WO1993008173A1 - Derives de quinoxaline ayant une affinite pour les recepteurs de quisqualate - Google Patents

Derives de quinoxaline ayant une affinite pour les recepteurs de quisqualate Download PDF

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WO1993008173A1
WO1993008173A1 PCT/DE1992/000895 DE9200895W WO9308173A1 WO 1993008173 A1 WO1993008173 A1 WO 1993008173A1 DE 9200895 W DE9200895 W DE 9200895W WO 9308173 A1 WO9308173 A1 WO 9308173A1
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Prior art keywords
dioxo
acid
nitro
alkyl
substituted
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PCT/DE1992/000895
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German (de)
English (en)
Inventor
Andreas Huth
Ralph Schmiechen
Ilse Beetz
Ingrid Schumann
Lechoslaw Turski
Peter Andreas LÖSCHMANN
David Norman Stephens
Dieter Seidelmann
Martin Krüger
Dieter Rahtz
Peter Hölscher
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Schering Aktiengesellschaft
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Priority claimed from DE4135871A external-priority patent/DE4135871A1/de
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to CZ19931387A priority Critical patent/CZ286351B6/cs
Priority to PL92299929A priority patent/PL171125B1/pl
Priority to KR1019930701948A priority patent/KR100262371B1/ko
Priority to AU28894/92A priority patent/AU664212B2/en
Priority to JP50735393A priority patent/JP3258008B2/ja
Priority to SK727-93A priority patent/SK281518B6/sk
Publication of WO1993008173A1 publication Critical patent/WO1993008173A1/fr
Priority to FI932959A priority patent/FI932959A0/fi
Priority to NO932116A priority patent/NO304693B1/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
    • C07F9/650994—Six-membered rings having the nitrogen atoms in the positions 1 and 4 condensed with carbocyclic rings or carbocyclic ring systems
    • 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
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • 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
    • A61P25/28—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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • 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
    • 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

