WO1997019066A1 - Nouveaux derives de quinoxaline dione, leur preparation et leur utilisation dans des medicaments - Google Patents

Nouveaux derives de quinoxaline dione, leur preparation et leur utilisation dans des medicaments Download PDF

Info

Publication number
WO1997019066A1
WO1997019066A1 PCT/DE1996/002227 DE9602227W WO9719066A1 WO 1997019066 A1 WO1997019066 A1 WO 1997019066A1 DE 9602227 W DE9602227 W DE 9602227W WO 9719066 A1 WO9719066 A1 WO 9719066A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
acid
alkyl
halogen
tπfluormethyl
Prior art date
Application number
PCT/DE1996/002227
Other languages
German (de)
English (en)
Inventor
Andreas Huth
Martin Krüger
Eckhard Ottow
Dieter Seidelmann
Roland Neuhaus
Herbert Schneider
Lechoslaw Turski
Original Assignee
Schering Aktiengesellschaft
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
Priority to PL96326844A priority Critical patent/PL326844A1/xx
Priority to EE9800163A priority patent/EE9800163A/xx
Priority to NZ330492A priority patent/NZ330492A/en
Priority to JP9519292A priority patent/JP2000500471A/ja
Priority to SK682-98A priority patent/SK68298A3/sk
Priority to IL12453496A priority patent/IL124534A0/xx
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to EP96946000A priority patent/EP0876357A1/fr
Priority to AU18674/97A priority patent/AU720083B2/en
Priority to KR1019980703872A priority patent/KR19990071596A/ko
Publication of WO1997019066A1 publication Critical patent/WO1997019066A1/fr
Priority to IS4740A priority patent/IS4740A/is
Priority to NO982349A priority patent/NO982349L/no

Links

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
    • 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
    • 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
    • A61P25/28—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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

