DE19545251A1 - New quinoxalinedione derivatives, their production and use in pharmaceuticals - Google Patents

Abstract

New quinoxalindone derivatives are disclosed having formula (I), in which R<1>, R<5>, R<6> and R<7> have the meanings given in the description, as well as their preparation and use in medicaments.

Description

The invention relates to quinoxalinedione derivatives, their preparation and use in Medicines.

It is known that quinoxaline derivatives have and have affinity for the quisqualate receptors due to the affinity as a drug for the treatment of diseases of the central Nervous system.

The compounds according to the invention have the formula I.

wherein
R¹ - (CH2) _n -CR²H- (CH₂) _m -Z and
R⁵ C₁-₆-alkyl, which can be substituted with halogen, -OR⁸, -NR⁹R¹⁰, SO₀-R¹¹, COR¹², optionally substituted aryl or optionally substituted hetaryl, C₂-₆- alkenyl, which can be substituted with halogen, -OR⁸, -NR⁹R¹⁰, SO₀-R¹¹, COR¹², optionally substituted aryl or optionally substituted hetaryl may be substituted, SO _p -R¹³, or -CH = R¹⁵,
R⁶ and R⁷ are the same or different and are hydrogen, halogen, NO₂, cyano, NR¹⁶R¹⁷, -COR¹⁴, OR¹⁸, optionally substituted aryl, optionally substituted hetaryl, C _1-6 - alkyl, which with halogen, -OR⁸, -NR⁹R¹⁰, SO₀ -R¹¹, COR¹², optionally substituted aryl or optionally substituted hetaryl may be substituted, C₂-₆-alkenyl, which may be substituted with halogen, -OR⁸, -NR⁹R¹⁰, SO₀-R¹¹, COR¹², optionally substituted aryl or optionally substituted hetaryl, SO _p -R¹³, or -CH = R¹⁵,
R² is hydrogen or - (CH₂) _q -R³
R³ is hydrogen, hydroxy, C₁-₆-alkoxy or NR¹⁹R²⁰,
n, m and q each 0, 1, 2 or 3
Z POXY, OPOXY, SO₂R²¹, CO₂R²², cyano or tetrazole,
R⁸ and R¹⁸ are hydrogen, C _1-6 -alkyl optionally substituted by halogen,
o and p each 0, 1 or 2,
R¹¹ and R¹³ are hydrogen, C _1-6 alkyl or optionally substituted aryl,
R¹², R¹⁴ and R²¹ OH, C _1-6 alkoxy or NR²³R²⁴,
R¹⁵ oxygen, = NOH or

X and Y are identical or different and denote hydroxy, C _1-6 alkoxy, C _1-4 alkyl or NR²⁵R²⁶,
R⁹ and R¹⁰, R¹⁶ and R¹⁷, R¹⁹ and R²⁰, R²³ and R²⁴, R²⁵ and R²⁶ are the same or different and form hydrogen, C _1-4 -alkyl, aryl or together with the nitrogen atom a 5-7-membered saturated heterocycle which contain another oxygen, sulfur or nitrogen atom and can be substituted or form an unsaturated 5-membered heterocycle which can contain 1-3 N atoms and can be substituted,
and their isomers or salts, where R⁵ 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 R⁵, R⁶ and R⁷ can be in any position, preferably in 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, with C _1-4 alkyl radicals being preferred.

Alkenyl means, for example, vinyl, 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 has 6-12 carbon atoms such as naphthyl, biphenyl and especially phenyl. Hetaryl includes optionally substituted 5-ring heteroaromatics To understand 1-2 N, O or S atoms such. B. thiophene, furan, oxazole, thiazole or optionally substituted 6-ring heteroaromatics with 1-3 N atoms such as pyridine, pyrimidine, Triazine, quinoline, isoquinoline.

Halogen, C _1-4 alkoxy, nitro, trifluoromethyl or C _1-4 alkyl are suitable as substituents of the aryl and hetaryl radical, which occur one to three times.

If R⁹ and R¹⁰, R¹⁶ and R¹⁷, R¹⁹ and R²⁰, R²³ and R²⁴ or R²⁵ and R²⁶ together with the nitrogen atom form a saturated heterocycle, then for example piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine or piperazine is meant. If the heterocycle is substituted, C _1-4 alkyl or aryl such as phenyl, which can be 1-3 times, is suitable as a substituent. Examples include N-methylpiperazine, N-phenylpiperazine, 2,6-dimethylmorpholine.

Form R⁹ and R¹⁰, R¹⁶ and R¹⁷, R¹⁹ and R²⁰, R²³ and R²⁴ or R²⁵ and R²⁶, together with the nitrogen atom an unsaturated heterocycle, for example imidazole, Called pyrazole, pyrrole and triazole.