Definitions

  • the invention relates to quinoxalinedione carboxylic acid and phosphonic acid derivatives, their preparation and use in medicaments.
  • quinxaline derivatives have affinity for the quisqualate receptors and, because of their affinity, are suitable as medicaments for the treatment of diseases of the central nervous system.
  • the compounds according to the invention have the formula I.
  • substituted with R 2 is substituted C 1-12 alkyl, with R 2
  • R 2 is substituted with C 3-7 cycloalkyl, - (CH 2) n -C 6-12 -aryl, which in the aryl radical or
  • Alkyl radical is substituted by R 2 or - (CH 2 ) n -hetaryl which is substituted by R 2 in the hetaryl or alkyl radical,
  • R 5 , R 6 , R 7 and R 8 are the same or different and are hydrogen, halogen, nitro, NR 9 R 10 , NHCOR 11 , SO R 12 , C 3-7 cycloalkyloxy, COR 13 , cyano, CF 3 , C 1-6 alkyl, C 1-4 alkoxy or optionally with cyano, C 1-4 alkyl or
  • R 5 and R 6 or R 7 and R 8 represent a fused-on benzene ring
  • R 2 -CO-R 3 or -PO-XY and R 2 is one or two times the same or different and n is 0, 1, 2, 3, 4 or 5 and
  • R 3 is hydroxy, C 1-6 alkoxy or NR 9 R 10 ,
  • X and Y are the same or different and are hydroxy, C 1-6 alkoxy, C 1-4 alkyl or NR 9 R 10 and
  • R 9 and R 10 are the same or different and are hydrogen, C 1-4 alkyl or together with the nitrogen atom a saturated 5- or
  • R 11 is C 1-6 alkyl or phenyl
  • R 12 is hydrogen, C 1-4 alkyl, NH-, N ⁇ C 1-4 alkyl), and
  • R 13 is hydroxy, C 1-6 alkoxy, C 1-6 alkyl or NR 9 R 10
  • R 1 cannot be carbamoylmethyl, 1-carboxy-1-phenylmethyl or straight-chain C 1-6 alkyl, that is substituted in the 1-position with -COOH or -COO-C 1-6 -alkyl, and if R is straight-chain C 1-6 -alkyl, which is in the 1-position with -COOH or
  • R 6 and / or R 7 or R 6 and R 8 cannot be fluorine, chlorine or bromine and R 4 -R 8 in each case
  • R 6 and R 7 are not methyl or simultaneously
  • R 6 or R 7 are not NO 2 and R 4 -R 8 are each hydrogen.
  • the compounds of general formula I also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, the racemates or enantiomers.
  • the substituents are preferably in the 6- and / or 7-position.
  • the substituent R 2 is one or two times the same or different in any position on the alkyl, alkenyl, alkynyl, cycloalkyl, hetaryl or aryl radical.
  • 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, h ⁇ xyl, heptyl, octyl, nonyl, decyl, C 1-6 alkyl radicals being preferred.
  • alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, h ⁇ xyl, heptyl, octyl, nonyl, decyl, C 1-6 alkyl radicals being preferred.
  • Alkenyl contains in particular C 2-6 alkenyl radicals, which can be straight-chain or branched, such as 2-propenyl, 2-butenyl,
  • alkynyl radicals are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl with 2-4 carbon atoms.
  • C 3-7 cycloalkyl is in each case cyclopropyl, cyclobutyl, cyclopentyl,
  • Cyclohexyl and cycloheptyl mean especially C 3-5 cycloalkyl.
  • 5- or 6-membered heteroaromatics with 1-3 nitrogen atoms are suitable as the hetaryl radical, for example pyrazole, imidazole, pyrazine, pyridine, pyrimidine, pyridazine, triazine.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • R 9 and R 10 form a saturated heterocycle together with the nitrogen atom, this means, for example, piperidine, pyrrolidine, morpholine, thiomorpholine or piperazine.
  • R 1 is C 1-12 -alkyl and R 2 COR 3 , R 5 -R 8 are in particular substituents such as NO 2 , NR 9 R 10 , NHCOR 11 , SO 2 R 12 , C 3-7 -cycloalkyloxy, COR 13 , Cyano, CF 3 , C 1-4 alkoxy, optionally substituted imidazole or a fused-on benzene ring.
  • Physiologically compatible salts include salts of organic and inorganic bases such as, for example, the readily soluble alkali and alkaline earth metal salts and also N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, To understand tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.
  • organic and inorganic bases such as, for example, the readily soluble alkali and alkaline earth metal salts and also N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, To understand tris-hydroxy-methyl-amino-methane, aminopropan
  • the compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their affinity for the quisqualate receptors.
  • the compounds according to the invention are suitable for the treatment of diseases which are caused by hyperactivity of 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 radioactively labeled specific agonist (RS) ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) from displace the AMPA receptors, they are particularly suitable for
  • AMPA receptor Treatment of diseases which can be influenced via the receptors of excitatory amino acids, in particular the AMPA receptor, such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, epilepsy, hypoglycemia, psychoses, muscle stiffness,
  • the invention also includes the combination of the compounds according to the invention with dopamine agonists such as lisuride, terguride, bromocriptine, amantadine derivatives, memantine and its derivatives and the compounds described in EP-A-351 352 and the combination with L-DOPA or L-DOPA and Benserazide.
