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EP0993461A1 - New quinoxaline dione derivatives, the production thereof and use of the same in medicaments - Google Patents

New quinoxaline dione derivatives, the production thereof and use of the same in medicaments

Info

Publication number
EP0993461A1
EP0993461A1 EP98942480A EP98942480A EP0993461A1 EP 0993461 A1 EP0993461 A1 EP 0993461A1 EP 98942480 A EP98942480 A EP 98942480A EP 98942480 A EP98942480 A EP 98942480A EP 0993461 A1 EP0993461 A1 EP 0993461A1
Authority
EP
European Patent Office
Prior art keywords
trifluoromethyl
compounds
tetrahydro
formula
hydrogen
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Withdrawn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
EP98942480A
Other languages
German (de)
French (fr)
Inventor
Andreas Huth
Eckhard Ottow
Ingrid Schumann
Martin Krüger
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.)
Bayer Pharma AG
Original Assignee
Schering 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 Schering AG filed Critical Schering AG
Publication of EP0993461A1 publication Critical patent/EP0993461A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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

Definitions

  • the compounds according to the invention not only have excellent affinity for the AMPA receptor, but are also distinguished by very good solubility in water.
  • the compounds according to the invention have the formula I.
  • R 1 - (CH 2 ) n -CR 2 H- (CH2) mZ and R5 and R6 are the same or different and are hydrogen, NO2, halogen, cyano or optionally halogenated C 1-8 alkyl,
  • R 2 is hydrogen or - (CH2> q -R 3
  • R 3 is hydrogen, hydroxy, C-
  • n, m and q each 0, 1, 2 or 3
  • R 3 and R9 together with the nitrogen atom mean pyrrolidine, morpholine, thiomorpholine, piperazine or hexahydroazepine, which can be substituted by C-
  • R 1 6 OH, C- ⁇ e alkoxy or NR 1 2 R 1 3
  • the compounds of the general formula I also include the possible tautomeric forms or, if a chiral center is present, the racemates or enantiomers.
  • the substituents R ⁇ , R6 and R 7 can be in any position, preferably in the 6- and 7-position.
  • Alkyl is in each case to be understood as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, hexyl, with C-1.4 alkyl radicals being preferred.
  • alkyl radical is halogenated, it can be present one to more times or perhalogenated and in particular means CF3.
  • the physiologically compatible salts of organic and inorganic bases are suitable as salts, for example the readily soluble alkali and alkaline earth metal salts and the salts with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1, 6- Hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethylamino-methane, aminopropanediol, sovak base, 1-amino-2,3,4-butanetriol.
  • physiologically compatible salts of organic and inorganic acids such as HCI, H2SO4, phosphoric acid, citric acid, tartaric acid and others are suitable.
  • the compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their affinity for the AM PA receptors.
  • the compounds according to the invention are suitable for the treatment of diseases caused by hyperactivity excitatory amino acids such as glutamate or aspartate. Since the new compounds act as antagonists of excitatory amino acids and show a high specific affinity for the AMPA receptors by using the radiolabelled specific agonist (RS) a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) from to displace the AMPA receptors, they are particularly suitable for the treatment of diseases which are influenced by the receptors of excitatory amino acids, in particular the AM PA receptor.
  • RS radiolabelled specific agonist
  • AMPA a-amino-3-hydroxy-5-methyl-4-isoxazole propionate
  • the compounds can be used for the treatment of neurological and psychiatric disorders which are triggered by overstimulation of the AMPA receptor.
  • the neurological diseases that can be treated functionally and preventively include, for example, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and olivopontocerebellar degeneration.
  • the compounds can be used for the prevention of post-ischemic cell death, cell death after brain trauma, stroke, hypoxia, anoxia and hypoglycemia and for the treatment of senile dementia, AIDS dementia, neurological symptoms associated with HIV infections, multi-infarct dementia as well as epilepsy and muscle spasticity become.
  • Psychiatric disorders include anxiety, schizophrenia, migraines, pain, as well as the treatment of sleep disorders and withdrawal symptoms after drug abuse such as alcohol, cocaine, benzodiazepine or opiate withdrawal.
  • the compounds can also find use in the prevention of tolerance development during long-term treatment with sedative drugs such as benzodiazepines, barbiturates and morphine.
  • the compounds can be used as anesthetics (anesthetic), anti-pain medication or antiemetics.
  • mice weighing 1 8-22 g were kept under controlled conditions (6 0 0 -1 8 0 0 o'clock light / dark rhythm, with free access to food and water) and their assignment to groups was randomized.
  • the groups consisted of 5 - 1 6 animals. The animals were observed between 8 ° and 13 °.
  • AMPA was injected into the left ventricle by freely moving mice.
  • the applicator consisted of a cannula with a stainless steel device that limits the depth of the injection to 3.2 mm.
  • the applicator was connected to an injection pump.
  • the injection needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow.
  • the animals were observed for up to 180 seconds until clonic or tonic cramps occurred.
  • the clonic movements that lasted longer than 5 seconds were counted as convulsions.
  • the beginning of the clonic cramps was used as the end point for the determination of the cramp threshold.
  • the dose required to increase or decrease the seizure threshold by 50% (THRD50) was determined in 4-5 experiments.
  • the THRD50 and confidence limits were determined in a regression analysis.
  • Treatment with the compounds according to the invention prevents or delays the cell damage and functional disorders which occur as a result of the disease and reduces the symptoms which arise as a result.
  • the indications can be shown by conventional pharmacological tests.
  • a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragées, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose is 0.5-1000 mg, preferably 50-200 mg, and the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
  • the compound of the invention is prepared by methods known per se.
  • compounds of the formula I are obtained by
  • R 2 'R 5 , R * ⁇ R 7 , n and m have the above meaning and Z' has the meaning of Z or -C ⁇ N, cyclized with oxalic acid or reactive oxalic acid derivatives or
  • m, - (e j have the above significance, if desired, hydrolyzed and then esterified carboxyl or amidated or the isomers are separated or forms, the salts.
  • R 1 'R 1 or (CH2) n-CR 2 - ( CH 2) rrf CsN and R 5 ', R 6 'and R 7 ' represent a leaving group or R ⁇ , R6 or R 7 , substituted a leaving group and the nitro group is reduced and cyclized analogously to process variant a) with oxalic acid or reactive oxalic acid derivatives.
  • the cyclization to compounds of formula I is carried out in a known manner with oxalic acid in a single stage in an acidic medium or with a reactive oxalic acid derivative in one or two stages.
  • the subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acidic environment, and solubilizers such as alcohol or acetonitrile can be added to the reaction mixture.
  • Suitable bases for the two-stage process are also alkali metal hydrides such as NaH, which are used in inert solvents such as hydrocarbons or ethers.
  • Halogens such as fluorine, chlorine, bromine, iodine or O-mesylate, O-tosylate, O-triflate or O-nonaflate are suitable as escape groups of the compounds of the formula III.
  • the nucleophilic substitution with amines is carried out at the lowest possible temperature, preferably at room temperature. An excess of amine is not a disadvantage.
  • the amine can also be used as a solvent. Suitable solvents are ethers such as tetrahydrofuran or hydrocarbons such as toluene or halogenated hydrocarbons such as methylene chloride.
  • alkenyl compounds takes place with the catalysis of transition metal complexes such as Pd (0), e.g.
  • Palladium tetrakistriphenylphosphine or Pd ⁇ 2 + such as palladium-bis-tri-o-tolylphosphine dichloride or nickel (O) according to methods known from the literature, if appropriate in the presence of a base and is preferably activated by an activating electron-withdrawing group such as nitro, cyano, trifluoromethyl Favored position.
  • the corresponding boronic acids are, for example, nucleophiles. or - boranes or organotin compounds, organozinc compounds, Grignard compounds or the alkenyls as such are suitable.
  • the reaction can be carried out in polar solvents such as dimethylformamide, dimethylacetamide, acetonitrile, in hydrocarbons such as toluene or in ethers such as tetrahydrofuran, dimethoxyethane or diethyl ether.
  • Suitable bases are inorganic bases such as alkali or alkaline earth metal hydroxides, carbonates or acetates or organic bases such as cyclic, alicyclic and aromatic amines such as pyridine, triethylamine, DBU, Hunig base, optionally with the addition of water.
