DE4439493A1 - New quinoxalinedione derivatives, their production and use in pharmaceuticals - Google Patents

Abstract

The description relates to quinoxalindione derivatives (I) and their production 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, R⁶, R⁷ and R⁸ are the same or different and are hydrogen, C _1-6 alkyl, 1- to 3-fold substituted with halogen C _1-4 alkyl, nitro, halogen, NR⁹R¹⁰, cyano, SO _p R¹¹, SO₂NR¹²R¹³, SO₃H , SO₃C _1-6 alkyl or OR¹⁴ mean
in which
R² is hydrogen or - (CH₂) _q -R³,
R³ is hydrogen, hydroxy, C _1-6 alkoxy or NR¹⁵R¹⁶,
n, m and q each 0, 1, 2 or 3
Z POXY, OPOXY, SO₂R¹⁷, CO₂R¹⁸, cyano or tetrazole,
R11 H, C _1-6 alkyl, phenyl,
p 0, 1 or 2
R¹², R¹³ and R¹⁸ are hydrogen or C _1-4 alkyl,
R¹⁴ H or optionally 1- to 3-fold substituted with halogen C _1-6 alkyl,
R¹⁷ hydroxy, C _1-6 alkoxy or NR¹⁹R²⁰,
X and Y are identical or different and denote hydroxy, C _1-6 alkoxy, C _1-4 alkyl or NR²¹R²²,
R⁹ and R¹⁰ together with the nitrogen atom form an optionally substituted 5- to 7-membered heterocycle which contains a further N atom which is substituted by optionally substituted aryl or hetaryl radicals,
R¹⁵ and R¹⁶, R²¹ and R²² are the same or different and form hydrogen, C _1-4 alkyl, aryl or together with the nitrogen atom a 5- to 7-membered saturated heterocycle which contain another oxygen, sulfur or nitrogen atom and be substituted can or form an unsaturated 5-membered heterocycle which can contain 1-3 N atoms and can be substituted,
R¹⁹ and R²⁰ are the same or different and form hydrogen, C _1-4 alkyl or together with the nitrogen atom a saturated 5- to 7-membered heterocycle which may contain a further oxygen, sulfur or nitrogen atom, and their isomers or salts, where at least one of the substituents R⁵, R⁶, R⁷ or R⁸ NR⁹R¹⁰ means and where, if R⁵ and R⁸ is hydrogen, R⁶ CF₃ and R⁷ is 4-phenyl-piperazin-1-yl, R¹ cannot be methanephosphonic acid or methanephosphonic acid diethyl ester.

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 substituent -NR⁹R¹⁰ is preferably in the 7- and / or 8-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, pentyl, isopentyl, hexyl, with C _1-4 alkyl radicals being preferred.

Halogen means fluorine, chlorine, bromine or iodine.

If R⁵, R⁶, R⁷ or R⁸ is a halogen-substituted alkyl radical, CF₃ is preferred.

When R⁹ and R¹⁰ form a heterocycle together with the nitrogen atom, this means piperazines, imidazolines, imidazolidines, diazepines, dihydrodiazepines, tetrahydrodiazepines or hexahydrodiazepines or their corresponding on-derivatives, optionally substituted by C _1-4 -alkyls, in which the further nitrogen atom means optionally substituted aryl or hetaryl is substituted.

Examples of aryl substituents of the heterocycle NR⁹R¹ycl are phenyl, naphthyl or Called biphenyl. 5- to 6-membered hetaryls come with 1-3 as hetaryl substituents  Heteroatoms such as nitrogen, oxygen and / or sulfur are considered, for example Pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, furan, imidazole, thiazole, oxazole, indole, Benzothiophene, benzofuran.

As substituents of the aryl and hetaryl radicals which are mono- to triple in any position, halogens, C _1-4 alkyl, C _1-4 alkoxy, benzyloxy, CF₃, NO₂, SO₃H, SO₂-aryl, SO₂- C _1-4 alkyl, SO₃NH₂, cyano, acylamino, NR²³R²⁴. Acyl means C _1-6 alkanoyl and benzoyl and the meaning of NR²³R²⁴ corresponds to the meaning of NR¹⁵R¹⁶.