If an acidic function is present, the physiologically acceptable salts are more organic than salts and inorganic bases, such as the readily soluble alkali and alkaline earth salts as well as the salts with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6- Hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, Aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.  

If a basic function is included, the physiologically acceptable salts are organic and inorganic acids suitable such as HCl, H₂SO₄, phosphoric acid, citric acid, tartaric acid u. a.

The compounds of formula I and their physiologically tolerable salts are based on their Affinity for the AMPA receptors can be used as a drug. Because of their active profile the compounds of the invention are suitable for the treatment of diseases caused by Hyperactivity of excitatory amino acids such as glutamate or aspartate are caused. Because the new compounds act as antagonists of excitatory amino acids act and show a high specific affinity for the AMPA receptors by the radiolabeled specific agonists (RS) a-amino-3-hydroxy-5-methyl-4- displacing isoxazole propionate (AMPA) from the AMPA receptors, they are particularly suitable for the treatment of such diseases via the receptors of excitatory amino acids, in particular the AMPA receptor.

According to the invention, the compounds can be used for the treatment of neurological and psychiatric disorders caused by overstimulation of the AMPA receptor will. On the neurological diseases that are treated functionally and preventively can include, for example, neurodegenerative disorders such as Parkinson's disease, disease Alzheimer's, Huntington's Chorus, Amyotrophic Lateral Sclerosis and Olivopontocerebellar Degeneration. According to the invention, the compounds for the prevention of post-ischemic Cell dying, cell dying after brain trauma, stroke, hypoxia, anoxia and Hypoglycemia and for the treatment of senile dementia, AIDS dementia, neurological Symptoms related to HIV infection, multi-infarct dementia and epilepsy and muscle spasticity can be used. Psychiatric disorders include Anxiety, schizophrenia, migraines, pain, and the treatment of Sleep disorders and withdrawal symptoms after drug abuse such as alcohol, cocaine, Benzodiazepine or opiate withdrawal. The connections can also have an application in the prevention of tolerance development during long-term treatment with sedative Find drugs such as benzodiazepines, barbiturates and morphine. In addition, the compounds can be used as anesthetics (anesthetic), anti-pain medication or Antiemetics are used.

To use the compounds according to the invention as medicaments, they are put into the form brought a pharmaceutical preparation that in addition to the active ingredient for enteral or parenteral application of suitable pharmaceutical, organic or inorganic inert Carrier materials such as, for example, 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, coated tablets, 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.

For parenteral use, especially injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, suitable.

Surface-active auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their Components are used.

Tablets, coated tablets or capsules with talc are particularly suitable for oral use and / or hydrocarbon carriers or binders, such as lactose, maize or Potato starch, suitable. They 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, The type and severity of the disease to be treated and similar factors vary. The daily Dose is 0.5-1000 mg, preferably 50-200 mg, taking the dose as one single dose 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
a compound of formula II

wherein R¹, R⁵, R⁶ and R⁷ have the above meaning, with oxalic acid or reactive oxalic acid derivatives cyclized and, if desired, then saponified the ester group or the Acid group esterified or amidated or introduces a tetrazole group or alcohols  Aldehydes or thioethers are oxidized to sulfoxides or sulfones or sulfoxides to sulfones, or aldehydes are converted into oximes or nitrones or the isomers are separated or the salts are formed.

Compounds of the formula II are obtained, for example, by working in a compound of the formula III

wherein R¹ has the above meaning and R ^{5 '} , R ^6' and R ^{7 'are} a leaving group or R⁵, R⁶ or R⁷, a leaving group is replaced by SR¹³ or by optionally substituted C _2-6 alkenyl and, if desired, then the double bond of the alkenyl group hydrogenates 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 one known manner with oxalic acid in an acidic environment or with a reactive oxalic acid derivative in one or two stages. As the two-stage process in which the diamine is combined with a Oxalic acid derivative such as the oxal ester half-chloride or reactive oxalic acid derivatives such as. B. Imidazolides in polar solvents such as cyclic or acyclic 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, Hünig base or dimethylaminopyridine or also soda or Sodium hydroxide solution is implemented. The subsequent cyclization can be basic or acidic, but are preferably carried out in an acidic environment, the reaction mixture Solubilizers such as alcohol or acetonitrile can be added.

Suitable bases for the two-stage process are also alkali metal hydrides such as NaH, which are described in inert solvents such as hydrocarbons or ethers can be used.

Halogens such as fluorine, chlorine, bromine and iodine are the escape groups of the compounds of the formula III or O-mesylate, O-tosylate, O-triflate or O-nonaflate.  