  • dopamine agonists such as lisuride, terguride, bromocriptine, amantadine derivatives, memantine and its derivatives and the compounds described in EP-A-351 352 and the combination with L-DOPA or L-DOPA and Benserazide.
  • the dose of the conventional drug to be administered is reduced and its effect is synergistically increased.
  • the compounds are potent, centrally acting AMPA antagonists. They are therefore suitable for the treatment of illnesses that are associated with a disturbance in the glutamate metabolism. They are particularly suitable for the treatment of cerebral ischemia of various origins, Parkinson's disease and also of the other diseases mentioned in the previous paragraph.
  • the compounds according to the invention 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 water, gelatin, gum arabic, milk sugar, starch, Contains magnesium stearate, talc, vegetable oils, polyalkylene glycols etc.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions. Suspensions or emulsions are present. 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, it being possible for the dose to be administered as a single dose to be administered once or divided into 2 or more daily doses.
  • R 1 , R 5 , R 6 , R 7 and R 8 have the above meaning, with reactive
  • R 4 , R 5 , R 6 , R 7 and R 8 have the above meaning, reacted with R 1 -X to give compounds of the formula I and, if desired, saponifying the ester group or esterifying or amidating the acid group or the
  • U and V are leaving groups and R 11 is hydrogen, cyano or COOC 1-6 alkyl and R 12 is hydrogen or C 1-6 alkyl, converted to an imidazole derivative or separating the isomers or forming the salts.
  • the cyclization of the compounds of formula II with a reactive oxalic acid derivative takes place in one or two stages.
  • the two-stage process is to be regarded as preferred, in which the diamine with an oxalic acid derivative such as the oxal ester half chloride in polar solvents such as dimethylformamide or cyclic or acyclic ethers or halogenated hydrocarbons, for example tetrayhdrofuran, diethyl ether or methylene chloride in the presence of a base such as organic amines, for example triethylamine, pyridine, Hünig -Base or Diethylaminopyridin is implemented.
  • polar solvents such as dimethylformamide or cyclic or acyclic ethers or halogenated hydrocarbons, for example tetrayhdrofuran, diethyl ether or methylene chloride
  • a base such as organic amines, for example triethylamine
  • the subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acidic environment, and alcohol can be added to the solvent.
  • the substituents R 1 and R 4 are introduced by the customary alkylation methods, by adding the quinoxalinedione with R 1 - or R 4 ' -X, where X is tosylate, mesylate or in particular triflate or halogen, in the presence of bases at room temperature or higher Temperature in aprotic solvents.
  • the anion can also be generated before R 1 - or R 4 ' X are added.
  • bases are, for example
  • Alkali compounds such as potassium carbonate, sodium hydroxide, alkali alcoholates and particularly suitable metal hydrides such as sodium hydride.
  • the alkali compounds can possibly also be reacted under phase transfer conditions. You get mixtures of compounds with the
  • Suitable solvents for the reaction are aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone but also cyclic ethers such as dioxane or tetrahydrofuran. If in process variant b) the reaction is carried out with 2 mol R -X under otherwise analogous reaction conditions, the substituents R 1 and R 4 are introduced simultaneously.
  • the subsequent saponification of an ester 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 high concentrated aqueous hydrochloric acid in solvents such as trifluoroacetic acid or alcohols.
  • acids such as high concentrated aqueous hydrochloric acid in solvents such as trifluoroacetic acid or alcohols.
  • Phosphonic acid esters are preferably hydrolyzed by heating in highly concentrated aqueous acids such as concentrated hydrochloric acid or by treatment with trimethylsilyl bromide and subsequent treatment with water.
  • esterification of the carboxylic acid or phosphonic acid takes place in a manner known per se with the corresponding alcohol in acid or in the presence of an activated acid derivative.
  • suitable acid derivatives are acid chloride, imidazolide or anhydride.
  • Phosphonic acids can be reacted with orthoesters of the corresponding alcohol.
  • the reaction with the adduct of dicyclohexylcarbodiimide and the corresponding alcohol also leads to the ester.
  • Methyl esters can be prepared by reaction with diazomethane.
  • 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 nitro group is reduced to the amino group catalytically in polar solvents at room temperature or elevated temperature below Hydrogen pressure.
  • Metals such as Raney nickel or noble metal catalysts such as palladium or platinum are optionally present as catalysts
  • Suitable for carriers instead of hydrogen, ammonium formate can also be used in a known manner.
  • Reducing agents such as tin (II) chloride or titanium (III) chloride can be used as well as complex metal hydrides, possibly in the presence of heavy metal salts. It may be advantageous to introduce the ester group before the reduction.