  • Any subsequent oxidative cleavage of the alkenyl compounds to the aldehyde can be carried out using methods known from the literature. Ozonation in solvents such as e.g. halogenated hydrocarbons or alcohols or mixtures thereof at temperatures from -78 ° C to room temperature.
  • solvents such as e.g. halogenated hydrocarbons or alcohols or mixtures thereof at temperatures from -78 ° C to room temperature.
  • the ozonide which forms is reductively cleaved to form the aldehyde by trapping with thiourea, trialkylphosphites or, preferably, with triarylphosphines.
  • the aldehyde can be chain extended by e.g. by Petersonolefinitation, or by Wittig or Wittig-Homer reaction initially produces an appropriate enol ether.
  • the aldehyde with the previously generated anion e.g. an appropriately substituted phosphonium salt or phosphonic acid ester in solvents such as toluene, tetrahydrofuran, diethyl ether or dimethoxyethane.
  • bases are e.g. Alkali hydrides, alkali amides, alkali alcoholates such as potassium tert-butoxide, alkali or alkaline earth carbonates or hydroxides, optionally in the presence of phase transfer catalysts such as e.g.
  • Crown ethers or organic bases such as triethylamine, diisopropylethylamine or diazabicycloundecane, if appropriate in the presence of salts such as lithium bromide, are suitable.
  • the corresponding enol ether can then be cleaved by acid.
  • the aldehydes can be reduced to the corresponding alcohols by methods known from the literature.
  • the reduction is preferably carried out with complex metal hydrides such as sodium boranate in solvents such as alcohol.
  • the hydroxyl group can be converted into escape groups such as chloride, bromide, iodide, triflate, mesylate or tosylate by methods known from the literature and by various processes. It is preferably converted into the chloride or tosylate with tosyl chloride in the presence of bases such as, for example, triethylamine, ethyldiisopropylamine or dimethylaminopyridine in solvents such as halogenated hydrocarbons or ethers.
  • bases such as, for example, triethylamine, ethyldiisopropylamine or dimethylaminopyridine in solvents such as halogenated hydrocarbons or ethers.
  • the nitro group is reduced in the customary manner catalytically or by reduction with iron powder in acetic acid at elevated temperature or else with sodium sulfide and ammonium hydroxide in alcohol.
  • the reduction of the alkenyl group takes place in the usual way catalytically and then usually takes place together with the reduction of the nitro group.
  • the optionally subsequent saponification of an ester group or the saponification of a nitrile group can be carried out in a basic or, preferably, acidic manner by hydrolysing at elevated temperature to the boiling point of the reaction mixture in the presence of acids such as highly concentrated aqueous hydrochloric acid, optionally in solvents such as trifluoroacetic acid or alcohols.
  • esterification of the carboxylic acid takes place in a manner known per se with the corresponding alcohol with acid catalysis or in the presence of an activated acid derivative.
  • suitable acid derivatives are acid chloride, imidazolide or anhydride.
  • the amidation takes place on the free acids or on their reactive derivatives such as acid chlorides, mixed anhydrides, imidazolides or azides by reaction with the corresponding amines at room temperature.
  • the amidation can also be carried out directly from the ester by reaction with an amine in the presence of trimethyl aluminum.
  • the isomer mixtures can be separated into the enantiomers or E / Z isomers by customary methods such as, for example, crystallization, chromatography or salt formation.
  • the salts are prepared in the customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is optionally in solution, and removing the precipitate or working up the solution in the customary manner.
  • the starting materials are produced by processes known from the literature.
  • the residue is taken up in 100 ml of ethanol, mixed with 100 ml of 1N hydrochloric acid and heated to a bath temperature of 110 ° C. for 2 h.
  • the ethanol is then drawn off and extracted three times with 100 ml of ethyl acetate each time.
  • the organic phase is washed with water, dried, filtered and concentrated.
  • the residue is covered with silica gel

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  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Addiction (AREA)
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  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to compounds of formula (I), the production thereof and the use of the same in medicaments.

Description

CHINOXALINDIONDERIVATE ALS AMPA-REZEPTOR-ANTAGONISTEN CHINOXALINDION DERIVATIVES AS AMPA RECEPTOR ANTAGONISTS
Die Erfindung betrifft Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln.The invention relates to quinoxalinedione derivatives, their preparation and use in medicaments.
Aus zahlreichen Publikationen wie beispielsweise aus W094/25469 ist es bekannt, daß Chinoxalinderivate Affinität an die Quisqualat-Rezeptoren besitzen und sich auf Grund der Affinität als Arzneimittel zur Behandlung von Krankheiten des zentralen Nervensystems eignen. Ferner ist von 1 - Carbonsäurechinoxalinderivaten bekannt, daß sie sehr schwer löslich sind und auf Grund ihres schlechten Löseverhaltens nicht als Arzneimittel eingesetzt werden können.It is known from numerous publications, for example from WO94 / 25469, that quinoxaline derivatives have affinity for the quisqualate receptors and, because of the affinity, are suitable as medicaments for the treatment of diseases of the central nervous system. Furthermore, 1-carboxylic acid quinoxaline derivatives are known to be very sparingly soluble and, because of their poor dissolving behavior, cannot be used as medicaments.
Es stellte sich daher die Aufgabe, neue Verbindungen zu synthetisieren, die sowohl sehr gut löslich sind und auf den AM PA-Rezeptor spezifisch antagonistisch einwirken, wodurch sie als Arzneimittel zur Behandlung von Erkrankungen geeignet sind, die durch die Hyperaktivität der excitatorischen Aminosäuren vermittelt werden.It was therefore the task of synthesizing new compounds which are both very soluble and specifically act antagonistically on the AM PA receptor, as a result of which they are suitable as medicaments for the treatment of diseases which are mediated by the hyperactivity of the excitatory amino acids.
Überraschenderweise wurde nun gefunden, daß die erfindungsgemäßen Verbindungen nicht nur hervorragende Affinität zu dem AMPA-Rezeptor aufweisen sondern sich gleichzeitig durch eine sehr gute Löslichkeit im Wasser auszeichnen.Surprisingly, it has now been found that the compounds according to the invention not only have excellent affinity for the AMPA receptor, but are also distinguished by very good solubility in water.
Die erfindungsgemäßen Verbindungen haben die Formel IThe compounds according to the invention have the formula I.
worinwherein
R1 -(CH2)n-CR2H-(CH2)m-Z und R5 und R6 gleich oder verschieden sind und Wasserstoff, NO2, Halogen, Cyano oder gegebenenfalls halogeniertes Cι _g-Alkyl bedeuten,R 1 - (CH 2 ) n -CR 2 H- (CH2) mZ and R5 and R6 are the same or different and are hydrogen, NO2, halogen, cyano or optionally halogenated C 1-8 alkyl,
R7 -(CH2)p -NR8R9R 7 - (CH 2 ) p -NR8R9
R2 Wasserstoff oder -(CH2>q-R3 R 2 is hydrogen or - (CH2> q -R 3
R3 Wasserstoff, Hydroxy, C-| _6-Alkoxy oder NR1 0R1 1 ,R 3 is hydrogen, hydroxy, C- | _6-alkoxy or NR 1 0 R 1 1 ,
n, m und q jeweils 0, 1 , 2 oder 3n, m and q each 0, 1, 2 or 3
p 0, 1 , 2, 3 oder 4,p 0, 1, 2, 3 or 4,
Z COR1 6,Z COR 1 6 ,
R3 und R9 gemeinsam mit dem Stickstoffatom Pyrrolidin, Morpholin, Thiomorpholin, Piperazin oder Hexahydroazepin bedeuten, die substituiert sein können mit C-| _4-Alkyl oder einem gegebenenfalls mit Halogen substituiertem Phenyl- Benzyl- oder Benzoylrest,R 3 and R9 together with the nitrogen atom mean pyrrolidine, morpholine, thiomorpholine, piperazine or hexahydroazepine, which can be substituted by C- | _4-alkyl or a phenyl, benzyl or benzoyl radical optionally substituted with halogen,
R1 6 OH, C-μe-Alkoxy oder NR1 2R1 3 R 1 6 OH, C-μe alkoxy or NR 1 2 R 1 3
R10 unc| R 1 1 , R 1 2 uncj R 1 3 gleich oder verschieden sind und Wasserstoff, Cι _4-Alkyl, Phenyl oder gemeinsam mit dem Stickstoffatom einen 5-7- gliedrigen gesättigten Heterocyclus bilden, der ein weiteres Sauerstoff-, Schwefel- oder Stickstoffatom enthalten und substituiert sein kannR10 unc | R 1 1, R 1 2 unc j R 1 3 are the same or different and form hydrogen, C 1-4 alkyl, phenyl or together with the nitrogen atom a 5-7 membered saturated heterocycle, which is another oxygen, sulfur or nitrogen atom can contain and be substituted
sowie deren Isomeren oder Salze.as well as their isomers or salts.
