethylamine or imidazole.
  • the reaction mixture is allowed to react for several hours, for example 1 to 24 hours, in a temperature range between -10 and 80 ° C.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. If dimethylformamide is used, the reaction mixture is stirred into a large amount of water and the precipitate which has separated out is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or ethyl acetate, or by column or flash chromatography on silica gel or aluminum oxide.
  • a suitable solvent for example ethanol or ethyl acetate
  • reaction product 4 can be inert with an appropriate aminonitrile and, if appropriate, a suitable base, preferably triethylamine, or a suitable acid, preferably hydrochloric acid Solvents such as acetone, toluene, chlorobenzene, ethanol, tetrahydrofuran or dimethyl sulfoxide are reacted.
  • the reaction mixture is allowed to react for several hours, for example 2 to 140 hours, in a temperature range between 20 and 135 ° C.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo.
  • the remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • reaction product 4 with an appropriate nitrile and optionally a suitable base, preferably sodium amide or sodium hexamethyl disilazide, or a suitable catalyst, for example aluminum trichloride, Trimethylaluminum, glacial acetic acid or sulfuric acid, in a suitable, inert solvent, such as tetrahydrofuran, toluene, or ethanol, or without a solvent.
  • a suitable base preferably sodium amide or sodium hexamethyl disilazide
  • a suitable catalyst for example aluminum trichloride, Trimethylaluminum, glacial acetic acid or sulfuric acid
  • a suitable, inert solvent such as tetrahydrofuran, toluene, or ethanol, or without a solvent.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo.
  • the remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol, or by column or flash chromatography on silica gel or aluminum oxide.
  • a mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • OH, SH and NH 2 groups can possibly undergo undesirable side reactions. It is therefore preferred to provide them with protecting groups or, in the case of NH 2 NO 2 by replacing and subsequently remove the protecting group or to reduce the NO 2 group.
  • At least one OH group for example by a benzyloxy group and / or at least one SH group, for example by an S-benzyl group and / or at least one NH 2 group by an NO 2 - Group to be replaced.
  • at least one - preferably all - benzyloxy group / s for example with hydrogen and palladium on carbon and / or at least one - preferably all - S-benzyl group / s, for example with sodium in ammonia, and / or at least one - preferably all - NO 2 group / s can be reduced to NH 2 , for example using hydrogen and Raney nickel.
  • carboxylic acid ester and carboxamide groups can potentially undergo undesirable side reactions. It is therefore preferred to produce carboxylic acid ester and carboxamide groups from process products which contain at least one OH and / or at least one NH 2 and / or at least one COOH group.
  • process products which have at least one OH group and / or which have at least one NH 2 group can be converted into carboxylic acid ester or carboxamide groups by reaction with an activated carboxylic acid group, for example a carboxylic acid chloride group.
  • process products which have at least one COOH group can be converted into carboxylic acid ester or carboxamide groups by reaction with an activating agent, such as, for example, thionyl chloride or carbonyldiimidazole, and subsequent reaction with a suitable alcohol or amine.
  • an activating agent such as, for example, thionyl chloride or carbonyldiimidazole
  • the pyrido [2,3-b] pyrazine derivatives according to the general formula I according to the invention are active substances in medicaments, in particular in malignant and other diseases based on pathological cell proliferation, such as, for. B. restenosis, psoriasis, arteriosclerosis and cirrhosis of the liver for the treatment of people, Suitable for mammals and poultry.
  • Mammals can be pets such as horses, cows, dogs, cats, rabbits, sheep and the like.
  • the medicinal effect of the pyrido [2,3-b] pyrazine derivatives according to the invention can be based, for example, on an inhibition of signal transduction by interaction with receptor tyrosine kinases as well as with cytoplasmic tyrosine and serine / threonine kinases.
  • receptor tyrosine kinases as well as with cytoplasmic tyrosine and serine / threonine kinases.
  • other known and unknown mechanisms of action to combat malignant processes are conceivable.
  • a method for combating tumors in humans and in mammals which is characterized in that at least one pyrido [2,3-b] pyrazine derivative according to the general formula I is used in humans or in a mammal an effective amount for tumor treatment is administered.
  • the therapeutically effective dose of the respective pyrido [2,3-bpyrazine derivative according to the invention to be administered for the treatment is directed inter alia. according to the type and stage of the tumor, the age and sex of the patient, the type of administration and the duration of treatment.
  • the pharmaceuticals according to the invention can be administered as liquid, semi-solid and solid pharmaceutical forms.
  • the pharmaceutical forms optionally contain auxiliaries, such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, antifoams, gelling agents, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell correctives.
  • auxiliaries such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, antifoams, gelling agents, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell correctives.