The nucleophilic substitution for the introduction of the -S-R¹³ group is with the corresponding Thiol in the presence of bases such as e.g. B. alkali or alkaline earth metal hydroxides or carbonates in polar protic or aprotic solvents such as e.g. B. water, alcohols or Dimethylformamide performed.

The substitution by alkenyl compounds takes place with the catalysis of transition metal complexes such as Pd (0), e.g. B. palladium tetrakistriphenylphosphine or Pd ( ²⁺ ), such as. B. palladium-bis-trio-tolylphosphine dichloride or nickel (0) according to methods known from the literature, optionally in the presence of a base and is activated by an activating electron-withdrawing group such. B. Nitro, cyano, trifluoromethyl preferably favored in the o-position.

Examples of suitable nucleophiles are the corresponding boronic acids or boranes or Organotin compounds, organotin compounds, Grignard compounds or also the alkenyls are suitable 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 made. As bases are 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, Hünig base, if necessary, with the addition of water.

The oxidative cleavage of the alkenyl compounds to the aldehyde can be according to the literature Methods are done. Ozonation in solvents such as, for. B. halogenated Hydrocarbons or alcohols or mixtures thereof at temperatures of -78 ° C to room temperature. The ozonide that forms is reductive by trapping with thiourea, Trialkylphosphiten or preferably cleaved with triarylphosphines to the aldehyde.

The aldehyde can olefinization reactions such. B. a peterson definition, a Wittig or Wittig-Horner reaction to an optionally substituted To produce alkenyl compound. For this purpose, the aldehyde is combined with the previously generated anion appropriately substituted phosphonium salt or phosphonic acid ester in solvents such as Tetrahydrofuran, diethyl ether or dimethoxyethane implemented. As bases are e.g. B. alkali hydrides, Alkali or alkaline earth carbonates or hydroxides optionally in the presence of Phase transfer catalysts such. B. crown ethers or organic bases such as triethylamine, Diisopropylethylamine or Diazabicycloundecan optionally in the presence of salts such as Suitable for lithium bromide.  

The aldehyde can be reduced to alcohol by processes known from the literature. Preferably, the reduction with complex metal hydrides such. B. sodium boronate in Solvents such as alcohol.

The hydroxyl group can in various methods according to methods known from the literature Escape groups such as chloride, bromide, iodide, triflate, mesylate or tosylate are transferred. Preferably with tosyl chloride in the presence of bases such as. B. triethylamine, Ethyldiisopropylamine or dimethylaminopyridine in solvents such as halogenated Converted hydrocarbons or ether into chloride.

The 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 or alkaline earth metal hydroxide or carbonate or also organic bases such as B. triethylamine, ethyldiisopropylamine 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 with sodium sulfide and Ammonium hydroxide in alcohol. The alkenyl group is reduced in a conventional manner catalytic.

The oxidation of thioethers to sulfoxides or sulfones is carried out according to the literature Methods. For example, sulfoxides are obtained selectively by oxidation with sodium periodate in a mixture of methanol and water. Sulfones can either be from the appropriate Sulfoxides or from the thioethers by oxidation with sodium periodate in a mixture Carbon tetrachloride, acetonitrile and water prepared under catalysis by ruthenium (III) will.

The optionally subsequent saponification of an ester group can be basic or preferably acidic by at elevated temperature to the boiling point of Reaction mixture in the presence of acids such as highly concentrated aqueous hydrochloric acid optionally hydro in solvents such as trifluoroacetic acid or alcohols lysed. Phosphonic acid esters are preferred by heating in highly concentrated aqueous Acids such as concentrated hydrochloric acid, optionally with the addition of an alcohol or by treatment with trimethylsilyl halide in inert solvents such as e.g. B. acetonitrile and subsequent treatment with water hydrolyzed.  

The esterification of the carboxylic acid or phosphonic acid takes place in a manner known per se the corresponding alcohol under acid catalysis or in the presence of an activated one Acid derivative. Activated acid derivatives include, for example, acid chloride, imidazolide or anhydride in question. In the case of the phosphonic acids, the esterification can be carried out by reaction with Achieve orthoesters with the addition of catalysts such as p-toluenesulfonic acid if necessary.

The amidation takes place on the free acids or on their reactive derivatives such as, for example Acid chlorides, mixed anhydrides, imidazolides or azides by reaction with the corresponding amines at room temperature.

The introduction of the tetrazole succeeds by converting the corresponding nitrile with a Azide such as B. trimethylsilyl azide, hydrochloric acid or sodium azide if necessary with the addition of a proton source such. B. ammonium chloride or triethylammonium chloride in polar solvents such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone Temperatures up to the boiling point of the solvent.