Die Verbindungen der allgemeinen Formel I beinhalten auch die möglichen tautomeren Formen oder, falls ein chirales Zentrum vorhanden ist, die Razemate oder Enantiomeren.The compounds of the general formula I also include the possible tautomeric forms or, if a chiral center is present, the racemates or enantiomers.
Die Substituenten R^, R6 und R7 können in beliebiger Position stehen, bevorzugt in 6- und 7-Stellung. Unter Alkyl ist jeweils ein geradkettiger oder verzweigter Alkylrest zu verstehen wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek. Butyl, tert. Butyl, Pentyl, Isopentyl, Hexyl, wobei C-1.4- Alkylreste bevorzugt werden.The substituents R ^, R6 and R 7 can be in any position, preferably in the 6- and 7-position. Alkyl is in each case to be understood as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, hexyl, with C-1.4 alkyl radicals being preferred.
Ist der Alkylrest halogeniert, so kann dieser ein- bis mehrfach bzw. perhalogeniert vorliegen und bedeutet insbesondere CF3.If the alkyl radical is halogenated, it can be present one to more times or perhalogenated and in particular means CF3.
Unter Halogen ist jeweils Fluor, Chlor, Brom und Jod zu verstehen.Halogen is to be understood as fluorine, chlorine, bromine and iodine.
Bilden R"O und R^ ' R^ 2 und R^ 3 gemeinsam mit dem Stickstoffatom einen gesättigten Heterocyclus, so ist beispielsweise Pyrrolidin, Morpholin, Thiomorpholin, Piperidin, Hexahydroazepin oder Piperazin gemeint. Die Heterocyclen können wie auch der Heterocyclus NR8R9 1 -3-fach substituiert sein mit C-| _4-Alkyl oder einem gegebenenfalls mit Halogen substituierten Phenyl-, Benzyl- oder Benzoylrest. Beispielsweise seien genannte N-Methyl- piperazin, 2,6-Dimethylmorpholin oder Phenylpiperazin .If R " O and R ^ 'R ^ 2 and R ^ 3 form a saturated heterocycle together with the nitrogen atom, this means, for example, pyrrolidine, morpholine, thiomorpholine, piperidine, hexahydroazepine or piperazine. Like the heterocycle NR8R9 1 -3, the heterocycles can -substituted with C 1-4 alkyl or a phenyl, benzyl or benzoyl radical which is optionally substituted with halogen, for example N-methylpiperazine, 2,6-dimethylmorpholine or phenylpiperazine.
Als bevorzugt sind Verbindungen zu betrachten, worin R^ CF3 und R7 Morpholin, Thiomorpholin bedeuten. Besonders bevorzugt sind Verbindungen mit Z = COOH.Compounds in which R ^ CF3 and R 7 are morpholine, thiomorpholine are to be regarded as preferred. Compounds with Z = COOH are particularly preferred.
Ist eine saure Funktion enthalten sind als Salze die physiologisch verträglichen Salze organischer und anorganischer Basen geeignet wie beispielsweise die gut löslichen Alkali- und Erdalkalisalze sowie die Salze mit N-Methyl-glukamin, Dimethyl-glukamin, Ethyl-glukamin, Lysin, 1 ,6- Hexadiamin, Ethanolamin, Glukosamin, Sarkosin, Serinol, Tris-hydroxy- methyl-amino-methan, Aminopropandiol, Sovak-Base, 1 -Amino-2,3,4- butantriol.If an acidic function is present, the physiologically compatible salts of organic and inorganic bases are suitable as salts, for example the readily soluble alkali and alkaline earth metal salts and the salts with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1, 6- Hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethylamino-methane, aminopropanediol, sovak base, 1-amino-2,3,4-butanetriol.
Ist eine basische Funktion enthalten sind die physiologisch verträglichen Salze organischer und anorganischer Säuren geeignet wie HCI, H2SO4, Phosphorsäure, Zitronensäure, Weinsäure u.a.If a basic function is included, the physiologically compatible salts of organic and inorganic acids such as HCI, H2SO4, phosphoric acid, citric acid, tartaric acid and others are suitable.
Die Verbindungen der Formel I sowie deren physiologisch verträglichen Salze sind auf Grund ihrer Affinität zu den AM PA-Rezeptoren als Arzneimittel verwendbar. Auf Grund ihres Wirkprofils eignen sich die erfindungsgemäßen Verbindungen zur Behandlung von Krankheiten, die durch Hyperaktivität excitatorischer Aminosäuren wie zum Beispiel Glutamat oder Aspartat hervorgerufen werden. Da die neuen Verbindungen als Antagonisten excitatorischer Aminosäuren wirken und eine hohe spezifische Affinität zu den AMPA-Rezeptoren zeigen, indem sie den radioaktiv markierten spezifischen Agonisten (RS)a-Amino-3-hydroxy-5-methyl-4-isoxazolpropionat (AMPA) von den AMPA-Rezeptoren verdrängen, eignen sie sich insbesondere zur Behandlung von solchen Krankheiten, die über die Rezeptoren excitatorischer Aminosäuren, insbesondere den AM PA-Rezeptor, beeinflußt werden .The compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their affinity for the AM PA receptors. Because of their activity profile, the compounds according to the invention are suitable for the treatment of diseases caused by hyperactivity excitatory amino acids such as glutamate or aspartate. Since the new compounds act as antagonists of excitatory amino acids and show a high specific affinity for the AMPA receptors by using the radiolabelled specific agonist (RS) a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) from to displace the AMPA receptors, they are particularly suitable for the treatment of diseases which are influenced by the receptors of excitatory amino acids, in particular the AM PA receptor.
Erfindungsgemäß können die Verbindungen verwendet werden zur Behandlung neurologischer und psychiatrischer Störungen, die durch die Überstimulation des AMPA-Rezeptors ausgelöst werden. Zu den neurologischen Erkrankungen , die funktionell und präventiv behandelt werden können, gehören zum Beispiel neurodegenerative Störungen wie Morbus Parkinson, Morbus Alzheimer, Chorea Huntington, Amyotrophe Lateralsklerose und Olivopontocerebelläre Degeneration. Erfindungsgemäss können die Verbindungen zur Prävention des postischämischen Zelluntergangs, des Zelluntergangs nach Hirntrauma, bei Schlaganfall, Hypoxie, Anoxie und Hypoglykämie und zur Behandlung der Senilen Demenz, Aids Demenz, neurologischer Symptome, die mit HIV-Infektionen zusammenhängen, Multiinfarkt Demenz sowie Epilepsie und Muskelspastik verwendet werden. Zu den psychiatrischen Erkrankungen gehören Angstzustände, Schizophrenie, Migräne, Schmerzzustände, sowie die Behandlung von Schlafstörungen und der Entzugssymptomatik nach Drogenmißbrauch wie bei Alkohol-, Kokain-, Benzodiazepin- oder Opiat- Entzug. Die Verbindungen können außerdem eine Anwendung in der Prävention der Toleranzentwicklung während der Langzeitbehandlung mit sedativen Arzneimitteln wie zum Beispiel Benzodiazepinen, Barbituraten und Morphin finden. Darüberhinaus können die Verbindungen als Anästhetika (Narkose), Anti-Schmerzmittel oder Antiemetika benutzt werden.According to the invention, the compounds can be used for the treatment of neurological and psychiatric disorders which are triggered by overstimulation of the AMPA receptor. The neurological diseases that can be treated functionally and preventively include, for example, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and olivopontocerebellar degeneration. According to the invention, the compounds can be used for the prevention of post-ischemic cell death, cell death after brain trauma, stroke, hypoxia, anoxia and hypoglycemia and for the treatment of senile dementia, AIDS dementia, neurological symptoms associated with HIV infections, multi-infarct dementia as well as epilepsy and muscle spasticity become. Psychiatric disorders include anxiety, schizophrenia, migraines, pain, as well as the treatment of sleep disorders and withdrawal symptoms after drug abuse such as alcohol, cocaine, benzodiazepine or opiate withdrawal. The compounds can also find use in the prevention of tolerance development during long-term treatment with sedative drugs such as benzodiazepines, barbiturates and morphine. In addition, the compounds can be used as anesthetics (anesthetic), anti-pain medication or antiemetics.