Form R¹⁵ and R¹⁶, R²¹ and R²², R¹⁹ and R²⁰ together with the nitrogen atom a saturated heterocycle, for example piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine or piperazine. If the heterocycle is substituted, C _1-4 alkyl or aryl such as phenyl, which can be 1 to 3 times, is suitable as the substituent. Examples include N-methylpiperazine, N-phenylpiperazine and 2,6-dimethylmorpholine.

Form R¹⁵ and R¹⁶, R²¹ and R²², together with the nitrogen atom, an unsaturated heterocycle, so for example imidazole, pyrazole, pyrrole and triazole may be mentioned, the one to two times with cyano, C _1-4 alkyl, phenyl or CO₂C _1-6 -Alkyl can be substituted.

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 N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, 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 compatible salts of organic and inorganic acids are suitable, such as HCl, H₂SO₄, phosphoric acid, citric acid, tartaric acid and others
The compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their affinity for the AMPA receptors. On the basis of their activity profile, 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. 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) α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) from displacing the AMPA receptors, they are particularly suitable for the treatment of diseases which can be influenced 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 and spinal cord trauma, in case of stroke, Hypoxia, anoxia and hypoglycemia and for the treatment of senile dementia, multi-infarct Dementia as well as epilepsy and muscle spasticity can be used. To the psychiatric Diseases include anxiety, schizophrenia, migraines, painful conditions, as well Treatment of sleep disorders and withdrawal symptoms after drug abuse as in Alcohol, cocaine, benzodiazepine, or opiate withdrawal.

For the use of the compounds according to the invention as pharmaceuticals, these are Form of a pharmaceutical preparation brought in addition to the active ingredient for enteral or parenteral application of suitable pharmaceutical, organic or inorganic inert Carrier materials such as water, gelatin, gum arabic, Contains milk sugar, starch, 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 are present. If necessary, they also contain auxiliary substances such as Preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffer.

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 as well as liposomes or whose 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. The application can also be in liquid form, such as 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 once 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) a compound of formula II wherein R¹ to R⁸ have the above meaning, cyclized with oxalic acid or reactive oxalic acid derivatives or
• b) a compound of formula III wherein R¹ has the meaning given above and one of the substituents R ^{5 '} , R ^6' , R ^{7 '} or R ^{8' represents} a leaving group, is nucleophilically substituted and, if desired, then saponifies the ester group or esterifies or amidates the acid group or the aryl or hetaryl group NR⁹R¹⁰ electrophilically substituted or separates the isomers or forms the salts.

The cyclization to compounds of the formula I is carried out in a known manner using oxalic acid single-stage in an acidic environment or with a reactive oxalic acid derivative single-stage or also two-stage. The two-stage process in which the diamine is also to be regarded as preferred an oxalic acid derivative such as oxal ester half chloride or reactive Oxalic acid imidazolide derivatives in polar solvents such as cyclic or acyclic ethers or halogenated hydrocarbons, for example tetrahydrofuran, diethyl ether or Methylene chloride or in water according to Schotten Baumann in the presence of a base such as organic amines, for example triethylamine, pyridine, Hünig base or Dimethylaminopyridine or soda or sodium hydroxide solution is implemented. The subsequent one Cyclization can be basic or acidic, but is preferably carried out in an acidic environment are added to the reaction mixture solubilizers such as alcohol or acetonitrile can be.

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.

As escape groups in process variant b) and in the production of Starting compounds of formula II are halogens such as fluorine, chlorine, bromine, iodine or O- Mesylate, O-tosylate, O-triflate or O-nonaflate are suitable. The nucleophilic substitution becomes after known methods in the presence of a base and is carried out by a activating electron-withdrawing group such as B. nitro, cyano, trifluoromethyl preferably in Favored o position.

Examples of nucleophiles are N-containing unsaturated or saturated heterocycles, Cyanide, alcoholates, thiolates and the like. a. suitable. The reaction can be carried out in polar solvents such as Alcohols, halogenated hydrocarbons, dimethylacetamide, acetonitrile or water or be made without solvent. 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 DBU, Hunig base, pyridine or dimethylaminopyridine are suitable.