The oxidation of an alcohol can be carried out by methods known from the literature. Preferably one uses the Jones variant (chromium trioxide in sulfuric acid) in solvents such as Acetone.

The aldehyde is converted into oximes and nitrones using methods known from the literature with the hydrochlorides of the corresponding hydroxylamines, optionally with the addition of a Base preferably in solvents such as alcohols or aromatic hydrocarbons or also mixtures of these.

The isomer mixtures can be prepared using customary methods such as, for example, crystallization, Chromatography or 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 to the Formula I with the equivalent amount or an excess of a base or acid, the is optionally in solution, added and the precipitate is separated off or in the usual way Worked up solution.  

If the preparation of the starting compounds is not described, these are known or analogous to known compounds, for example according to WO93 / 08173, WO94 / 25469 or here described method can be produced.

The following examples are intended to explain the process according to the invention:  

Production of raw materials

• A.) 3.3 g (30 mmol) aminomethanephosphonic acid in 120 ml water and 120 ml Acetonitrile together with 3.37 g (31.8 mmol) of sodium carbonate and with 7.8 g (97%, 30 mmol) of 3- Trifluoromethyl-4,6-dichlomitrobenzol added and 4 h at 120 ° C bath temperature at reflux touched. After removing the acetonitrile on a rotary evaporator, three times with 100 ml Extracted ethyl acetate. The organic phase is washed with a little water. It contains Starting material and is discarded. The collected aqueous phase is with 4N hydrochloric acid acidified to pH1 and extracted three times with 100 ml of ethyl acetate. The organic phase will washed with water, dried, filtered and concentrated. 6.85 g (68% of theory) of N- (2- Nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphonic acid, melting point 207.3 ° C.
• C.) 1.67 g of N- (2-nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphonic acid are in 25 ml of triethyl orthoformate are mixed with 190 mg of p-toluenesulfonic acid and 3 h at 150 ° C. Bath temperature heated. After evaporation in vacuo, it is taken up in 25 ml of water and extracted three times with 25 ml of ethyl acetate. The collected ethyl acetate phase is washed once with water washed, dried, filtered and concentrated. 2 g (<100% of theory) of N- (2-nitro-4- trifluoromethyl-5-chlorophenyl) aminomethanephosphonic acid diethyl ester.

The following are produced in an analogous manner:
N- (2-Nitro-4-trifluoromethyl-5-phenylthio) phenylaminomethanephosphonic acid diethyl ester.

• D.) 8.5 g N- (2-nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphonic acid diethyl ester are in 250 ml of toluene with 60 ml of ethanol, 50 ml of 2M sodium carbonate solution, 0.9 g Palladium tetrakistriphenylphosphine and 3.7 g of styrylboronic acid were added and the mixture was left under argon for 7 hours 110 ° C bath temperature heated. After concentration, the mixture is distributed in ethyl acetate and water and the Dried ethyl acetate phase, filtered and concentrated. The residue is twice over silica gel chromatographed, first with the eluent toluene: ethyl acetate = 1: 1 and then the correspondingly combined fractions first with cyclohexane to separate Triphenylphosphine and later with ethyl acetate. 5.8 g (58% of theory) of N- (4-nitro-2- trifluoromethyl-5-styryl) -phenyl-aminomethanephosphonic acid diethyl ester.

The following are produced in an analogous manner:

Diethyl N- (2-nitro-4-trifluoromethyl-5- (4-chlorostyryl) phenyl) aminomethanephosphonate.

N- (2-nitro-4-trifluoromethyl-5- (4-methoxystyryl) phenyl) aminomethane p-phosphonic acid diethyl ester.

Diethyl N- (2-nitro-4-trifluoromethyl-5- (4-fluorostyryl) phenyl) aminomethanephosphonate.  

N- (2-nitro-4-trifluoromethyl-5- (pyrid-2-ylvinyl) phenyl) aminomethane p -phosphonic acid diethyl ester.

• E.) 1 g of diethyl N - [(2-nitro-4-trifluoromethyl-5-styryl) phenyl] aminomethanephosphonate are dissolved in 100 ml of ethanol and with 2 g of Raney nickel at room temperature and normal pressure hydrated. After suctioning off the catalyst over diatomaceous earth and concentrating the filtrate, one obtains 885 mg of N- (2-amino-4-trifluoromethyl-5-phenethyl) phenyl aminomethanephosphonic acid diethyl ester, which without further purification in the next stage be used.

The following are produced in an analogous manner:

N- (2-amino-4-trifluoromethyl-5- (4-chlorophenylethyl) phenyl) - aminomethanephosphonic acid diethyl ester.

N- (2-Amino-4-trifluoromethyl-5- (4-methoxyphenylethyl) phenyl) aminomethanephosphonic acid diethyl ester.