Definitions

  • the invention relates to quinoxalinedione derivatives, their preparation and use in medicaments
  • 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.
  • 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.
  • WO9308173 6-methyl-1-alkyl-substituted chionoxaline-2,3-dionondvate
  • EPA-03771 12 6-methyl- and 7-ethyl] -l-hydroxy-chionoxaline-2,3-dione are described.
  • the compounds according to the invention have the formula I.
  • R6 and R ⁇ are identical or different and are hydrogen, halogen, NO2, cyano, NR 16R 17 -COR ' 4 , OR ⁇ 8 , optionally substituted aryl, optionally substituted hetaryl, C j.
  • R 2 is hydrogen or - (CH2) q -R 3
  • R 3 is hydrogen, hydroxy, Cj.g-alkoxy or NR 19 R 20 ,
  • n, m and q each 0, 1, 2 or 3
  • R 8 and R 18 are hydrogen, C 1.5 alkyl optionally substituted by halogen,
  • o and p each 0, 1 or 2
  • R 1 y and R ' 3 are hydrogen, C 6 alkyl or optionally substituted aryl,
  • R 12 , R 14 , R 21 and R 22 OH, C ⁇ _ 6 alkoxy or NR 23 R 24 ,
  • X and Y are identical or different and denote hydroxy, C j .g-alkoxy, C 1.4 alkyl or NR 25 R 26,
  • R 9 and R 10 , R 16 and R 17 , R 19 and R 20 , R 23 and R 24 , R 25 and R 26 are the same or different and are hydrogen, C 1.4 alkyl, aryl or together with the nitrogen atom a 5- Form a 7-membered saturated heterocycle which may contain a further oxygen, sulfur or nitrogen atom and may be substituted or form an unsaturated 5-membered heterocycle which may contain 1-3 N atoms and may be substituted, and their isomers or salts, where R ⁇ is not CF3 or CH3.
  • 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 R ⁇ , R ⁇ and R 7 can be in any position, preferably in the 6- and / or 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, C 1 -C 4 -alkyl radicals being preferred.
  • the alkyl radical is halogenated, it can be present one to more times or perhalogenated.
  • Alkenyl means, for example, Vmyl, 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, 1-butenyl, methallyl.
  • Halogen is to be understood as fluorine, chlorine, bromine and iodine
  • the aryl radical each has 6-12 carbon atoms, such as naphthyl, biphenyl and especially phenyl.
  • Hetaryl means optionally substituted 5-ring heteroaromatics with 1 -2 N, O or S atoms, such as Thiophene, furan, oxazole, thiazole or optionally substituted 6-ring heteroaromatics with 1-3 N atoms such as pyridine, pynmidine, t ⁇ azine, quinoline, isoquinone.
  • Halogen, C 1.4 alkoxy, nitro, trifluoromethyl or C 4 alkyl are suitable as substituents of the aryl and hetaryl radicals, which occur one to three times
  • the heterocycle can be 1-3 times substituted with C 1-4 alkyl or a phenyl, benzyl or benzoyl radical optionally substituted with halogen. Examples include N-methyl-pipcrazine, 2,6-dimethylmorpholine, phenylpiperazine or 4- (4-fluorobenzoyl) -p ⁇ peridin.
  • R5 is alkyl
  • R5 is alkyl
  • R5 may be substituted by -OR 8 , - NR 9 R 10 , SOQ-R '1, COR 12 , optionally substituted aryl or optionally substituted hetaryl
  • the physiologically acceptable salts of organic and inorganic bases are suitable as salts, such as the readily soluble alkali and alkaline earth metal salts and the salts with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1, 6- Hexadiamine, ethanolamm, glucosamine, sarcosine, Se ⁇ noi, Tns-hydroxy-methyl-amino-methane, ammopropanediol, Sovak base, l-Am ⁇ no-2,3,4-butant ⁇ ol
  • physiologically acceptable 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 medicinal products due to their affinity for the AMPA 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, for example, glutamate or aspartate
  • excitatory amino acids such as, for example, glutamate or aspartate
  • RS radioactively labeled 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 the overstimulation of the AMPA receptor.
  • the neurological disorders which can be treated functionally and preventively include, for example, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's chorea , Amyotrophic Lateral Sclerosis and Ohvopontocerebellar Degeneration
  • the compounds 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-part dementia as well as epilepsy and muscle spasticity are examples of the compounds.
  • Psychiatric diseases include anxiety, schizophrenia, migraines, painful conditions, 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 be used 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 ), Pain relievers or anti-emetics are used
  • mice Male NMRI mice weighing 18-22 g were kept under controlled conditions (6:00 am - 6:00 pm light / dark rhythm, with free access to food and water) and their assignment to groups was randomized. The groups consisted of 5 - 16 animals The animals were observed between 8 am and 1 pm