  • alkylation can be carried out using alkyl halides, for example, using customary methods. Reductive amination with an aldehyde and reducing agents such as sodium cyanoborohydride is also possible.
  • the acylation takes place according to the known methods. For example, it is reacted in an aqueous medium in the presence of a base with the corresponding acid anhydrides or acid halides.
  • the cyano group can be introduced using the Sandmeyer reaction; for example, the diazonium salts formed as intermediates from the amino compounds with nitrites can be reacted with cyanides in the presence of Cu-I cyanide or with K 2 Ni (CN) 4 .
  • the introduction of the halogens chlorine, bromine or iodine via the amino group cannot be aqueous or aqueous; for example, according to Sandmeyer, aqueous, by reacting the diazonium salts formed intermediately with nitrites with Cu (I) chloride or Cu (I) bromide in the presence of the corresponding acid, hydrochloric acid or hydrobromic acid, or with potassium iodide.
  • the hydrochloride is reacted in non-aqueous manner in a known manner with i-amyl nitrite and, for example, methylene iodide or bromoform in aprotic solvents such as dimethylformamide.
  • Fluorine can be introduced, for example, through the Balz-Schiemann reaction of diazonium tetrafluoroborate.
  • the reaction of the amino group with 2-azabutadienes of the formula IV to the imidazole derivatives takes place in the presence of acids at temperatures from 0 to 150 ° C.
  • the escape groups U and V can be the same or different; C 1-3 dialkylamines, such as dimethyl,
  • the reaction is carried out, for example, in such a way that the amine derivative and the azadiene are initially in an organic acid, such as, for example, formic acid, acetic acid, propionic acid or trifluoroacetic acid
  • organic acid such as, for example, formic acid, acetic acid, propionic acid or trifluoroacetic acid
  • Reaction mixture (up to about 120 ° C) is heated.
  • the acid can be used both as a reactant and as
  • solvents such as alcohols, ethers, ketones, esters such as ethyl acetate, hydrocarbons such as toluene or halogenated hydrocarbons such as carbon tetrachloride can also be added.
  • the amount of acid can be varied within wide limits, but is used in excess. A 3-10-fold excess of acid, based on the amine and the azadiene, is preferably selected.
  • the isomer mixtures can be converted into diastereomers such as e.g. by conventional methods such as crystallization, chromatography or conversion. Salt formation can be separated into the enantiomers or E / Z isomers.
  • the salts are prepared in a customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of an alkali metal or alkaline earth metal compound, which is optionally in solution, and separating off the precipitate or working up the solution in a conventional manner.
  • the compounds of formula II can be prepared by preparing 2,4-dinitroarylamines according to the Sanger method, in that o-halo-nitroaromatics, preferably o-fluoro-nitroaromatics such as dinitrofluorobenzene in aqueous solution with amino acid derivatives in the presence of a base like sodium carbonate or Sodium bicarbonate at temperatures between 0 ° C to reflux and then reduced.
  • o-halo-nitroaromatics preferably o-fluoro-nitroaromatics such as dinitrofluorobenzene in aqueous solution with amino acid derivatives in the presence of a base like sodium carbonate or Sodium bicarbonate at temperatures between 0 ° C to reflux and then reduced.
  • This reaction can also be applied to other substituted 2-nitrohalogen compounds.
  • Diarylamino compounds can also be obtained by Ulimann's reaction of dinitrochlorobenzene with an aromatic amine.
  • High-boiling solvents such as dimethylform
  • Enantiomer separation can be carried out on the final stage or in the intermediate stages by optically active auxiliary bases such as e.g. Brucine or 1-phenethylamine take place or also by chromatography over optically active carrier materials.
  • optically active auxiliary bases such as e.g. Brucine or 1-phenethylamine take place or also by chromatography over optically active carrier materials.
  • the enantiomers can also be synthesized
  • Aminoethylphoshonic acid added dropwise in 10 ml of water and 600 mg of sodium carbonate. The mixture is stirred at temperature for 1.5 hours. After the ethanol has been distilled off, the mixture is extracted against acetic acid. The aqueous phase is mixed with 200 mg of imidazole and heated to 110 ° C. for 2 hours. Then another 200 mg of imidazole are added and the mixture is heated to 110 ° C. for 2 hours. It is acidified with 4N hydrochloric acid, suctioned off from the undissolved and the filtrate washed with ethyl acetate. The aqueous phase is concentrated and boiled with ethanol.
  • the hydrochloride is placed well dried in 10 ml of dimethylformamide and 4 ml of methylene iodide and 0.6 ml of i-amyl nitrite are added in succession. After 2 hours at 80 ° C bath temperature, everything has dissolved. It is concentrated in vacuo at the Kugelrohr and the residue is silanized