N- (2-amino-4-trifluoromethyl-5- (4-fiuorphenylethyl) phenyl) - aminomethanephosphonic acid diethyl ester.

N- (2-Amino-4-trifluoromethyl-5- (pyrid-2-ylethyl) phenyl) aminomethane p -phosphonic acid diethyl ester.

• F. 2.96 g diethyl N- (2-nitro-4-trifluoromethyl-5-styryl) phenyl aminomethanephosphonate  are dissolved in 140 ml of methanol and 140 ml of methylene chloride and cooled to -78 ° C. It ozone is then bubbled into the solution for 15 min. After that by DC control 2.8 g triphenylphosphine is added. You let go Room temperature come in and constricts. The residue is covered with silica gel Acetone: hexane = 1: 1 chromatographed. 1.8 g of N- (2-nitro-4-trifluoromethyl-5-formyl) are obtained - phenyl-aminomethanephosphonic acid diethyl ester.
• G. 2.56 g N- (2-nitro-4-trifluoromethyl-5-formyl) phenyl) aminomethanephosphonic acid rediethyl ester are dissolved in 130 ml of methanol and 260 mg of sodium boranate are slowly added in portions. When the addition is complete, the mixture is stirred at room temperature for 2 h. It is then concentrated and in Distributed ethyl acetate and 1N hydrochloric acid. The ethyl acetate phase is washed with water, dried, filtered and concentrated. The residue is over silica gel with acetone: hexane = 1: 1 chromatographed. 2.2 g of N- (2-nitro-4-trifluoromethyl-5-hydroxymethyl) are obtained. phenylaminomethanephosphonic acid diethyl ester.
• H.) 0.76 g of N- (2-nitro-4-trifluoromethyl-5-hydroxymethyl) phenyl-aminomethanephosphonic acid - diethyl ester are in 75 ml of ethanol with 0.24 g of palladium / carbon (10%)  Hydrogen normal pressure hydrogenated at room temperature. After suction from the catalyst The filtrate is concentrated in diatomaceous earth. The residue of 0.73 g of N- (2-amino-4-trifluoromethyl-5- hydroxymethyl) phenyl aminomethanephosphonic acid diethyl ester is in without further purification the next stage.

The following are produced in an analogous manner:

N- (2-Amino-4-trifluoromethyl-5-N-morpholinomethyl) phenyl aminomethane phosphonic acid diethyl ester.

N- (2-Amino-4-trifluoromethyl-5 - (2-carbethoxyeth-1-yl) phenyl aminomethanephosphonic acid diethyl ester (from N- (2-nitro-4-trifluoromethyl-5- (2-carbethoxyethen-1-yl) phenyl aminomethane diethyl phosphonic acid).

• I.) 1.75 g of N- (2-nitro-4-trifluoromethyl-5-hydroxymethyl) phenyl-aminomethanephosphonic acid diethyl esters are dissolved in 60 ml of methylene chloride and successively with 634 mg of dimethylamino pyridine and 980 mg of tosyl chloride. It is stirred overnight at room temperature. Then another 266 mg of dimethylaminopyridine and 400 mg of tosyl chloride are added and a further 7 h stirred at room temperature. It is diluted with methylene chloride once with 1N hydrochloric acid and washed with saturated saline. The organic phase is dried, filtered and constricted. The residue is chromatographed on silica gel using ethyl acetate as the eluent. 1.4 g of N- (2-nitro-4-trifluoromethyl-5-chloromethyl) phenyl are obtained. aminomethanephosphonic acid diethyl ester.
• K.) 550 mg of N- (2-nitro-4-trifluoromethyl-5-chloromethyl) -phenyl-aminomethanephosphonic acid diethyl ester in 10 ml of ethanol under argon first with 317 mg of potassium carbonate and then 0.12 ml of ethyl mercaptan was added dropwise. The mixture is stirred at room temperature for 1.5 h. It is diluted with water, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The The ethyl acetate phase is concentrated and the residue is evaporated over silica gel using ethyl acetate chromatographed. 460 mg of N- (2-nitro-4-trifluoromethyl-5-ethylthiomethyl) phenyl are obtained aminomethanephosphonic acid diethyl ester.
• L.) 356 mg of N- (2-nitro-4-trifluoromethyl-5-ethylthiomethyl) phenylaminomethanephosphonic acid diethyl ester are dissolved in 14 ml of methanol and a solution of 212 mg of ammonium chloride in 14 ml of water, which was mixed with 140 mg of iron powder. After the addition is complete Heated to 80 ° C for 1 h. After suction filtration over diatomaceous earth, the filtrate is concentrated. The residue is used in the next stage without further cleaning.