In the case of amines, the nucleophile itself can be used in excess as a base, where one can optionally work without further solvent. If the boiling point of the is too low Amines can optionally be worked under pressure in an autoclave.

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. Examples of activated acid derivatives are 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 as in for example, acid chlorides, mixed anhydrides, imidazolides or azides Reaction with the corresponding amines at room temperature.

The electrophilic aromatic substitution which may follow is carried out after methods known from the literature for the introduction of the abovementioned substituents on the aryl and Hetaryl residues.

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 at temperatures up to the boiling point of the solvent.

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.  

Insofar as the preparation of the starting compounds is not described, they are known or analogously to known compounds, for example according to WO 93/08173 or here described method can be produced.

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

Preparation of the starting compounds

100 g of 2,4-dichloro-5-nitro-1-trifluoromethylbenzene are mixed with 89.5 g of potassium fluoride and the Azeotropic separation of water three times with 50 ml of toluene on a rotary evaporator Dry evaporated. It is then taken up in 200 ml of absolute dimethylformamide and heated to 150 ° C for 7 h. It is taken up in 300 ml of water, with 200 ml of ethyl acetate added, and decanted from the inorganic precipitate. The rainfall is repeated several times Washed ethyl acetate and shaken the aqueous phase with the collected ethyl acetate. The organic phase is twice with 100 ml of saturated saline and once with 100 ml Washed water, dried over sodium sulfate, filtered and carefully on Rotary evaporator (50 ° C, max 150 mbar) concentrated. The residue is about 20 cm Vigreux column distilled. At 130 ° C and 20-30 mbar, 26 g of one is obtained in two fractions 70% and 48.7 g of a 95% 2,4-difluoro-5-nitro-1-trifluoromethylbenzene, which without further Cleaning can be used in the next stages.

example 1

A.) 1.85 g of 2,4-difluoro-5-nitro-1-trifluoromethylbenzene are dissolved in 15 ml of acetonitrile and added a solution of 0.83 g aminomethanephosphonic acid, 1.5 g sodium carbonate and 15 ml water given. The mixture is then stirred at a bath temperature of 120 ° C. for 4.5 h. After distilling off the acetonitrile on a rotary evaporator, the mixture is extracted three times with 20 ml of ethyl acetate and the organic phase discarded. The aqueous phase is adjusted to pH 2 with 4N hydrochloric acid and three times with 25 ml each Extracted ethyl acetate. This collected ethyl acetate phase is washed with water, dried, filtered and concentrated. After drying, 1.9 g (82% of theory) of N - [(5-fluoro-2-nitro-4- trifluoromethyl) phen-1-yl] aminomethanephosphonic acid.

B.) 3.2 g [(5-fluoro-2-nitro-4-trifluoromethyl) phen-1-yl] aminomethanephosphonic acid are re 80 ml of 1N sodium hydroxide solution with 3.24 g of 1- (3-chlorophenyl) piperazine hydrochloride and one hour stirred at 100 ° C bath temperature. After cooling, stirring and cooling with an ice bath adjusted dropwise with 3N hydrochloric acid pH3. The precipitated product is suctioned off. You get 5.34 g (<100% of theory) N - [(5- (4- (3-chlorophenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phe-n-1-yl] - aminomethanephosphonic acid.

The following are produced in an analogous manner:
N - [(5- (4- (3-Trifluoromethylphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phen-1-yl] aminomethanephosphonic acid
N - [(5- (4- (4-Fluorophenyl) piperazin-1-yl-2-nitro-4-trifluoromethyl) phen-1-yl] aminomethanephosphonic acid
N - [(5- (4- (2-pyridyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phen-1-yl] aminomethanephosphonic acid
N - [(5- (4- (4-Methylphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) ph-en-1-yl] aminomethanephosphonic acid
N - [(5- (4- (3-Methoxyphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) p-hen-1-yl] aminomethanephosphonic acid
N - [(5- (4- (4-Chlorophenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phe-n-1-yl] - amomethanephosphonic acid
N - [(5- (4- (4-Trifluoromethylphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phen-1-yl] aminomethanephosphonic acid
N - [(5- (4- (3-Benzyloxyphenyl) piperazin-1-yl-2-nitro-4-trifluoromethyl) phen-1-yl] aminomethanephosphonic acid.