Die pharmakologische Wirksamkeit der Verbindungen der Formel I wurde mittels der nachfolgend beschriebenen Teste bestimmt:The pharmacological activity of the compounds of the formula I was determined using the tests described below:
Männliche NMRI Mäuse mit einem Gewicht von 1 8-22 g wurden unter kontrollierten Verhältnissen (60 0-1 80 0 Uhr Hell/Dunkelrythmus, bei freiem Zugang zu Futter und Wasser) gehalten und ihre Zuordnung zu Gruppen wurde randomisiert. Die Gruppen bestanden aus 5 - 1 6 Tieren. Die Beobachtung der Tiere wurde zwischen 8 ° ° und 1 3 ° ° Uhr vorgenommen.Male NMRI mice weighing 1 8-22 g were kept under controlled conditions (6 0 0 -1 8 0 0 o'clock light / dark rhythm, with free access to food and water) and their assignment to groups was randomized. The groups consisted of 5 - 1 6 animals. The animals were observed between 8 ° and 13 °.
AMPA wurde in den linken Ventrikel von frei beweglichen Mäusen gespritzt. Der Applikator bestand aus einer Kanüle mit einer Vorrichtung aus rostfreiem Stahl, die die Tiefe der Injektion auf 3,2 mm begrenzt. Der Applikator war an eine Injektionspumpe angeschlossen. Die Injektionsnadel wurde perpendicular zu der Oberfläche des Schädels nach den Koordinaten von Montemurro und Dukelow eingeführt. Die Tiere wurden bis zum Auftreten von clonischen bzw. tonischen Krämpfen bis zu 1 80 sec. beobachtet. Die clonischen Bewegungen, die länger als 5 sec. andauern, wurden als Krämpfe gezählt. Der Anfang der clonischen Krämpfe wurde als Endpunkt für die Bestimmung der Krampf-schwelle verwendet. Die Dosis, die notwendig war, um die Krampfschwelle um 50% herauf- bzw. herabzusetzen (THRD50) wurde in 4-5 Experimenten bestimmt. Die THRD50- und die Vertrauensgrenze wurde in einer Regressionsanalyse bestimmt.AMPA was injected into the left ventricle by freely moving mice. The applicator consisted of a cannula with a stainless steel device that limits the depth of the injection to 3.2 mm. The applicator was connected to an injection pump. The injection needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow. The animals were observed for up to 180 seconds until clonic or tonic cramps occurred. The clonic movements that lasted longer than 5 seconds were counted as convulsions. The beginning of the clonic cramps was used as the end point for the determination of the cramp threshold. The dose required to increase or decrease the seizure threshold by 50% (THRD50) was determined in 4-5 experiments. The THRD50 and confidence limits were determined in a regression analysis.
Die Ergebnisse dieser Versuche zeigen, daß die Verbindung der Formel I und deren Säureadditionssalze funktionelle Störungen des AM PA-Rezeptors beeinflussen. Sie eignen sich daher zu Herstellung von Arzneimitteln zur symptomatischen und präventiven Behandlung von Erkrankungen, die durch Veränderung der Funktion des AMPA-Rezeptor-Komplexes ausgelöst werden.The results of these experiments show that the compound of the formula I and its acid addition salts influence functional disorders of the AM PA receptor. They are therefore suitable for the manufacture of pharmaceuticals for the symptomatic and preventive treatment of diseases which are triggered by changes in the function of the AMPA-receptor complex.
Die Behandlung mit den erfindungsgemäßen Verbindungen verhindert bzw. verzögert die infolge der Erkrankung auftretenden Zellschädigungen und funktioneilen Störungen und vermindert die dadurch entstehenden Symptome.Treatment with the compounds according to the invention prevents or delays the cell damage and functional disorders which occur as a result of the disease and reduces the symptoms which arise as a result.
Durch übliche pharmakologische Teste können die Indikationen gezeigt werden.The indications can be shown by conventional pharmacological tests.
Zur Verwendung der erfindungsgemäßen Verbindungen als Arzneimittel werden diese in die Form eines pharmazeutischen Präparats gebracht, das neben dem Wirkstoff für die enterale oder parenterale Applikation geeignete pharmazeutische, organische oder anorganische inerte Trägermaterialien, wie zum Beispiel, Wasser, Gelantine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Polyalkylenglykole usw. enthält. Die pharmazeutischen Präparate können in fester Form, zum Beispiel als Tabletten, Dragees, Suppositorien, Kapseln oder in flüssiger- Form, zum Beispiel als Lösungen, Suspensionen oder Emulsionen vorliegen. Gegebenenfalls enthalten sie drüber hinaus Hilfsstoffe wie Konservierungs-, Stabilisierungs-, Netzmittel oder Emulgatoren, Salze zur Veränderung des osmotischen Drucks oder Puffer.To use the compounds according to the invention as pharmaceuticals, they are brought into the form of a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains. The pharmaceutical preparations can be in solid form, for example as tablets, dragées, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
Für die parenterale Anwendung sind insbesondere Injektionslösungen oder Suspensionen, insbesondere wäßrige Lösungen der aktiven Verbindungen in polyhydroxyethoxyliertem Rizinusöl, geeignet.Injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
Als Trägersysteme können auch grenzflächenaktive Hilfsstoffe wie Salze der Gallensäuren oder tierische oder pflanzliche Phospholipide, aber auch Mischungen davon sowie Liposome oder deren Bestandteile verwendet werden.Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
Für die orale Anwendung sind insbesondere Tabletten, Dragees oder Kapseln mit Talkum und/oder Kohlenwasserstoffträger oder -binder, wie zum Beispiel Lactose, Mais- oder Kartoffelstärke, geeignet. Die Anwendung kann auch in flüssiger Form erfolgen, wie zum Beispiel als Saft, dem gegebenenfalls ein Süßstoff beigefügt ist.Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
Die Dosierung der Wirkstoffe kann je nach Verabfolgungsweg, Alter und Gewicht des Patienten, Art und Schwere der zu behandelnden Erkrankung und ähnlichen Faktoren variieren. Die tägliche Dosis beträgt 0,5-1000 mg, vorzugsweise 50-200 mg, wobei die Dosis als einmal zu verabreichende Einzeldosis oder unterteilt in 2 oder mehreren Tagesdosen gegeben werden kann.The dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, and the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
Die Herstellung der erfindungsgemäßen Verbindung erfolgt nach an sich bekannten Methoden. Beispielsweise gelangt man zu Verbindungen der Formel I dadurch, daß manThe compound of the invention is prepared by methods known per se. For example, compounds of the formula I are obtained by
a) eine Verbindung der Formel II (CH2)n-CR'H-(CH2)m-Z'a) a compound of formula II (CH 2 ) n -CR'H- (CH 2 ) m -Z '
(H)(H)
worin R2' R5, R*\ R7, n und m die obige Bedeutung haben und Z' die Bedeutung von Z oder -C≡N hat, mit Oxalsäure oder reaktiven Oxalsäurederivaten cyciisiert oderwherein R 2 'R 5 , R * \ R 7 , n and m have the above meaning and Z' has the meaning of Z or -C≡N, cyclized with oxalic acid or reactive oxalic acid derivatives or
b) eine Verbindung der Formel IIIb) a compound of formula III
worin R2, R^, R6, ^ n unc| m ,-(je obige Bedeutung haben, hydrolysiert und gewünschtenfalls anschließend die Carboxylgruppe verestert oder amidiert oder die Isomeren trennt oder die Salze bildet.where R 2 , R ^, R6, ^ n unc | m, - (e j have the above significance, if desired, hydrolyzed and then esterified carboxyl or amidated or the isomers are separated or forms, the salts.