The following is produced in an analogous manner:

Diethyl N- (2-amino-4-trifluoromethyl-5-phenylthio) phenylaminomethanephosphonate.

• M.) To a suspension of 60 mg of sodium hydride (80% in oil) in 1 ml of dimethoxyethane 0.5 ml of triethyl phosphonoacetate in 1 ml of dimethoxyethane was added dropwise. After stirring for 1 h Room temperature becomes 384 mg of N- (2-amino-4-trifluoromethyl-5-formyl-phenyl) -aminomethane Phosphonic acid diethyl ester in 8 ml of dimethoxyethane added dropwise to the batch and after the end Addition heated to 80 ° C bath temperature for 4 h. Then put on ice, Distilled off dimethoxyethane and extracted with ethyl acetate. The organic phase is dried filtered and concentrated and the residue on silica gel with acetone: hexane = 1: 1 as the eluent Cut. 350 mg of N- (2-amino-4-trifluoromethyl-5- (2-carbethoxyethen-1-yl) -phenyl- aminomethanephosphonic acid diethyl ester.
• N.) 1.6 g of N- (2-nitro-4-rifluoromethyl-5-fiuorphenyl) aminomethanephosphonic acid - in 20 ml Dissolved water and mixed with 1.6 g of sodium carbonate. It is then mixed with 660 mg of thiophenol added and heated to 120 ° C bath temperature for 1.25 h. After cooling, first use Extracted ethyl acetate. This extract is discarded. The aqueous phase is washed with 4N hydrochloric acid acidified and extracted three times with ethyl acetate. This collected ethyl acetate phase will dried, filtered and concentrated and used in the esterification C.) without further purification.
• O.) 1.1 g of N- (2-nitro-4-trifluoromethyl-5-chloromethyl) -phenyl- diethyl aminomethanephosphonate are heated to 60 ° C. in 25 ml of morpholine for 2 h. It will concentrated, the residue taken up in ethyl acetate and extracted with 1 N sodium hydroxide solution. The Washed ethyl acetate phase with water, dried, filtered and concentrated. The backlog will Chromatographed on silica gel with acetone: hexane = 1: 1 as the eluent. 600 mg of N- (2-nitro-4-trifluoromethyl-5- (N-morpholino-methyl) -phenyl- aminomethanephosphonic acid diethyl ester.

example 1

870 mg N - [(2-amino-4-trifluoromethyl-5-phenethyl) phenyl] - aminomethanephosphonic acid diethyl ester are dissolved in 50 ml of absolute tetrahydrofuran and mixed with 0.57 g of triethylamine are added. A solution of 0.6 g is added to this solution Drops of oxalic acid chloride in 12 ml of absolute tetrahydrofuran at room temperature. When the addition is complete, stirring is continued for 4 h at room temperature. It is then from Suction filtered off and the filtrate was concentrated. The residue is dissolved in 50 ml of 1N hydrochloric acid and 50 ml of ethanol were added and the mixture was stirred at a bath temperature of 120 ° C. for 3 h. The precipitation will  suction filtered and the filtrate discarded. After recrystallization from ethanol, 230 mg (60% i.e.) N - [(6-trifluoromethyl-7-phenylethyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] - diethyl methanephosphonate.

The following are produced in an analogous manner:

[(6-Trifluoromethyl-7- (4- (chlorophenylethyl) -1,2,3,4-tetrahydroquinoxa-lin-2,3-dione) -1yl] - diethyl methanephosphonate.

[(6-Trifluoromethyl-7- (4-fiuorphenylethyl) -1,2,3,4-tetrahydroquinoxal-in-2,3-dione) -1yl] - diethyl methanephosphonate.

[(6-trifluoromethyl-7- (4-methoxyphenylethyl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] - diethyl methanephosphonate.

[(6-trifluoromethyl-7-hydroxymethyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] - diethyl methanephosphonate.

[(6-trifluoromethyl-7-ethylthiomethyl-1,2,3,4-tetrahydroquinoxaline-2, -3-dione) -1yl] - diethyl methanephosphonate.

[(6-trifluoromethyl-7-phenylthio-1,2,3,4-tetrahydroquinoxaline-2,3-dio-n) -1yl] - diethyl methanephosphonate.

[(6-Trifluoromethyl-7- (N-morpholinomethyl-1,2,3,4-tetrahydroquinoxali-n-2,3-dione) -1yl] - diethyl methanephosphonate.

[(6-Trifluoromethyl-7- (2-hydroxycarbonyleth-1-yl) -1,2,3,4-tetrahydroc-hinoxalin-2,3-dione) -1yl] - diethyl methanephosphonate. (The carboxylic ester originally present is among the Reaction conditions saponified).