  • AMPA was injected into the left ventricle by freely moving mice.
  • the apphcator consisted of a cannula with a stainless steel device that limits the depth of the injection to 3.2 mm.
  • the apphcator was connected to an injection pump.
  • the injection needle was perpendicular to the surface of the Schadeis introduced according to the coordinates of Montemurro and Dukelow.
  • the animals were observed up to the occurrence of clonic or tonic cramps up to 180 sea.
  • the clonic movements longer than 5 sea. persisted were paid as cramps.
  • the beginning of the clonic convulsions was used as the end point for the determination of the convulsive threshold.
  • the dose which was necessary to increase or decrease the convulsive threshold by 50% (THRD50) was determined in 4-5 experiments.
  • the THRD50 and the confidence limit was determined in a regression analysis
  • 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, dragees, 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. For example, compounds of the formula I are obtained by
  • R 1 ' R 5 , R 6 and R 7 have the above meaning, cyclized with oxalic acid or reactive oxalic acid derivatives and if desired subsequently saponifying the ester group or esterifying or amidating the acid group or introducing a tetrazole group or alcohols to aldehydes or thioethers to sulfoxides or Sulfones or sulfoxides are oxidized to sulfones, or aldehydes are converted into oximes or nitrones, or the isomers are separated or the salts are formed
  • R 1 has the above meaning and R ⁇ , R ° and R 7 are a leaving group or R * , R ° or R 7 , a leaving group is replaced by SR 1 3 or by optionally substituted C2-6-alkenyl and, if desired, then the double bond the alkenyi group is hydrogenated or cleaves oxidatively, converts the aldehyde to an alkenyl compound or reduces the aldehyde to alcohol; the OH group is converted into a leaving group and substituted nucleophilically and then the nitro group is reduced
  • the cyclization to compounds of the formula I is carried out in a known manner with oxalic acid in one stage in an acidic environment or with a reactive oxalic acid derivative in one or two stages.
  • the two-stage process in which the diamine is treated with an oxalic acid derivative such as oxal ester half-chloride or reactive oxalic acid derivatives such as z Imidazohden in polar solvents such as cyclic or acychic ethers or halogenated Hydrocarbons, for example tetrahydrofuran, diethyl ether or methylene chloride, or also in water according to Schotten Baumann in the presence of a base such as organic amines, for example triethylamine, pyridine, Hunig base or dimethylaminopy ⁇ din, or even sodium carbonate or sodium hydroxide solution.
  • the subsequent cyclization can be basic or acidic, but preferably in acidic environment can be carried out, whereby solution mediators such as
  • 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
  • nucleophilic substitution for the introduction of the -SR 1 3 group is carried out with the corresponding thiol in the presence of bases such as, for example, alkali or alkaline earth hydroxides or carbonates in polar protic or aprotic solvents such as, for example, water, alcohols or dimethylformamide
  • alkenyl compounds is carried out with the catalysis of transition metal complexes such as Pd (0), for example palladium tetrakist ⁇ phenylphosphine or Pd ( 2+ ⁇ such as Pallad ⁇ um-b ⁇ sT ⁇ -o-tolylphosph ⁇ n-d ⁇ chlo ⁇ d or N ⁇ ckel (O) according to methods known from the nature of the base, and is given by means of the presence of known methods an activating electron-withdrawing group such as nitro, cyano, trifluoromethyl, preferably in the o-position
  • transition metal complexes such as Pd (0), for example palladium tetrakist ⁇ phenylphosphine or Pd ( 2+ ⁇ such as Pallad ⁇ um-b ⁇ sT ⁇ -o-tolylphosph ⁇ n-d ⁇ chlo ⁇ d or N ⁇ ckel (O)
  • Pd (0) for example palladium tetrakist ⁇ phenylphosphine or
  • Suitable nucleophiles are, for example, the corresponding boronic acids or boranes or organotin compounds, organozinc compounds, G ⁇ gnard compounds or alkenyls as such.
  • 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 can be used as bases, inorganic bases such as alkali or alkaline earth metal hydroxides or carbonates or organic bases such as cyclic, alicyclic and aromatic amines, such as pyridine, triethylamine, DBU, Hunig base, optionally with the addition of water
  • the oxidative cleavage of the alkenyl compounds to form the aldehyde can be carried out by methods known from the literature. Ozonization in solvents such as, for example, halogenated hydrocarbons or alcohols or mixtures thereof at temperatures of -78 ° C. is preferred to room temperature.