Verbindungen der Formel II und III erhält man beispielsweise, indem man in einer Verbindung der Formel IVCompounds of the formula II and III are obtained, for example, by reacting in a compound of the formula IV
worin R1 ' R1 oder (CH2)n-CR2 -(CH2)rrfCsN bedeutet und R5', R6'und R7' eine Fluchtgruppe oder R§, R6 oder R7 bedeuten, eine Fluchtgruppe substituiert und die Nitrogruppe reduziert und analog zu der Verfahrensvariante a) mit Oxalsäure oder reaktiven Oxalsäurederivaten cyciisiert. Die Cyclisierung zu Verbindungen der Formel I erfolgt mit Oxalsäure in bekannter Weise einstufig in saurem Milieu oder mit einem reaktiven Oxalsäurederivat einstufig oder auch zweistufig. Als bevorzugt ist das Zweistufenverfahren zu betrachten, bei dem das Diamin mit einem Oxalsäurederivat wie dem Oxalesterhalbchlorid oder reaktiven Oxalsäurederivaten wie z.B. Imidazoliden in polaren Lösungsmitteln wie cyclischen oder acyclischen Ethern oder halogenierten Kohlenwasserstoffen beispielsweise Tetrahydrofuran, Diethylether oder Methylenchlorid oder auch in Wasser nach Schotten Baumann in Gegenwart einer Base wie organischen Aminen beispielsweise Triethylamin, Pyridin, Hünig-Base oder Dimethylaminopyridin oder auch Soda oder Natronlauge umgesetzt wird. Die anschließende Cyclisierung kann basisch oder auch sauer, vorzugsweise aber in saurem Milieu durchgeführt werden, wobei der Reaktionsmischung Lösungsvermittler wie Alkohol oder Acetonitril zugesetzt werden kann.wherein R 1 'R 1 or (CH2) n-CR 2 - ( CH 2) rrf CsN and R 5 ', R 6 'and R 7 ' represent a leaving group or R§, R6 or R 7 , substituted a leaving group and the nitro group is reduced and cyclized analogously to process variant a) with oxalic acid or reactive oxalic acid derivatives. The cyclization to compounds of formula I is carried out in a known manner with oxalic acid in a single stage in an acidic medium or with a reactive oxalic acid derivative in one or two stages. The two-stage process in which the diamine is present in the presence of an oxalic acid derivative such as oxal ester half-chloride or reactive oxalic acid derivatives such as imidazolides in polar solvents such as cyclic or acyclic ethers or halogenated hydrocarbons, for example tetrahydrofuran, diethyl ether or methylene chloride, or in water according to Schotten Baumann, is to be regarded as preferred a base such as organic amines, for example triethylamine, pyridine, Hünig base or dimethylaminopyridine or also soda or sodium hydroxide solution. The subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acidic environment, and solubilizers such as alcohol or acetonitrile can be added to the reaction mixture.
Geeignete Basen für das Zweistufenverfahren stellen auch Alkalihydride dar wie NaH, die in inerten Lösungsmitteln wie Kohlenwasserstoffen oder Ethern eingesetzt werden.Suitable bases for the two-stage process are also alkali metal hydrides such as NaH, which are used in inert solvents such as hydrocarbons or ethers.
Als Fluchtgruppen der Verbindungen der Formel III sind Halogene wie Fluor, Chlor, Brom, Jod oder O-Mesylat, O-Tosylat, O-Triflat oder O-Nonaflat geeignet.Halogens such as fluorine, chlorine, bromine, iodine or O-mesylate, O-tosylate, O-triflate or O-nonaflate are suitable as escape groups of the compounds of the formula III.
Die nucleophile Substitution mit Aminen wird bei möglichst niedriger Temperatur vorzugsweise bei Raumtemperatur durchgeführt. Ein Uberschuss an Amin ist nicht von Nachteil. Das Amin kann auch als Lösungsmittel benutzt werden. Als Lösungsmittel geeignet sind Ether wie Tetrahydrofuran oder Kohlenwasserstoffe wie Toluol oder auch halogenierte Kohlenwasserstoffe wie Methylenchlorid.The nucleophilic substitution with amines is carried out at the lowest possible temperature, preferably at room temperature. An excess of amine is not a disadvantage. The amine can also be used as a solvent. Suitable solvents are ethers such as tetrahydrofuran or hydrocarbons such as toluene or halogenated hydrocarbons such as methylene chloride.
Die Substitution durch Alkenylverbindungen erfolgt unter Katalyse von Übergangsmetallkomplexen wie Pd(0), z.B.The substitution by alkenyl compounds takes place with the catalysis of transition metal complexes such as Pd (0), e.g.
Palladiumtetrakistriphenylphosphin oder Pd<2 + ), wie z.B. Palladium-bisTri-o- tolylphosphin-dichlorid oder Nickel(O) nach literaturbekannten Methoden gegebenenfals in Gegenwart einer Base und wird durch eine aktivierende elektronenziehende Gruppe wie z.B. Nitro, Cyano, Trifluormethyl vorzugsweise in o-Stellung begünstigt. Als Nucleophile sind beispielsweise die entsprechenden Boronsäuren. oder - borane oder Zinnorganische Verbindungen, Zinkorganische Verbindungen, Grignard-Verbindungen oder auch die Alkenyle als solche geeignet. Die Umsetzung kann in polaren Lösungsmitteln wie Dimethylformamid, Dimethylacetamid, Acetonitril, in Kohlenwasserstoffen wie Toluol oder in Ethern wie Tetrahydrofuran, Dimethoxyethan oder Diethylether vorgenommen werden. Als Basen sind anorganische Basen wie Alkali- oder Erdalkalihydroxide, -carbonate oder -acetate oder organische Basen wie cyclische, alicyclische und aromatische Amine, wie Pyridin, Triethylamin, DBU, Hünigbase gegebenenfalls unter Zugabe von Wasser geeignet.Palladium tetrakistriphenylphosphine or Pd < 2 + ), such as palladium-bis-tri-o-tolylphosphine dichloride or nickel (O) according to methods known from the literature, if appropriate in the presence of a base and is preferably activated by an activating electron-withdrawing group such as nitro, cyano, trifluoromethyl Favored position. The corresponding boronic acids are, for example, nucleophiles. or - boranes or organotin compounds, organozinc compounds, Grignard compounds or the alkenyls as such are suitable. The reaction can be carried out in polar solvents such as dimethylformamide, dimethylacetamide, acetonitrile, in hydrocarbons such as toluene or in ethers such as tetrahydrofuran, dimethoxyethane or diethyl ether. Suitable bases are inorganic bases such as alkali or alkaline earth metal hydroxides, carbonates or acetates or organic bases such as cyclic, alicyclic and aromatic amines such as pyridine, triethylamine, DBU, Hunig base, optionally with the addition of water.
Die sich gegebenenfalls anschließende oxydative Spaltung der Alkenylverbindungen zum Aldehyd kann nach literaturbekannten Methoden erfolgen. Bevorzugt ist die Ozonisierung in Lösungsmitteln wie z.B. halogenierten Kohlenwasserstoffen oder Alkoholen oder aber Mischungen davon bei Temperaturen von -78°C bis Raumtemperatur. Das sich bildende Ozonid wird reduktiv durch Abfang mit Thioharnstoff, Trialkylphosphiten oder vorzugsweise mit Triarylphosphinen zum Aldehyd gespalten.Any subsequent oxidative cleavage of the alkenyl compounds to the aldehyde can be carried out using methods known from the literature. Ozonation in solvents such as e.g. halogenated hydrocarbons or alcohols or mixtures thereof at temperatures from -78 ° C to room temperature. The ozonide which forms is reductively cleaved to form the aldehyde by trapping with thiourea, trialkylphosphites or, preferably, with triarylphosphines.