  • auxiliaries such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents
  • the medicaments according to the invention can be applied to the skin in a suitable dosage form, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste or plaster; via the oral and tongue mucosa, buccal, lingual or sublingual as a tablet, lozenge, dragees, linctus or gargle water; via the gastric and intestinal mucosa, enterally as tablets, coated tablets, capsules, solutions, suspensions or emulsions; via the rectal mucosa, rectally as a suppository, rectal capsule or ointment; through the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, pulmonally or by inhalation as aerosol or inhalation; via the conjunctiva, conjunctival as eye drops, eye ointment, eye tablets, lamellae or eyewash; via the mucous membranes of the genital organ
  • the compounds of general structure I according to the invention can be extended with regard to practical therapeutic requirements by means of suitable measures in their drug action. This goal can be achieved chemically and / or galenically. Examples of achieving an increase in activity are the use of implants and liposomes, the formation of poorly soluble salts and complexes or the use of crystal suspensions.
  • compositions which contain at least one compound from the following group of the pyrido [2,3-b] pyrazine derivatives of the general structure I and which can be present in the form of their free base or as pharmaceutically acceptable salts of physiologically acceptable acids are particularly preferred:
  • a solution of 1.22 g of 2,6-diamino-3-nitropyridine (7.92 mmol) in 210 ml of ethanol is hydrogenated with Raney nickel as a catalyst at 50 ° C. and 5 bar. After the hydrogenation has ended, the catalyst is suctioned off through a glass fiber filter. Before the filtration, 1.68 g of phenylglyoxal hydrate (11.03 mmol) in 50 ml of ethanol are placed in the receiver. The catalyst is then filtered off under nitrogen as a protective gas and the hydrogenation solution is sucked directly into the reaction flask. The green-blue reaction mixture is under nitrogen for 30 min. heated under reflux. The mixture is allowed to cool and the solvent is removed in vacuo.
  • 0.246 g of sodium hydride (6.14 mmol) are placed in 5 ml of anhydrous dimethylformamide under nitrogen as a protective gas. The mixture is cooled to 0 ° C. in an ice bath. 1.05 g of 3-phenyl-pyrido [2,3-b] pyrazin-6-ylamine (4.72 mmol) are dissolved in 5 ml of anhydrous dimethylformamide and added dropwise. The cooling bath is removed and the mixture is allowed to stir at RT for 30 minutes. The mixture is then cooled again to 0 ° C.
  • Example 5 1 - (2-methyl-allyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
  • Example 6 1 - (2-methyl-allyl) -3- (3-naphthalen-2-yl-pyrido [2,3-b] pyrazin-6-yl) thiourea
  • Example 7 1 - [3- (4-methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] -3- (2-methyl-allyl) thiourea
  • Example 8 1 - (3-Naphthalin-2-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-nitro-phenyl) thiourea
  • Example 9 1 - [3- (4-methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] -3- (4-nitro-phenyl) thiourea
  • Example 12 1-Methyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
  • Example 14 1 - (4-Fluoro-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea M.p .: 225-226 ° C
  • Example 15 1 - (3-Phenylpyrido [2,3-b] pyrazin-6-yl) -3-p-tolylurea
  • Example 16 1 - (4-Chloro-3-trifluoromethyl-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) urea
  • Example 17 1 - (2-Morpholin-4-yl-ethyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) urea
  • the inhibitory activity of the compounds according to the invention was tested on the following human serine / threonine and tyrosine kinases in classic kinase assays: PKB / Akt1, c-Raf, B-Raf, Mek, PDGFRbeta, Flt-3, c-Kit, c-Abl, KDR , FGFR1 and IGF1 R. Both full-length kinases and truncated fragments were used - but at least the cytoplasmic, constitutively active kinase domains.
  • the kinases were produced as recombinant fusion proteins with GST (glutathione S-transferase) or HIS tag in Sf9 cell culture. Depending on the type of substrate, the various kinase reactions were carried out in sandwich ELISA formats or using a simple substrate adsorption test on 96-well flashplates (Perkin Elmer).
  • a typical kinase batch was carried out in a final volume of 50 // I with 20-150ng Raf, Mek, Erk kinase protein, 1mM ATP, 10mM MgCl 2 , 150mM NaCl, 25mM beta-glycerophosphate, 25mM Hepes pH 7.5.
  • the test substances were individually preincubated with each of the three kinase proteins for 30 minutes at room temperature.
  • the kinases preincubated with the test substance were combined and incubated at 26 ° C. for 30 minutes. The reaction was stopped by a final concentration of 2% SDS and 10 minutes at 50 ° C in the heating block.
  • the reaction mixtures were transferred to anti-Erk-Ak (K-23, Santa Cruz Biotechnology) -coated 96 MTPs, incubated for 60 minutes at room temperature and washed 3 times with TBST.
  • Anti-phospho-Erk-Ak (# 9106, New England Biolabs) 1: 500 in 50 l TBST / 1% BSA was added and incubated overnight at 4 ° C.
  • secondary anti-mouse IgG POD conjugate # NA931, Pharmacia
  • OPD o-phenyldiamine dihydrochloride
  • the compounds according to the invention show an effective inhibition of Erk phosphorylation with IC-50 values up to 400 nm (see working examples 4 and 12).

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