[(6-trifluoromethyl-7- (2-pyridylethyl) -1,2,3,4-tetrahydroquinoxaline-2-, 3-dione) -1yl] - diethyl methanephosphonate.

Example 2

150 mg [(6-trifluoromethyl-7-phenylthio-1,2,3,4-tetrahydroquinoxaline-2,3-dio-n) -1yl] - diethyl methanephosphonate are dissolved in 10 ml of methanol and mixed with a solution of 110 mg of sodium periodate in 3 ml of water are added and the mixture is stirred at room temperature for 10 h. It will then diluted with water and shaken three times with ethyl acetate. The organic phase will concentrated and twice over silica gel first with the eluent Toluene: ice dough: water = 10: 10: 1 and the second time with methylene chloride: ethanol = 10: 1 chromatographed. 121 mg of 6-trifluoromethyl-7-sulfoxyphenyl-1,2,3,4- tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester.

The following is produced in an analogous manner:
6-Trifluoromethyl-7- (ethylsulfoxymethyl) -1,2,3,4-tetrahydroquinoxaline - 2,3-dione) -1yl] - methanephosphonic acid diethyl ester.

Example 3

122 mg 6-trifluoromethyl-7-phenylthio-1,2,3,4-tetrahydroquinoxaline-2,3-dione) - 1yl] - diethyl methanephosphonate are dissolved in 2 ml of acetonitrile and successively with 2 ml Carbon tetrachloride, 4 ml water, 160 mg sodium periodate and a spatula tip Ruthenium trichloride added. After 8 hours of stirring at room temperature, 30 ml of water diluted, and shaken three times with 30 ml of ethyl acetate. The collected organic phase is filtered through kieselguhr, concentrated and the residue with silica gel Chromatographed methylene chloride: ethanol = 10: 1, but it is still necessary to use methanol Wash remnants of the compound from the column. 98 mg of 6-trifluoromethyl-7- are obtained. phenylsulfonyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] -methanephosphonic acid diethyl ester.

The following is produced in an analogous manner:
6-Trifluoromethyl-7- (ethylsulfonylmethyl) -1,2,3,4-tetrahydroquinoxali-n-2,3-dione) -1yl] - methanephosphonic acid diethyl ester.

Example 4

220 mg [(6-trifluoromethyl-7-phenylethyl-1,2,3,4-tetrahydroquinoxaline-2,3-di-one) -1yl] - diethyl methanephosphonate are in 20 ml of concentrated hydrochloric acid for 3 h at 120 ° C. Bath temperature warmed. It is concentrated and 200 mg [(6-trifluoromethyl-7- phenylethyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] -methanephosphonic acid from the melting point 260 ° C.

The following are produced in an analogous manner:

[(6-trifluoromethyl-7-hydroxycarbonylethyl-1,2,3,4-tetrahydroquinoxal-in-2,3-dione) -1yl] - methanephosphonic acid.

[(6-trifluoromethyl-7-phensulfonyl-1,2,3,4-tetrahydroquinoxaline-2,3-d-ion) -1yl] - methanephosphonic acid.

[(6-trifluoromethyl-7-phenythio-1,2,3,4-tetrahydroquinoxaline-2,3-dione -) - 1yl] - methanephosphonic acid.

[(6-Trifluoromethyl-7-formyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1-yl] methanephosphonic acid.

Example 5

200 mg [(6-trifluoromethyl-7-hydroxymethyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] - diethyl methanephosphonate are placed in 9 ml of acetonitrile and 0.44 ml Trimethylbromosilane added. The mixture is stirred at room temperature for 8 h, then with water spiked and concentrated. The residue is stirred with water and suction filtered. You get 80 mg [(6-trifluoromethyl-7-hydroxymethyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] - methanephosphonic acid.

The following are produced in an analogous manner:

[(6-trifluoromethyl-7-ethylthiomethyl-1,2,3,4-tetrahydroquinoxaline-2, -3-dione) -1yl] methanephosphonic acid.

[(6-trifluoromethyl-7ethysulfonylmethyl-1,2,3,4-tetrahydroquinoxaline - 2,3-dione) -1yl] - methanephosphonic acid.

[(6-trifluoromethyl-7-morpholinomethyl-1,2,3,4-tetrahydroquinoxaline-2, 3-dione) -1yl] - methanephosphonic acid.

[(6-Trifluoromethyl-7- (2-pyridylethyl) -1,2,3,4-tetrahydroquinoxaline-2-, 3-dione) -1yl] methane phosphonic acid.