Der Aldehyd kann kettenverlängert werden, indem man z.B. durch Petersonolefinierung, oder durch Wittig- oder Wittig-Homer-Reaktion zunächst einen entsprechenden Enoläther herstellt. Dazu wird der Aldehyd mit dem vorher erzeugten Anion z.B. eines entsprechend substituierten Phosphoniumsalzes oder Phosphonsäureesters in Lösungsmitteln wie Toluol, Tetrahydrofuran, Diethylether oder Dimethoxyethan umgesetzt. Als Basen sind z.B. Alkalihydride, Alkaliamide, Alkalialkoholate wie beispielsweise Kaliumtertiärbutylat, Alkali- oder Erdalkalicarbonate oder- hydroxide gegebenenfalls in Gegenwart von Phasentransferkatalysatoren wie z.B. Kronenäthern oder auch organische Basen wie Triethylamin, Diisopropylethylamin oder Diazabicycloundecan gegebenenfalls in Gegenwart von Salzen wie Lithiumbromid geeignet. Der entsprechende Enoläther kann anschliessend durch Säure gespalten werden.The aldehyde can be chain extended by e.g. by Petersonolefinierung, or by Wittig or Wittig-Homer reaction initially produces an appropriate enol ether. For this purpose, the aldehyde with the previously generated anion e.g. an appropriately substituted phosphonium salt or phosphonic acid ester in solvents such as toluene, tetrahydrofuran, diethyl ether or dimethoxyethane. As bases are e.g. Alkali hydrides, alkali amides, alkali alcoholates such as potassium tert-butoxide, alkali or alkaline earth carbonates or hydroxides, optionally in the presence of phase transfer catalysts such as e.g. Crown ethers or organic bases such as triethylamine, diisopropylethylamine or diazabicycloundecane, if appropriate in the presence of salts such as lithium bromide, are suitable. The corresponding enol ether can then be cleaved by acid.
Die Aldehyde können nach literaturbekannten Verfahren zu den entsprechenden Alkoholen reduziert, werden. Vorzugsweise wird die Reduktion mit komplexen Metallhydriden wie z.B. Natriumboranat in Lösungsmitteln wie Alkohol durchgeführt. Die Hydroxygruppe kann nach literaturbekannten Methoden , nach verschiedenen Verfahren in Fluchtgruppen wie Chlorid, Bromid, Jodid, Triflat, Mesylat oder Tosylat überführt werden. Vorzugsweise wird mit Tosylchlorid in Gegenwart von Basen wie z.B. Triethylamin, Etyldiisopropylamin oder Dimethylaminopyridin in Lösungsmitteln wie halogenierten Kohlenwasserstoffen oder Äthern in das Chlorid oder auch Tosylat überführt.The aldehydes can be reduced to the corresponding alcohols by methods known from the literature. The reduction is preferably carried out with complex metal hydrides such as sodium boranate in solvents such as alcohol. The hydroxyl group can be converted into escape groups such as chloride, bromide, iodide, triflate, mesylate or tosylate by methods known from the literature and by various processes. It is preferably converted into the chloride or tosylate with tosyl chloride in the presence of bases such as, for example, triethylamine, ethyldiisopropylamine or dimethylaminopyridine in solvents such as halogenated hydrocarbons or ethers.
Die nucleophile Substitution erfolgt durch Nucleophile wie Amine in Lösungsmitteln wie Alkoholen, halogenierten Kohlenwasserstoffen oder Ketonen oder ohne Lösungsmittel gegebenenfalls unter Zugabe einer Base wie Alkali- oder Erdalkalihydroxid oder -carbonat oder auch organischen Basen wie z.B. Triethylamin, Ethyldiisopropylamin oderThe nucleophilic substitution is carried out by nucleophiles such as amines in solvents such as alcohols, halogenated hydrocarbons or ketones or without solvents, optionally with the addition of a base such as alkali or alkaline earth metal hydroxide or carbonate or else organic bases such as e.g. Triethylamine, ethyldiisopropylamine or
Dimethylaminopyridin.Dimethylaminopyridine.
Die Reduktion der Nitrogruppe erfolgt in üblicher Weise katalytisch oder durch Reduktion mit Eisenpulver in Essigsäure bei erhöhter Temperatur oder auch mit Natriumsulfid und Ammoniumhydroxid in Alkohol. Die Reduktion der Alkenylgruppe erfolgt in üblicher Weise katalytisch und läuft dann üblicherweise mit der Reduktion der Nitrogruppe zusammen ab.The nitro group is reduced in the customary manner catalytically or by reduction with iron powder in acetic acid at elevated temperature or else with sodium sulfide and ammonium hydroxide in alcohol. The reduction of the alkenyl group takes place in the usual way catalytically and then usually takes place together with the reduction of the nitro group.
Die sich gegebenenfalls anschließende Verseifung einer Estergruppe oder die Verseifung einer Nitrilgruppe kann basisch oder vorzugsweise sauer erfolgen, indem man bei erhöhter Temperatur bis zur Siedetemperatur des Reaktionsgemisches in Gegenwart von Säuren wie hoch konzentrierter wäßriger Salzsäure gegebenenfalls in Lösungsmitteln wie beispielsweise Trifluoressigsäure oder Alkoholen hydrolysiert.The optionally subsequent saponification of an ester group or the saponification of a nitrile group can be carried out in a basic or, preferably, acidic manner by hydrolysing at elevated temperature to the boiling point of the reaction mixture in the presence of acids such as highly concentrated aqueous hydrochloric acid, optionally in solvents such as trifluoroacetic acid or alcohols.
Die Veresterung der Carbonsäure geschieht in an sich bekannter Weise mit dem entsprechenden Alkohol unter Säurekatalyse oder in Gegenwart eines aktivierten Säurederivats. Als aktivierte Säurederivate kommen zum Beispiel Säurechlorid, -imidazolid oder -anhydrid in Frage.The esterification of the carboxylic acid takes place in a manner known per se with the corresponding alcohol with acid catalysis or in the presence of an activated acid derivative. Examples of suitable acid derivatives are acid chloride, imidazolide or anhydride.
Die Amidierung erfolgt an den freien Säuren oder an deren reaktiven Derivaten wie beispielsweise Säurechloriden, gemischten Anhydriden, Imidazoliden oder Aziden durch Umsetzung mit den entsprechenden Aminen bei Raumtemperatur. Die Amidierung kann auch direkt vom ester durch Umsetzung mit einem Amin in gegenwart von Trimethylaluminium erfolgen. Die Isomerengemische können nach üblichen Methoden wie beispielsweise Kristallisation, Chromatographie oder Salzbildung in die Enantiomeren bzw. E/Z-Isomeren aufgetrennt werden.The amidation takes place on the free acids or on their reactive derivatives such as acid chlorides, mixed anhydrides, imidazolides or azides by reaction with the corresponding amines at room temperature. The amidation can also be carried out directly from the ester by reaction with an amine in the presence of trimethyl aluminum. The isomer mixtures can be separated into the enantiomers or E / Z isomers by customary methods such as, for example, crystallization, chromatography or salt formation.
Die Herstellung der Salze erfolgt in üblicher Weise, indem man eine Lösung der Verbindung der Formel I mit der äquivalenten Menge oder einem Überschuß einer Base oder Säure, die gegebenenfalls in Lösung ist, versetzt und den Niederschlag abtrennt oder in üblicher Weise die Lösung aufarbeitet.The salts are prepared in the customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is optionally in solution, and removing the precipitate or working up the solution in the customary manner.
Soweit die Herstellung der Ausgangsverbindungen nicht beschrieben wird, sind diese bekannt oder analog zu bekannten Verbindungen, beispielsweise nach WO94/25469, PCT/DE96/0227 oder hier beschriebenen Verfahren herstellbar.If the preparation of the starting compounds is not described, they are known or can be prepared analogously to known compounds, for example according to WO94 / 25469, PCT / DE96 / 0227 or the processes described here.
Die nachfolgenden Beispiele sollen das erfindungsgemäße Verfahren erläutern:The following examples are intended to explain the process according to the invention:
Herstellung der Ausgangsmaterialien erfolgt nach literaturbekannten Verfahren.The starting materials are produced by processes known from the literature.