The corresponding chlorine compound is prepared in an analogous manner:
N - [(5- (4- (4-Methoxyphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) p-hen-1-yl] aminomethanephosphonic acid

C.) 2 g [(5-chloro-2-nitro-4-trifluoromethyl) phen-1-yl] aminomethanephosphonic acid are added with 4.84 g of 1- (2-methoxyphenyl) piperazine heated to 160 ° C. bath temperature under argon for 2.5 h. Man receives N - [(5- (4- (2-methoxyphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) p-hen-1-yl] - aminomethanephosphonic acid, which is used in step D.) without further purification.

D.) 1.9 g of N - [(5- (4- (3-chlorophenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phe-n-1-yl] - aminomethanephosphonic acid are dissolved in 15 ml of triethyl orthoformate with 133 mg of p- Toluene sulfonic acid stirred for 2.5 h on a water separator. It is then concentrated in vacuo, and the residue was taken up in 50 ml of water and made alkaline with 1N sodium hydroxide solution. It will extracted three times with 50 ml of ethyl acetate. The collected ethyl acetate phase is diluted 50 ml Hydrochloric acid extracted and the organic phase dried, filtered and concentrated. 1.9 g are obtained (92.7% of theory) N - [(5- (4- (3-chlorophenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phe-n-1-yl] - aminomethanephosphonic acid diethyl ester.

The following are produced in an analogous manner:
N - [(5- (4- (3-Trifluoromethylphenyl) piperazin-1-yl-2-nitro-4-trifluoromethyl) phen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4 - (- fluorophenylpiperazin-1-yl) -2-nitro-4-trifluoromethyl) phen - 1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (2-pyridyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (4-Methylphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) ph-en-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (4-Methoxyphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) p-hen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (3-Methoxyphenyl) piper azin-1-yl) -2-nitro-4-trifluoromethyl) phen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (2-Methoxyphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) p-hen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (4-Chlorophenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (4-Trifluoromethylphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (3-Benzyloxyphenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl-) phen-1-yl] - diethyl aminomethanephosphonate

E.) 2.2 g of N - [(5- (4- (3-chlorophenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phe-n-1-yl] - aminomethanephosphonic acid diethyl ester in 100 ml of ethanol with 850 mg of palladium Activated carbon (10%) stirred for 1 h; after suctioning off with 850 mg palladium on activated carbon (10%) added and hydrogenated under normal pressure and at room temperature. After vacuuming from Catalyst and concentration are obtained 1.9 g of N - [(5- (4- (3-chlorophenyl) piperazin-1-yl) -2-amino-4- trifluoromethyl) phen-1-yl] aminomethanephosphonic acid diethyl ester.

The following are produced in an analogous manner:
N - [(5- (4- (3-Trifluoromethylphenyl) piperazin-1-yl) -2-amino-4-trifluoromethyl) phen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4 - (- Fluorophenylpiperazin-1-yl) -2-amino-4-trifluoromethyl) phen - 1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (2-Pyridyl) piperazin-1-yl) -2-amino-4-trifluoromethyl) phen-1 - yl] - diethyl aminomethanephosphonate
N - [(5- (4- (4-Methylphenyl) piperazin-1-yl) -2-amino-4-trifluoromethyl) ph-en-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (4-Methoxyphenyl) piperazin-1-yl) -2-amino-4-trifluoromethyl) p-hen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (3-Methoxyphenyl) piperazin-1-yl) -2-amino-4-trifluoromethyl) p-hen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (2-Methoxyphenyl) piperazin-1-yl) -2-amino-4-trifluoromethyl) p-hen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (4-Chlorophenyl) piperazin-1-yl) -2-amino-4-trifluoromethyl) phe-n-1-yl) - diethyl aminomethanephosphonate
N - [(5- (4- (4-Trifluoromethylphenyl) piperazin-1-yl) -2-amino-4-trifluoromethyl-phen-1-yl] - diethyl aminomethanephosphonate
N - [(5- (4- (3-Benzyloxyphenyl) piperazin-1-yl) -2-amino-4-trifluoromethyl-) phen-1-yl] - diethyl aminomethanephosphonate