Example 6

650 mg [(6-trifluoromethyl-7-hydroxymethyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] - diethyl methanephosphonate are placed in 10 ml acetone and with 1.2 ml Jones reagent (made from 26.7 g chromium trioxide, 23 ml concentrated sulfuric acid made up to 100 ml with Water) stirred for 4 h at room temperature. Then 3 ml of isopropanol is added and 10 min. stirred. It is then concentrated and distributed in ethyl acetate: water. The organic phase will dried, filtered and concentrated. The residue is covered with silica gel Toluene: glacial acetic acid: water = 10: 10: 1 chromatographed. 160 mg [(6-trifluoromethyl-7- formyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid rediethyl ester in addition to Recovery of 375 mg of starting material.

Example 7

215 mg [(6-trifluoromethyl-7-formyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1-yl] - diethyl methanephosphonate are placed in 10 ml of benzene and successively with 0.1 ml Triethylamine and 63 mg of N-isopropylhydroxylamine hydrochloride were added. It gets 8 h at Room temperature stirred. The solid is then suctioned off. The solid is over Chromatograph silica gel with toluene: glacial acetic acid: water = 10: 10: 1. 120 mg [6- Trifluoromethyl-7- [N-oxy- (N-isopropylformylimino)] - 1,2,3,4-tetrahydro-quinoxaline-2,3-dione) -1yl] - diethyl methanephosphonate.  

The following is produced in an analogous manner:

[(6-Trifluoromethyl-7- [N-oxy- (N-isopropylformylimino)] - 1,2,3,4-tetrahydroquinoxaline-2,3-dione) - 1yl] methanephosphonic acid.

Claims (3)

1.) Compounds of formula I. wherein
R¹ - (CH2) _n -CR²H- (CH₂) _m -Z and
R⁵ C _1-6 alkyl, which can be substituted with halogen, -OR⁸, -NR⁹R¹⁰, SO₀-R¹¹, COR¹², optionally substituted aryl or optionally substituted hetaryl, C _2-6 - alkenyl, which with halogen, -OR⁸, - NR⁹R¹⁰, SO₀-R¹¹, COR¹², optionally substituted aryl or optionally substituted hetaryl may be substituted, SO _p -R¹³, or -CH = R¹⁵,
R⁶ and R⁷ are the same or different and are hydrogen, halogen, NO₂, cyano, NR¹⁶R¹⁷, -COR¹⁴, OR¹⁸, optionally substituted aryl, optionally substituted hetaryl, C _1-6 - alkyl, which with halogen, -OR⁸, -NR⁹R¹⁰, SO₀ -R¹¹, COR¹², optionally substituted aryl or optionally substituted hetaryl can be substituted, C _2-6 alkenyl which can be substituted with halogen, -OR⁸, -NR⁹R¹⁰, SO₀-R¹¹, COR¹², optionally substituted aryl or optionally substituted hetaryl, SO _p -R¹³, or -CH = R¹⁵,
R² is hydrogen or - (CH₂) _q -R³
R³ is hydrogen, hydroxy, C _1-6 alkoxy or NR¹⁹R²⁰,
n, m and q each 0, 1, 2 or 3
Z POXY, OPOXY, SO₂R²¹, CO₂R²², cyano or tetrazole,
R⁸ and R¹⁸ are hydrogen, C _1-6 -alkyl optionally substituted by halogen,
o and p each 0, 1 or 2,
R¹¹ and R¹³ are hydrogen, C _1-6 alkyl or optionally substituted aryl,
R¹², R¹⁴ and R²¹ OH, C _1-6 alkoxy or NR²³R²⁴,
R¹⁵ oxygen, = NOH or X and Y are identical or different and denote hydroxy, C _1-6 alkoxy, C _1-4 alkyl or NR²⁵R²⁶,
R⁹ and R¹⁰, R¹⁶ and R¹⁷, R¹⁹ and R²⁰, R²³ and R²⁴, R²⁵ and R²⁶ are the same or different and form hydrogen, C _1-4 -alkyl, aryl or together with the nitrogen atom a 5-7-membered saturated heterocycle which contain another oxygen, sulfur or nitrogen atom and can be substituted or form an unsaturated 5-membered heterocycle which can contain 1-3 N atoms and can be substituted,
and their isomers or salts, where R⁵ is not CF₃ or CH₃. 2. Medicament containing a compound of formula I according to claim 1. 3. A process for the preparation of the compounds of formula I, characterized in that a compound of formula II wherein R¹, R⁵, R⁶ and R⁷ have the above meaning, cyclized with oxalic acid or reactive oxalic acid and, if desired, then saponified the ester group or esterified or amidated the acid group or introduced a tetrazole group or alcohols to aldehydes or thioethers to sulfoxides or sulfones or sulfoxides to sulfones oxidized, or aldehydes converted into oximes or nitrones or separating the isomers or forming the salts.