  • the ozonide which forms is reductively cleaved to form the aldehyde by trapping with thiourea, T ⁇ alkylphosphiten or preferably with T ⁇ arylphosphinen
  • the aldehyde can be subjected to olefinization reactions such as a Petersonolefinung, a Wittig or Wittig-Horner reaction to produce an optionally substituted alkenyl compound.
  • olefinization reactions such as a Petersonolefinung, a Wittig or Wittig-Horner reaction to produce an optionally substituted alkenyl compound.
  • the aldehyde with the previously generated anion for example a correspondingly substituted phosphonium salt or phosphonic acid ester in Solvents such as toluene, tetrahydrofuran, diethyl ether or dimethoxyethane implemented.
  • bases are e.g.
  • the aldehyde can be reduced to alcohol by processes known from the literature.
  • the reduction is preferably carried out using complex metal hydrides, such as, for example, sodium amide, in solvents such as alcohol
  • the hydroxyl group can be converted into escape groups such as chloride, bromide, iodide, triflate, mesylate or tosylate using methods known from the literature and preferably converted to chloride with tosylchloride in the presence of bases such as, for example, triethylamine, ethyldusopropylamine or dimethylaminopyrin in solvents such as halogenated hydrocarbons or ethers
  • nucleophilic substitution is carried out by nucleophiles such as amines or thiols in solvents such as alcohols, halogenated hydrocarbons or ketones or without solvents, optionally with the addition of a base such as alkali metal or alkaline earth metal hydroxide or carbonate or else organic bases such as, for example, triethylamine, ethyldnsopropylamine or dimethylaminopyridine
  • the nitro group is reduced in the usual way 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 alkenyi group takes place in the usual way catalytically and then usually takes place together with the reduction of the nitro group
  • oxidation of thioethers to sulfoxides or sulfones is carried out by methods known from the literature.
  • sulfoxides are obtained selectively by oxidation with sodium pirate iodate in a mixture of methanol and water.
  • Sulfones can either be from the appropriate Sulfoxides or from the thioethers by oxidation with Nat ⁇ umperjodat in a mixture of carbon tetrachloride, acetonitrile and water are prepared with catalysis by ruthenium (III)
  • the optionally subsequent saponification of an ester group can be carried out in a basic or, preferably, acidic manner by hydrolyzing at elevated temperature to the boiling point of the reaction mixture in the presence of acids such as highly concentrated aqueous hydrochloric acid, if appropriate in solvents such as trifluoroacetic acid or alcohols.
  • acids such as highly concentrated aqueous hydrochloric acid, if appropriate in solvents such as trifluoroacetic acid or alcohols.
  • Phosphonic acid esters are preferably heated by highly concentrated aqueous acids such as, for example, concentrated hydrochloric acid, optionally with the addition of an alcohol or by treatment with methyl methyl silide in inert solvents such as, for example Acetonitrile and subsequent treatment with water hydrolyzed
  • esterification of the carboxylic acid or phosphonic 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 activated acid derivatives are, for example, acid chloride, imidazide or anhydride.
  • the esterification can be achieved by reaction with orthoesters, if appropriate with the addition of catalysts such as p-toluenesulfonic acid
  • amidation takes place on the free acids or on their reactive derivatives such as, for example, acid chlorides, mixed anhydrides, inndazohden or azides by reaction with the corresponding amines at room temperature
  • the tetrazole can be introduced by reacting the corresponding nit ⁇ les m ⁇ t_e ⁇ nem azide such as, for example, t ⁇ methylsilylazide, hydrochloric acid or sodium azide, if appropriate with the addition of a proton source such as, for example, ammonium chloride or t ⁇ ethylammonium chloride in polar solvents such as dimethylformamide, dimethylacetrohmidone or N-methyl solvent
  • the oxidation of an alcohol can be carried out by methods known from the literature.
  • the Jones variant (chromium oxide in sulfuric acid) is preferably used in solvents such as acetone
  • the aldehyde is converted to oximes and nitrones using methods known from the literature with the hydrochlorides of the corresponding hydroxylammes, optionally with the addition of a Base preferably in solvents such as alcohols or aromatic hydrocarbons or mixtures thereof
  • 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 separating the precipitate or working up the solution in the customary manner