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Abstract

Des dérivés de quinoxaline répondent à la formule (I), dans laquelle R1 désigne alkyle C1-12 substitué par R2, alcényle C2-12 substitué par R2, alcinyle C2-12 substitué par R2, cycloalkyle C3-7 substitué par R2, -(CH2)n-C6-12-aryle substitué par R2 dans le résidu aryle ou alkyle, ou -(CH2)n-hétaryle substitué par R2 dans le résidu hétaryle ou alkyle; R4 désigne hydrogène, alkyle C1-12 substitué par R2, alcényle C2-12 substitué par R2, alcényle C2-12 substitué par R2, (CH2)n-C6-12-aryle substitué par R2 dans le résidu aryle ou alkyle, ou -(CH2)n-hétaryle, substitué par R2 dans le résidu hétaryle ou alkyle; R5, R6, R7 et R8 sont identiques ou différents et désignent hydrogène, halogène, nitro, NR9R10, NHCOR11, SO2R12, cycloalkyloxy C3-7, COR13, cyano, CF3, alkyle C1-6, alkoxy C1-4 ou imidazole éventuellement substitué par cyano, alkyle C1-4 ou -COO-C1-6-alkyle; ou bien R5 et R6 ou R7 et R8 désignent un cycle benzénique condensé, et R2 désigne -CO-R3, ou -PO-XY et est présent une ou deux fois sous des formes identiques ou différentes. L'invention concerne également la préparation de ces composés et leur utilisation dans des médicaments.
PCT/DE1992/000895 1991-10-26 1992-10-25 Derives de quinoxaline ayant une affinite pour les recepteurs de quisqualate WO1993008173A1 (fr)

Priority Applications (8)

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CZ19931387A CZ286351B6 (cs) 1991-10-26 1992-10-25 Deriváty chinoxalinu, způsob jejich výroby, jejich použití v léčivech a farmaceutický prostředek tyto látky obsahující
PL92299929A PL171125B1 (pl) 1991-10-26 1992-10-25 Sposób wytwarzania nowych pochodnych chinoksaliny PL PL PL PL
KR1019930701948A KR100262371B1 (ko) 1991-10-26 1992-10-25 퀴스퀄레이트 수용체에 대한 친화성이 있는 퀴녹살린 유도체
AU28894/92A AU664212B2 (en) 1991-10-26 1992-10-25 Quinoxaline derivates with affinity for quisqualate-receptors
JP50735393A JP3258008B2 (ja) 1991-10-26 1992-10-25 キノキサリン誘導体、その製造および医薬中での使用
SK727-93A SK281518B6 (sk) 1991-10-26 1992-10-25 Deriváty chinoxalínu, spôsob ich výroby a ich použitie v liečivách
FI932959A FI932959A0 (fi) 1991-10-26 1993-06-24 Kinoxalin derivat, deras framstaellning och anvaendning i laekemedel
NO932116A NO304693B1 (no) 1991-10-26 1993-06-25 Kinoksalinderivater med affinitet for quisqualatreseptorer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE4135871A DE4135871A1 (de) 1991-10-26 1991-10-26 Chinoxalinderivate, deren herstellung und verwendung in arzneimitteln
DEP4135871.6 1991-10-26
DEP4224200.2 1992-07-17
DE4224200 1992-07-17