F.) 1.9 g N - [(5- (4- (3-chlorophenyl) piperazin-1-yl) -2-nitro-4-trifluoromethyl) phe-n-1-yl] - aminomethanephosphonic acid diethyl ester are dissolved in 70 ml of absolute tetrahydrofuran and mixed with 842 mg of triethylamine were added. A solution of 1.1 g is added to this solution Drops of oxalic acid chloride in 30 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 40 ml of 1N hydrochloric acid and 40 ml of ethanol were added and the mixture was stirred at a bath temperature of 120 ° C. for 2 h. After constriction is in 50 ml of water taken up and extracted twice with 50 ml of ethyl acetate. The ethyl acetate phase is washed once with water, filtered, dried and concentrated. The backlog is over Chromatograph silica gel with dichloromethane: ethanol = 10: 1. 1.2 g [(6- Trifluoromethyl-7 - [(4- (3-chlorophenyl) piperazin-1-yl) -1-2-3-4-tetrahydroquinoxaline-2,3-dione) -1yl] - diethyl methanephosphonate

The following are produced in an analogous manner:
[(6-Trifluoromethyl-7 - [(4- (3-trifluoromethylphenyl) piperazin-1-yl) -1,2-, 3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester
[(6-Trifluoromethyl-7 - [(4- (4-fluorophenyl) piperazin-1-yl) -1,3,4-tetrah-ydroquinoxaline-2,3-dione) - 1yl)] - methanephosphonic acid diethyl ester
[(6-Trifluoromethyl-7 - [(4- (2-pyridylphenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester
[(6-Trifluoromethyl-7 - [(4- (4-methylphenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) 1yl] methanephosphonic acid diethyl ester
[(6-Trifluoromethyl-7 - [(4- (4-methoxyphenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester
[(6-Trifluoromethyl-7 - [(4- (3-methoxyphenyl) piperazin-1-yl) -1,2,3,4-te-trahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester
[(6-Trifluoromethyl-7 - [(4- (2-methoxyphenyl) piperazin-1-yl) -1,2,3,4-te-trahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester
[(6-Trifluoromethyl-7 - [(4- (4-chlorophenyl) piperazin-1-yl) -1,2,3,4-tetr-ahydroquinoxaline-2,3-dione) - 1yl] methanephosphonic acid diethyl ester
[(6-Trifluoromethyl-7 - [(4- (4-trifluoromethylphenyl) piperazin-1-yl) -1,2-, 3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester
[(6-Trifluoromethyl-7 - [(4- (4-benzyloxyphenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid diethyl ester

Example 2

1.1 g [(6-trifluoromethyl-7 - [(4- (3chlorophenyl) piperazin-1-yl) -1,2,3,4-tetra-hydroquinoxaline-2,3- dion) -1yl] -methanephosphonsäurediethylester in 10 ml of concentrated hydrochloric acid for 2 h 120 ° C bath temperature warmed. After concentration in vacuo, the mixture is stirred in water and aspirated. 900 mg of [(6-trifluoromethyl-7 - [(4- (3-chlorophenyl) piperazin-1-yl) -1,2,3,4- tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid with a melting point <300 ° C.