  • the collected aqueous phase is acidified to pH 1 with 4N hydrochloric acid and extracted three times with 100 ml of ethyl acetate each time.
  • the organic phase is washed with water, dried, filtered and concentrated. 6.85 g (68% of theory) N- (2 - N ⁇ tro-4-t ⁇ fluormethyl-5-chlorophenyl) -am ⁇ nomethanphosphonsaure of melting point 207.3 ⁇ C
  • N- (2-nitro-4-t ⁇ fluoromethyl-5-chlorophenyl) aminomethanephosphonic acid are mixed in 190 ml of orthoformate with 190 mg of p-toluenesulfonic acid and heated to a bath temperature of 150 ° C. for 3 hours. After evaporation in a vacuum, the mixture is in 25 ml Water taken up and extracted three times with 25 ml of ethyl acetate. The collected ethyl acetate phase is washed once with water, dried, filtered and concentrated. 2 g (> 100% of theory) of N- (2-nitro-4-fluorofluoromethyl-5-chlorophenyl) are obtained. -am ⁇ nomethanphosphonsaured ⁇ ethylester
  • N - [(2-nitro-4-trifluoromethyl-5-styryl) phenyl] aminomethanephosphonic acid ethers are dissolved in 100 ml of ethanol and hydrogenated with 2 g of Raney nickel at room temperature and normal pressure. After suctioning off the catalyst over diatomaceous earth and concentration of the filtrate, 885 mg of N- (2-amino-4-t ⁇ fluoromethyl-5-phenethyl) phenyl are obtained aminomethanephosphonate, which are used in the next step without further purification
  • N- (2-nitro-4-trifluoromethyl-5-chloromethyl) phenyl-aminomethanephosphonic acid diethyl ester are first mixed with 107 mg of potassium carbonate in 10 ml of ethanol under argon and then dropwise with 0, 12 ml of ethyl mercaptan. The mixture is stirred at room temperature for 1.5 hours. It is diluted with water, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is concentrated and the residue is chromatographed on silica gel using ethyl acetate as the eluent. 460 mg of diethyl N- (2-nitro-4-trifluoromethyl-5-ethylth ⁇ omethyl) -phenylaminomethanephosphonate are obtained.
  • 220mg [(6-trifluoromethyl-7-phenylethyl-1, 2,3,4-tetrahydrochmoxalion-2,3-dionone) - 1 yl] - methanephosphonic acid diethyl ester are heated in 20 ml of concentrated hydrochloric acid for 3 hours at a bath temperature of 120 ° C. It is concentrated and you get 200mg [(6-T ⁇ fluormethyl-7-phenylethyl-l, 2,3,4-tetrahydrochionoxane-2,3-dion) -lyl] methanephosphonic acid with a melting point of 260 ° C.
  • 650mg [(6-trifluoromethyl-7-hydroxymethyl-l, 2,3,4-tetrahydroquinoxaline-2,3-dione) -lyl] - methanephosphonic acid diethyl ester are placed in 10 ml acetone and mixed with 1.2 ml Jones reagent (made from 26, 7g chromium trioxide, 23ml concentrated sulfuric acid made up to 100ml with water) stirred for 4h at room temperature. Then 3 ml of isopropanol is added and 10 minutes. stirred. It is then concentrated and distributed in ethyl acetate: water. The organic phase is dried, filtered and concentrated.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurosurgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouveaux dérivés de quinoxaline dione de formule (I), dans laquelle R?1, R5, R6 et R7¿ ont la signification donnée dans la description, leur préparation et leur utilisation dans des médicaments.
PCT/DE1996/002227 1995-11-24 1996-11-15 Nouveaux derives de quinoxaline dione, leur preparation et leur utilisation dans des medicaments WO1997019066A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
EE9800163A EE9800163A (et) 1995-11-24 1996-11-15 Uued kinoksaliindiooni derivaadid, nende valmistamine ja ravimitena kasutamine
NZ330492A NZ330492A (en) 1995-11-24 1996-11-15 New quinoxalindione derivatives, their preparation and use in medicaments
JP9519292A JP2000500471A (ja) 1995-11-24 1996-11-15 新規のキノキサリンジオン誘導体、その製造および薬剤中での使用
SK682-98A SK68298A3 (en) 1995-11-24 1996-11-15 New quinoxalindione derivatives, their preparation and use in medicaments
IL12453496A IL124534A0 (en) 1995-11-24 1996-11-15 Quinoxalinedione derivatives pharmaceutical compositions containing the same and a process for the production thereof
PL96326844A PL326844A1 (en) 1995-11-24 1996-11-15 Novel derivatives of quinosalinodione, their production and implementation in drugs
EP96946000A EP0876357A1 (fr) 1995-11-24 1996-11-15 Nouveaux derives de quinoxaline dione, leur preparation et leur utilisation dans des medicaments
AU18674/97A AU720083B2 (en) 1995-11-24 1996-11-15 New quinoxalindione derivatives, their production and use in pharmaceutical agents
KR1019980703872A KR19990071596A (ko) 1995-11-24 1996-11-15 신규한 퀴녹살린디온 유도체, 그의 제조 방법및 약제에서의 용도
IS4740A IS4740A (is) 1995-11-24 1998-05-13 Nýjar kínoxalindíón afleiður, framleiðsla þeirra og notkun í læknislyf
NO982349A NO982349L (no) 1995-11-24 1998-05-22 Nye kinoksalindionderivater, deres fremstilling og anvendelse i legemidler