Publications (1)

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WO1993008173A1 true WO1993008173A1 (fr) 1993-04-29

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PCT/DE1992/000895 WO1993008173A1 (fr) 1991-10-26 1992-10-25 Derives de quinoxaline ayant une affinite pour les recepteurs de quisqualate

Country Status (17)

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EP (1) EP0565683A1 (fr)
JP (1) JP3258008B2 (fr)
KR (1) KR100262371B1 (fr)
CN (1) CN1038840C (fr)
AU (1) AU664212B2 (fr)
CA (1) CA2099270A1 (fr)
CZ (1) CZ286351B6 (fr)
FI (1) FI932959A0 (fr)
HU (1) HUT64756A (fr)
IL (1) IL103538A (fr)
NO (1) NO304693B1 (fr)
NZ (1) NZ244896A (fr)
PL (1) PL171125B1 (fr)
PT (1) PT101004B (fr)
RU (1) RU2117663C1 (fr)
SK (1) SK281518B6 (fr)
WO (1) WO1993008173A1 (fr)

Cited By (16)

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WO1994025470A1 (fr) * 1993-04-28 1994-11-10 Schering Aktiengesellschaft Derives de benzo[f]quinoxalinedione, leur fabrication et leur utilisation dans des medicaments
WO1994025469A1 (fr) * 1993-04-28 1994-11-10 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur fabrication et leur utilisation dans des medicaments
EP0647137A1 (fr) * 1992-06-22 1995-04-12 The Regents Of The University Of California Antagonistes des recepteurs de glycine et leur utilisation
US5504085A (en) * 1991-09-20 1996-04-02 Novo Nordisk A/S Triazolo quinoxalines and their preparation and use
WO1996012725A1 (fr) * 1994-10-25 1996-05-02 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments
WO1996012724A1 (fr) * 1994-10-25 1996-05-02 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments
WO1997019066A1 (fr) * 1995-11-24 1997-05-29 Schering Aktiengesellschaft Nouveaux derives de quinoxaline dione, leur preparation et leur utilisation dans des medicaments
EP0784054A1 (fr) * 1994-09-27 1997-07-16 Yamanouchi Pharmaceutical Co. Ltd. Derive de 1,2,3,4-tetrahydroquinoxalindione
WO1999000384A1 (fr) * 1997-06-27 1999-01-07 Schering Aktiengesellschaft Nouveaux derives de dione de quinoxaline, leur preparation et leur utilisation dans des medicaments
EP0900567A2 (fr) * 1997-09-05 1999-03-10 Pfizer Products Inc. Quinazoline-4-ones antagonistes d'AMPA pour le traitement des dyscinésies associées à la thérapie aux agonistes de la dopamine
EP0900568A2 (fr) * 1997-09-05 1999-03-10 Pfizer Products Inc. Antagonistes d'AMPA pour le traitement des dyscinésies associées à la thérapie aux agonistes de la dopamine
EP0919554A1 (fr) * 1996-06-06 1999-06-02 Yamanouchi Pharmaceutical Co. Ltd. Derives de quinoxalinedione a substitution imidazole
US6015800A (en) * 1997-09-03 2000-01-18 Warner-Lambert Company Substituted quinoxaline-2-ones as glutamate receptor antagonists
US6110911A (en) * 1995-06-07 2000-08-29 Warner-Lambert Company Cyclic amine derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists
EP0783495B1 (fr) * 1994-09-24 2002-02-27 Pfizer Limited Derives de quinoxaline utiles en therapie
EP1625134A2 (fr) * 2003-05-17 2006-02-15 QUEEN MARY & WESTFIELD COLLEGE Detecteurs fluorescents au phosphonate substitue et leur utilisation