Beispiel 1example 1
A.) 2,3g 2,4-Difluor-5-trifluormethyl-nitrobenzol werden in 10ml Toluol gelöst, mit 0,84g Natriumhydrogencarbonat versetzt und mit einem Zweiphasengemisch von 0,95g Aminoacetonitril in 5 ml Toluol versetzt. Es wird dann 3,75h auf 1 20°C Badtemperatur erwärmt. Nach Abkühlen wird mit 50ml Wasser versetzt, und dreimal mit je 50ml Essigester extrahiert. Die organische Phase wird nacheinander mit wasser gewasschen, getrocknet, filtriert und eingeengt. Man erhält 2,6g 2-Cyanomethylamino-4-fluor-5- trifluormethyl-nitrobenzol.A.) 2.3 g of 2,4-difluoro-5-trifluoromethyl-nitrobenzene are dissolved in 10 ml of toluene, mixed with 0.84 g of sodium hydrogen carbonate and mixed with a two-phase mixture of 0.95 g of aminoacetonitrile in 5 ml of toluene. It is then heated to a bath temperature of 120 ° C. for 3.75 hours. After cooling, 50 ml of water are added and the mixture is extracted three times with 50 ml of ethyl acetate each time. The organic phase is washed successively with water, dried, filtered and concentrated. 2.6 g of 2-cyanomethylamino-4-fluoro-5-trifluoromethyl-nitrobenzene are obtained.
In analoger Weise wird hergestellt:The following is produced in an analogous manner:
2-(2-Cyanoethylamino)-4-fluor-5-trifluormethyl-nitrobenzol B.) 3,5g 2-Cyanomethylamino-4-fluor-5-trifluormethylbenzol werden in 1 5ml Morpholin 6,5h bei Raumtemperatur gerührt. Nach Stehen über Nacht wird mit Wasser versetzt und abgesaugt. Man erhält 3,97g 2-Cyanomethylamino- 4-morpholino-5-trifluormethyl-nitrobenzol.2- (2-cyanoethylamino) -4-fluoro-5-trifluoromethyl-nitrobenzene B.) 3.5 g of 2-cyanomethylamino-4-fluoro-5-trifluoromethylbenzene are stirred in 1 5 ml of morpholine for 6.5 hours at room temperature. After standing overnight, water is added and suction filtered. 3.97 g of 2-cyanomethylamino-4-morpholino-5-trifluoromethyl-nitrobenzene are obtained.
In analoger Weise wird hergestellt:The following is produced in an analogous manner:
2-Cyanomethylamino-4-(thiomorpholin-1 -yl)-5-trifluormethyl-nitrobenzol 2-Cyanomethylamino-4-(2,6-dimethylmorpholin-1 -yl)-5-trifluormethyl- nitrobenzol2-cyanomethylamino-4- (thiomorpholin-1-yl) -5-trifluoromethyl-nitrobenzene 2-cyanomethylamino-4- (2,6-dimethylmorpholin-1-yl) -5-trifluoromethyl-nitrobenzene
2-(2-Cyanoethylamino)-4-morpholino-5-trifluormethyl-nitrobenzol2- (2-cyanoethylamino) -4-morpholino-5-trifluoromethyl-nitrobenzene
C.) 2,95g Ammoniumchlorid werden in 60ml Wasser gelöst und mit 1 ,88g Eisenpulver versetzt. Zu diesem Ansatz wird eine Aufschlämmung von 3,7g 2-Cyanomethylamino-4-morpholino-5-trifluormethyl-nitrobenzol in 1 20ml Methanol getropft. Während der Zutropfzeit wird der Ansatz auf 80°C Badtemperatur gebracht und nach beendetem Zutropfen 1 ,5h auf diese Temperatur erwärmt. Nach Absaugen über Kieselgur und Nachwaschen mit heissem Methanol wird das Filtrat bis zum Wasser eingeengt und das ausgefallenen Produkt abgesaugt. Man erhält 3,09g 3-Amino-4- cyanomethylamino-6-morpholino-trifluormethylbenzol.C.) 2.95 g of ammonium chloride are dissolved in 60 ml of water and mixed with 1.88 g of iron powder. A slurry of 3.7 g of 2-cyanomethylamino-4-morpholino-5-trifluoromethyl-nitrobenzene in 1 20 ml of methanol is added dropwise to this batch. During the dropwise addition, the batch is brought to a bath temperature of 80 ° C. and, after the dropwise addition has ended, heated to this temperature for 1.5 hours. After suction filtration over diatomaceous earth and washing with hot methanol, the filtrate is evaporated down to the water and the precipitated product is filtered off with suction. 3.09 g of 3-amino-4-cyanomethylamino-6-morpholino-trifluoromethylbenzene are obtained.
In analoger Weise wird hergestellt:The following is produced in an analogous manner:
3-Amino-4-cyanomethylamino-6-(thiomorpholin-1 -yl)-trifluormethylbenzol 3-Amino-4-cyanomethylamino-6-(2,6-dimethylmorpholin-1 -yl)- trifluormethylbenzol 3-Amino-4-(2-cyanoethylamino)-6-(morpholin-1 -yl)-trifluormethylbenzol3-amino-4-cyanomethylamino-6- (thiomorpholin-1-yl) trifluoromethylbenzene 3-amino-4-cyanomethylamino-6- (2,6-dimethylmorpholin-1-yl) trifluoromethylbenzene 3-amino-4- (2nd -cyanoethylamino) -6- (morpholin-1-yl) trifluoromethylbenzene
D.) 3,09g 3-Amino-4-cyanomethylamino-6-morpholino-trifluormethylbenzol werden in 250ml Tetrahydrofuran gelöst und mit 2,35g Triethylamin versetzt. Zu dieser Lösung wird unter Eiskühlung eine Lösung von 3, 1 6g Oxalsäureesterchlorid in 50ml Tetrahydrofuran getropft. Nach beendeter Zugabe wird 3,5h bei Raumtemperatur gerührt. Der Ansatz wird vom Triethylaminhydrochlorid abgesaugt und die Mutterlauge eingeengt. Der Rückstand wird in 1 00ml Ethanol aufgenommen, mit 100ml 1 N-Salzsäure versetzt und für 2h auf 1 1 0°C Badtemperatur erwärmt. Es wird dann das Ethanol abgezogen, und dreimal mit je 1 00ml Essigester extrahiert. Die organische Phase wird mit Wasser gewaschen, getrocknet, filtriert und eingeengt. Der Rückstand wird über Kieselgel mitD.) 3.09 g of 3-amino-4-cyanomethylamino-6-morpholino-trifluoromethylbenzene are dissolved in 250 ml of tetrahydrofuran and mixed with 2.35 g of triethylamine. A solution of 3.16 g of oxalic acid ester chloride in 50 ml of tetrahydrofuran is added dropwise to this solution while cooling with ice. After the addition has ended, the mixture is stirred at room temperature for 3.5 hours. The batch is suctioned off from the triethylamine hydrochloride and the mother liquor is concentrated. The residue is taken up in 100 ml of ethanol, mixed with 100 ml of 1N hydrochloric acid and heated to a bath temperature of 110 ° C. for 2 h. The ethanol is then drawn off and extracted three times with 100 ml of ethyl acetate each time. The organic phase is washed with water, dried, filtered and concentrated. The residue is covered with silica gel
Methylenchlorid:Etanol = 10: als Elutionsmittel chromatographiert. Man erhält 1 ,67g 1 -Cyanomethyl-6-trifluoromethyl-7-morpholino-1 ,2,3,4-tetrahydro- 2,3-dioxo-chinoxalin vom Schmelzpunkt 279°C.Methylene chloride: ethanol = 10: chromatographed as eluent. 1.67 g of 1-cyanomethyl-6-trifluoromethyl-7-morpholino-1, 2,3,4-tetrahydro-2,3-dioxo-quinoxaline with a melting point of 279 ° C. are obtained.