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19545251.8 1995-11-24
DE19545251A DE19545251A1 (de) 1995-11-24 1995-11-24 Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln

Publications (1)

Publication Number Publication Date
WO1997019066A1 true WO1997019066A1 (fr) 1997-05-29

Family

ID=7779176

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE1996/002227 WO1997019066A1 (fr) 1995-11-24 1996-11-15 Nouveaux derives de quinoxaline dione, leur preparation et leur utilisation dans des medicaments

Country Status (20)

Country Link
EP (1) EP0876357A1 (fr)
JP (1) JP2000500471A (fr)
KR (1) KR19990071596A (fr)
CN (1) CN1202891A (fr)
AU (1) AU720083B2 (fr)
CA (1) CA2238023A1 (fr)
CZ (1) CZ160498A3 (fr)
DE (1) DE19545251A1 (fr)
EE (1) EE9800163A (fr)
HU (1) HUP9902041A3 (fr)
IL (1) IL124534A0 (fr)
IS (1) IS4740A (fr)
MX (1) MX9804068A (fr)
NO (1) NO982349L (fr)
NZ (1) NZ330492A (fr)
PL (1) PL326844A1 (fr)
SK (1) SK68298A3 (fr)
TR (1) TR199800904T2 (fr)
WO (1) WO1997019066A1 (fr)
ZA (1) ZA969832B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19737446A1 (de) * 1997-08-22 1999-02-25 Schering Ag Verfahren zur Herstellung von Phosphonsäurederivaten
WO2011076946A2 (fr) 2009-12-24 2011-06-30 Universidad Del País Vasco Procédés et compositions pour le traitement de la maladie d'alzheimer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106619953A (zh) * 2016-10-31 2017-05-10 山东省海盟生化科技有限公司 一种用于皮肤病的外用中药组合物及其制备方法和应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO1993008173A1 (fr) * 1991-10-26 1993-04-29 Schering Aktiengesellschaft Derives de quinoxaline ayant une affinite pour les recepteurs de quisqualate
WO1994025469A1 (fr) * 1993-04-28 1994-11-10 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur fabrication et leur utilisation dans des medicaments
DE4439492A1 (de) * 1994-10-25 1996-05-02 Schering Ag Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
DE4439493A1 (de) * 1994-10-25 1996-05-02 Schering Ag Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
DE19519979A1 (de) * 1995-05-24 1996-11-28 Schering Ag Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO1993008173A1 (fr) * 1991-10-26 1993-04-29 Schering Aktiengesellschaft Derives de quinoxaline ayant une affinite pour les recepteurs de quisqualate
WO1994025469A1 (fr) * 1993-04-28 1994-11-10 Schering Aktiengesellschaft Nouveaux derives de quinoxalinedione, leur fabrication et leur utilisation dans des medicaments
DE4439492A1 (de) * 1994-10-25 1996-05-02 Schering Ag Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
DE4439493A1 (de) * 1994-10-25 1996-05-02 Schering Ag Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
DE19519979A1 (de) * 1995-05-24 1996-11-28 Schering Ag Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19737446A1 (de) * 1997-08-22 1999-02-25 Schering Ag Verfahren zur Herstellung von Phosphonsäurederivaten
WO2011076946A2 (fr) 2009-12-24 2011-06-30 Universidad Del País Vasco Procédés et compositions pour le traitement de la maladie d'alzheimer