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DE4428152A1 (de) * 1994-06-22 1996-01-04 Basf Ag Neue Amido-chinoxalindione, ihrer Herstellung und Verwendung
DE19521058A1 (de) * 1995-06-09 1996-12-12 Basf Ag Verfahren zur Herstellung von Aromaten enthaltenden Polyetherpolyolen
DE19624808A1 (de) 1996-06-21 1998-01-02 Basf Ag Pyrrolylchinoxalindione, ihre Herstellung und Verwendung
FR2769309B1 (fr) 1997-10-08 2001-06-15 Oreal Composition de teinture d'oxydation des fibres keratiniques comprenant un derive d'aminoacide en tant que base d'oxydation et nouveaux derives d'aminoacides

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EP0118982A1 (fr) * 1983-02-01 1984-09-19 Sumitomo Chemical Company, Limited Composés organo-phosphorés de la quinoxalinone, leur production et utilisation
EP0315959A2 (fr) * 1987-11-10 1989-05-17 Novo Nordisk A/S Quinoxalines et leur préparation et application
WO1991013878A1 (fr) * 1990-03-16 1991-09-19 Novo Nordisk A/S Composes de quinoxaline, preparation et utilisation

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EP0118982A1 (fr) * 1983-02-01 1984-09-19 Sumitomo Chemical Company, Limited Composés organo-phosphorés de la quinoxalinone, leur production et utilisation
EP0315959A2 (fr) * 1987-11-10 1989-05-17 Novo Nordisk A/S Quinoxalines et leur préparation et application
WO1991013878A1 (fr) * 1990-03-16 1991-09-19 Novo Nordisk A/S Composes de quinoxaline, preparation et utilisation