In analoger Weise wird hergestellt:The following is produced in an analogous manner:
1 -Cyanomethyl-6-trifluoromethyl-7-(thiomorpholin-1 -yl)-1 ,2,3,4-tetrahydro- 2,3-dioxo-chinoxalin1-cyanomethyl-6-trifluoromethyl-7- (thiomorpholin-1-yl) -1, 2,3,4-tetrahydro-2,3-dioxo-quinoxaline
1 -Cyanomethyl-6-trifluoromethyl-7-(2,6-dimethylmorpholin-1 -yl)-1 ,2,3,4- tetrahydro-2,3-dioxo-chinoxalin1-cyanomethyl-6-trifluoromethyl-7- (2,6-dimethylmorpholin-1-yl) -1, 2,3,4-tetrahydro-2,3-dioxo-quinoxaline
1 -Cyanoeth-2-yl-(6-trifluoromethyl)-7-morpholino-1 ,2,3,4-tetrahydro-2,3- dioxo-chinoxalin1-cyanoeth-2-yl- (6-trifluoromethyl) -7-morpholino-1, 2,3,4-tetrahydro-2,3-dioxo-quinoxaline
E.) 300mg 1 -Cyanomethyl-6-trifluoromethyl-7-morpholino-1 , 2,3,4- tetrahydro-2,3-dioxochinoxalin werden mit 1 5ml konzentrierter Salzsäure 3h auf 1 20°C Badtemperatur erwärmt. Nach Einengen wird in Wasser kristallin gerührt, und abgesaugt. Man erhält 300mg 1 -(6-Trifluoromethyl-7-E.) 300 mg of 1-cyanomethyl-6-trifluoromethyl-7-morpholino-1, 2,3,4-tetrahydro-2,3-dioxoquinoxaline are heated with 1 5 ml of concentrated hydrochloric acid for 3 hours at a bath temperature of 20 ° C. After concentration, the mixture is stirred in water in crystalline form and filtered off with suction. 300 mg of 1 - (6-trifluoromethyl-7-
[morpholinl -yl]-1 ,2,3,4-tetrahydro-2,3-dioxo-chinoxalin-1 -yDessigsäure vom Schmelzpunkt > 300°C.[morpholinl -yl] -1, 2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-y-acetic acid with a melting point> 300 ° C.
In analoger Weise werden hergestellt: 1 -(6-Trifluoromethyl-7-[thiomorpholin1 -yl]-1 ,2,3,4-tetrahydro-2,3-dioxo- chinoxalin-1 -yDessigsäureThe following are prepared in an analogous manner: 1 - (6-trifluoromethyl-7- [thiomorpholin1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-y-acetic acid
1 -(6-Trifluoromethyl-7-[2,6-dimethylmorpholin1 -yl]-1 ,2,3,4-tetrahydro-2,3- dioxo-chinoxalin-1 -yDessigsäure1 - (6-Trifluoromethyl-7- [2,6-dimethylmorpholin1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-y-acetic acid
2-(6-Trifluormethyl-7-[morpholin1 -yl]-1 ,2,3,4-tetrahydro-2,3-dioxo- chinoxalin-1 -yl)propionsäure 2- (6-trifluoromethyl-7- [morpholin1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl) propionic acid

Claims

Patentansprüche claims
1 .) Verbindungen der Formel I1.) Compounds of the formula I.
worinwherein
R1 -(CH2)n-CR2H-(CH2)m-Z undR 1 - (CH 2 ) n -CR 2 H- (CH 2 ) mZ and
R5 und R6 gleich oder verschieden sind und Wasserstoff, NO2, Halogen, Cyano oder gegebenenfalls halogeniertes C -] _6-Alkyl bedeuten,R5 and R6 are identical or different and are hydrogen, NO2, halogen, cyano or optionally halogenated C -] _6-alkyl,
R7 -(CH2)p -NR8R9 R 7 - (CH 2 ) p -NR 8 R 9
R2 Wasserstoff oder -(CH2>q-R3 R 2 is hydrogen or - (CH2> q -R 3
R3 Wasserstoff, Hydroxy, C-μe-Alkoxy oder NR1 0R1 1 ,R 3 is hydrogen, hydroxy, C-μe alkoxy or NR 1 0 R 1 1,
n, m und q jeweils 0, 1 , 2 oder 3n, m and q each 0, 1, 2 or 3
p 0, 1 , 2, 3 oder 4,p 0, 1, 2, 3 or 4,
Z COR1 6,Z COR 1 6 ,
R8 und R9 gemeinsam mit dem Stickstoffatom Pyrrolidin, Morpholin, Thiomorpholin, Piperazin oder Hexahydroazepin bedeuten, die substituiert sein können mit C-| _4-Alkyl oder einem gegebenenfalls mit Halogen substituiertem Phenyl- Benzyl- oder Benzoylrest,R8 and R9 together with the nitrogen atom mean pyrrolidine, morpholine, thiomorpholine, piperazine or hexahydroazepine, which can be substituted by C- | _4-alkyl or a phenyl, benzyl or benzoyl radical optionally substituted with halogen,
R1 6 OH, C-| _6-Alkoxy oder NR1 2R1 3 RI O und R1 1 ' R^ 2 und R^ 3 gleich oder verschieden sind und Wasserstoff, C-| _4-Alkyl, Phenyl oder gemeinsam mit dem Stickstoffatom einen 5-7- gliedrigen gesättigten Heterocyclus bilden, der ein weiteres Sauerstoff-, Schwefel- oder Stickstoffatom enthalten und substituiert sein kannR 1 6 OH, C- | _6-alkoxy or NR1 2 R 1 3 RI O and R1 1 'R ^ 2 and R ^ 3 are the same or different and are hydrogen, C- | _4-alkyl, phenyl or together with the nitrogen atom form a 5-7-membered saturated heterocycle which may contain and be substituted by another oxygen, sulfur or nitrogen atom
sowie deren Isomeren oder Salze.as well as their isomers or salts.
2.) 1 -(6-Trifluoromethyl-7-[morpholin1 -yl]-1 ,2,3,4-tetrahydro-2,3-dioxo- chinoxalin-1 -yDessigsäure 1 -(6-Trifluoromethyl-7-[thiomorpholin1 -yl]-1 ,2,3,4-tetrahydro-2,3-dioxo- chinoxalin-1 -yDessigsäure2.) 1 - (6-Trifluoromethyl-7- [morpholin1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-y-acetic acid 1 - (6-trifluoromethyl-7- [thiomorpholine1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-y-acetic acid
1 -(6-Trifluoromethyl-7-[2,6-dimethylmorpholin1 -yl]-1 ,2,3,4-tetrahydro-2,3- dioxo-chinoxalin-1 -yDessigsäure1 - (6-Trifluoromethyl-7- [2,6-dimethylmorpholin1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxo-quinoxalin-1-y-acetic acid
2-(6-Trifluormethyl-7-[morpholin 1 -yl]-1 ,2,3,4-tetrahydro-2,3-dioxo- chinoxalin-1 -yl)propionsäure gemäß Anspruch 1 .2- (6-trifluoromethyl-7- [morpholin 1 -yl] -1, 2,3,4-tetrahydro-2,3-dioxoquinoxalin-1 -yl) propionic acid according to claim 1.
3.) Arzneimittel enthaltend eine Verbindung nach Anspruch 1 oder 2 und einen oder mehrere übliche pharmazeutische Trägerstoffe.3.) Medicament containing a compound according to claim 1 or 2 and one or more conventional pharmaceutical carriers.
4.) Verfahren zur Herstellung der Verbindungen der Formel I dadurch, daß man4.) Process for the preparation of the compounds of formula I in that
a) eine Verbindung der Formel IIa) a compound of formula II
ÖDPS
worin R2' R^, R6, R7, n und m die obige Bedeutung haben und Z' die Bedeutung von Z oder -C≡N hat, mit Oxalsäure oder reaktiven Oxalsäure- derivaten cyciisiert oderwherein R 2 'R ^, R6, R7, n and m have the above meaning and Z' has the meaning of Z or -C≡N, cyciisiert with oxalic acid or reactive oxalic acid derivatives or
b) eine Verbindung der Formel III b) a compound of formula III
worin R2, R5, R6, R7, n und m die obige Bedeutung haben, hydrolysiert und gewünschtenfalls anschließend die Carboxylgruppe verestert oder amidiert oder die Isomeren trennt oder die Salze bildet. in which R 2 , R5, R6, R 7 , n and m have the above meaning, hydrolyze and, if desired, then esterify or amidate the carboxyl group or separate the isomers or form the salts.
EP98942480A 1997-06-27 1998-06-26 New quinoxaline dione derivatives, the production thereof and use of the same in medicaments Withdrawn EP0993461A1 (en)

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