The following are produced in an analogous manner:
[(6-Trifluoromethyl-7 - [(4- (3-trifluoromethylphenyl) piperazin-1-yl) -1,2-, 3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid
[(6-Trifluoromethyl-7 - [(4- (4-fluorophenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid
[(6-Trifluoromethyl-7 - [(4- (2-pyridylphenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid
[(6-Trifluoromethyl-7 - [(4- (4-methylphenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid
[(6-Trifluoromethyl-7 - [(4- (4-methoxyphenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid
[(6-Trifluoromethyl-7 - [(4- (3-methoxyphenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid
[(6-Trifluoromethyl-7 - [(4- (2-methoxyphenyl) piperazin-1-yl) -1,2,3,4-te-trahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid
[(6-Trifluoromethyl-7 - [(4- (4-chlorophenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid
[(6-Trifluoromethyl-7 - [(4- (4-trifluoromethylphenyl) piperazin-1-yl) -1,2-, 3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid
[(6-Trifluoromethyl-7 - [(4- (4-benzyloxyphenyl) piperazin-1-yl) -1,2,3,4-tetrahydroquinoxaline-2,3-dione) -1yl] methanephosphonic acid

Claims (4)

1. Compounds of formula I. wherein
R¹ - (CH₂) _n -CR²H- (CH₂) _m -Z and
R⁵, R⁶, R⁷ and R⁸ are the same or different and are hydrogen, C _1-6 alkyl, CF₃, nitro, halogen, NR⁹R¹⁰, cyano, SO _p R¹¹, SO₂NR¹²R¹³, SO₃H, SO₃C _1-6 alkyl or OR¹⁴,
in which
R² is hydrogen or - (CH₂) _q -R³,
R³ is hydrogen, hydroxy, C _1-6 alkoxy or NR¹⁵R¹⁶,
n, m and q each 0, 1, 2 or 3
Z POXY, OPOXY, SO₂R¹⁷, CO₂R¹⁸, cyano or tetrazole,
R11 H, C _1-6 alkyl, phenyl,
p 0, 1 or 2
R¹², R¹³ and R¹⁸ are hydrogen or C _1-4 alkyl,
R¹⁴ H or optionally 1- to 3-fold substituted with halogen C _1-6 alkyl,
R¹⁷ hydroxy, C _1-6 alkoxy or NR¹⁹R²⁰,
X and Y are identical or different and denote hydroxy, C _1-6 alkoxy, C _1-4 alkyl or NR²¹R²²,
R⁹ and R¹⁰ together with the nitrogen atom form an optionally substituted 5- to 7-membered heterocycle which contains a further N atom which is substituted by optionally substituted aryl or hetaryl radicals,
R¹⁵ and R¹⁶, R²¹ and R²² are the same or different and form hydrogen, C _1-4 alkyl, aryl or together with the nitrogen atom a 5- to 7-membered saturated heterocycle which contain another oxygen, sulfur or nitrogen atom and be substituted can or form an unsaturated 5-membered heterocycle which can contain 1-3 N atoms and can be substituted,
R¹⁹ and R²⁰ are the same or different and form hydrogen, C _1-4 alkyl or together with the nitrogen atom a saturated 5- to 7-membered heterocycle which may contain a further oxygen, sulfur or nitrogen atom, and their isomers or salts, where at least one of the substituents R⁵, R⁶, R⁷ or R⁸ NR⁹R¹⁰ means and where, if R⁵ and R⁸ is hydrogen, R⁶ CF₃ and R⁷ is 4-phenyl-piperazin-1-yl, R¹ cannot be methanephosphonic acid or methanephosphonic acid diethyl ester. 2. [(6-trifluoromethyl-7 - [(4- (3-chlorophenyl) piperazin-1-yl) -1,2,3,4-tetr-ahydroquinoxaline-2,3-dione) -1yl] - methanephosphonic acid. 3. Medicament based on the compounds of formula I according to claim 1. 4. A process for the preparation of the compounds of formula I according to claim 1, characterized in that

• a) a compound of formula II wherein R¹ to R⁸ have the above meaning, cyclized with oxalic acid or reactive oxalic acid derivatives or
• b) a compound of formula III wherein R¹ has the above meaning and one of the substituents R ^{5 '} , R ^6' , R ^{7 '} or R ^{8' represents} a leaving group, nucleophilically substituted and, if desired, then saponified the ester group or esterified or amidated the acid group or introduces a tetrazolyl group or the aryl - Or hetaryl group on NR⁹R¹⁰ electrophilically substituted or the isomers are separated or the salts are formed.