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5504085A (en) * 1991-09-20 1996-04-02 Novo Nordisk A/S Triazolo quinoxalines and their preparation and use
EP0647137A4 (fr) * 1992-06-22 1998-09-16 Univ California Weber Eckard Antagonistes des recepteurs de glycine et leur utilisation.
EP0647137A1 (fr) * 1992-06-22 1995-04-12 The Regents Of The University Of California Antagonistes des recepteurs de glycine et leur utilisation
AU683258B2 (en) * 1993-04-28 1997-11-06 Schering Aktiengesellschaft Benzo(F)quinoxalindione derivatives, their preparation and their use in drugs
US5955461A (en) * 1993-04-28 1999-09-21 Schering Aktiengesellschaft Quinoxalinedione derivatives, their production and use in pharmaceutical agents
US5710138A (en) * 1993-04-28 1998-01-20 Schering Aktiengesellschaft Benzo f!quinoxalinedione derivatives, their production and use in pharmaceutical agents
US5750525A (en) * 1993-04-28 1998-05-12 Schering Aktiengesellschaft Quinoxalinedione derivatives, their production and use in pharmaceutical agents
WO1994025469A1 (fr) * 1993-04-28 1994-11-10 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur fabrication et leur utilisation dans des medicaments
WO1994025470A1 (fr) * 1993-04-28 1994-11-10 Schering Aktiengesellschaft Derives de benzo[f]quinoxalinedione, leur fabrication et leur utilisation dans des medicaments
EP0783495B1 (fr) * 1994-09-24 2002-02-27 Pfizer Limited Derives de quinoxaline utiles en therapie
EP0784054A1 (fr) * 1994-09-27 1997-07-16 Yamanouchi Pharmaceutical Co. Ltd. Derive de 1,2,3,4-tetrahydroquinoxalindione
EP0784054A4 (fr) * 1994-09-27 1998-01-07 Yamanouchi Pharma Co Ltd Derive de 1,2,3,4-tetrahydroquinoxalindione
US6096743A (en) * 1994-09-27 2000-08-01 Yamanouchi Pharmaceuticals Co., Ltd. 1,2,3,4-tetrahydroquinoxalinedione derivative
WO1996012725A1 (fr) * 1994-10-25 1996-05-02 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments
WO1996012724A1 (fr) * 1994-10-25 1996-05-02 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments
US6143733A (en) * 1994-10-25 2000-11-07 Schering Aktiengesellschaft Quinoxalinedione derivatives, their production and use in pharmaceutical agents
US6110911A (en) * 1995-06-07 2000-08-29 Warner-Lambert Company Cyclic amine derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists
AU720083B2 (en) * 1995-11-24 2000-05-25 Schering Aktiengesellschaft New quinoxalindione derivatives, their production and use in pharmaceutical agents
WO1997019066A1 (fr) * 1995-11-24 1997-05-29 Schering Aktiengesellschaft Nouveaux derives de quinoxaline dione, leur preparation et leur utilisation dans des medicaments
EP0919554A1 (fr) * 1996-06-06 1999-06-02 Yamanouchi Pharmaceutical Co. Ltd. Derives de quinoxalinedione a substitution imidazole
EP0919554A4 (fr) * 1996-06-06 2002-05-29 Yamanouchi Pharma Co Ltd Derives de quinoxalinedione a substitution imidazole
WO1999000384A1 (fr) * 1997-06-27 1999-01-07 Schering Aktiengesellschaft Nouveaux derives de dione de quinoxaline, leur preparation et leur utilisation dans des medicaments
US6015800A (en) * 1997-09-03 2000-01-18 Warner-Lambert Company Substituted quinoxaline-2-ones as glutamate receptor antagonists
EP0900568A2 (fr) * 1997-09-05 1999-03-10 Pfizer Products Inc. Antagonistes d'AMPA pour le traitement des dyscinésies associées à la thérapie aux agonistes de la dopamine
EP0900567A2 (fr) * 1997-09-05 1999-03-10 Pfizer Products Inc. Quinazoline-4-ones antagonistes d'AMPA pour le traitement des dyscinésies associées à la thérapie aux agonistes de la dopamine
EP0900568A3 (fr) * 1997-09-05 2001-05-02 Pfizer Products Inc. Antagonistes d'AMPA pour le traitement des dyscinésies associées à la thérapie aux agonistes de la dopamine
EP0900567A3 (fr) * 1997-09-05 2001-05-02 Pfizer Products Inc. Quinazoline-4-ones antagonistes d'AMPA pour le traitement des dyscinésies associées à la thérapie aux agonistes de la dopamine
EP1625134A2 (fr) * 2003-05-17 2006-02-15 QUEEN MARY & WESTFIELD COLLEGE Detecteurs fluorescents au phosphonate substitue et leur utilisation

Also Published As

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FI932959A (fi) 1993-06-24
PT101004A (pt) 1994-01-31
CN1038840C (zh) 1998-06-24
RU2117663C1 (ru) 1998-08-20
JP3258008B2 (ja) 2002-02-18
CA2099270A1 (fr) 1993-04-27
SK72793A3 (en) 1993-10-06
AU664212B2 (en) 1995-11-09
AU2889492A (en) 1993-05-21
CZ138793A3 (en) 1994-01-19
PL171125B1 (pl) 1997-03-28
NZ244896A (en) 1995-07-26
CZ286351B6 (cs) 2000-03-15
IL103538A (en) 2001-07-24
EP0565683A1 (fr) 1993-10-20
NO932344L (no) 1993-06-25
PL299929A1 (en) 1994-04-05
KR100262371B1 (ko) 2000-08-01
PT101004B (pt) 1999-10-29
KR930703271A (ko) 1993-11-29
IL103538A0 (en) 1993-03-15
NO304693B1 (no) 1999-02-01
HU9301877D0 (en) 1993-09-28
JPH06503583A (ja) 1994-04-21
NO932344D0 (no) 1993-06-25
CN1072929A (zh) 1993-06-09
HUT64756A (en) 1994-02-28
SK281518B6 (sk) 2001-04-09
FI932959A0 (fi) 1993-06-24

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