Also Published As

Publication number Publication date
EP0876357A1 (fr) 1998-11-11
IL124534A0 (en) 1998-12-06
CZ160498A3 (cs) 1998-09-16
KR19990071596A (ko) 1999-09-27
HUP9902041A3 (en) 2000-07-28
NO982349D0 (no) 1998-05-22
NZ330492A (en) 1999-10-28
EE9800163A (et) 1998-12-15
NO982349L (no) 1998-07-01
TR199800904T2 (xx) 1998-08-21
SK68298A3 (en) 1998-12-02
DE19545251A1 (de) 1997-05-28
CN1202891A (zh) 1998-12-23
ZA969832B (en) 1997-06-17
HUP9902041A2 (hu) 2000-04-28
IS4740A (is) 1998-05-13
AU1867497A (en) 1997-06-11
CA2238023A1 (fr) 1997-05-29
MX9804068A (es) 1998-09-30
JP2000500471A (ja) 2000-01-18
PL326844A1 (en) 1998-10-26
AU720083B2 (en) 2000-05-25

Similar Documents

Publication Publication Date Title
EP0696288B1 (fr) Nouveaux derives de quinoxalinedione, leur fabrication et leur utilisation dans des medicaments
DE10021246A1 (de) Substituierte Benzoesäureamide und deren Verwendung als Arzneimittel
EP0041215B1 (fr) Imidazoazolalkénylcarboxamides, intermédiaires pour leur préparation, leur préparation et leur application comme médicaments
EP0888313B1 (fr) Derives de 2,3-benzodiazepine et leur utilisation comme inhibiteurs de recepteurs d'ampa
WO1996012725A1 (fr) Nouveaux derives de quinoxalinedione, leur preparation et leur utilisation dans des medicaments
DE4027278A1 (de) Heterocyclisch substituierte indolsulfonamide
DE4439492A1 (de) Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln
EP1265904B1 (fr) Nouveaux modulateurs (paarm) allosteriques positifs de recepteurs ampa, leur methode de production et leur utilisation comme medicaments
WO1997019066A1 (fr) Nouveaux derives de quinoxaline dione, leur preparation et leur utilisation dans des medicaments
US6136805A (en) Quinoxaline dione derivatives, their production and their use in medicaments
EP0389425B1 (fr) Benzothiopyranylamines
EP0088323B1 (fr) Amides d'acides imidazothiadiazolealcanecarboxyliques, produits intermédiaires pour leur fabrication, leur fabrication et leur application en médicaments
DE3301198A1 (de) N-arylalkylamin-3-propoxypyridin-derivate, verfahren zu ihrer herstellung, sie enthaltende pharmazeutische praeparate und deren verwendung
WO1999000384A1 (fr) Nouveaux derives de dione de quinoxaline, leur preparation et leur utilisation dans des medicaments
EP0696291B1 (fr) Derives de pyrido(1,2,3-de)quinoxaline, leur procede de preparation et leur utilisation dans des medicaments
DE2319872A1 (de) Neue 2-benzoyl-3-amino-pyridine
DD215540A5 (de) Verfahren zur herstellung von benzazepinderivaten
EP0141072A2 (fr) Carboxamides aminoalquilimidazothiadiazoliques, intermédiaires, leur préparation et application comme intermédaires
EP0159964A2 (fr) 3-Thiopyrone substituée
DE19824673A1 (de) Neue 2,3-Benzodiazepinderivate, deren Herstellung und Verwendung als Arzneimittel
DE3134956A1 (de) Imidazolderivate
FR2696457A1 (fr) Dérivés de 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxyde, leur préparation et les médicaments les contenant.

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 96198529.1

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BB BG BR BY CA CN CZ EE GE HU IL IS JP KE KG KP KR KZ LK LR LS LT LV MD MG MK MN MW MX NO NZ PL RO RU SD SG SI SK TJ TM TR TT UA UG US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1996946000

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2238023

Country of ref document: CA

Ref document number: 2238023

Country of ref document: CA

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 1997 519292

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 68298

Country of ref document: SK

Ref document number: PA/a/1998/004068

Country of ref document: MX

Ref document number: PV1998-1604

Country of ref document: CZ

Ref document number: 330492

Country of ref document: NZ

Ref document number: 1998/00904

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 1019980703872

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: PV1998-1604

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1996946000

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1019980703872

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1996946000

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1019980703872

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV1998-1604

Country of ref document: CZ