EP0876357A1 - New quinoxalindione derivatives, their preparation and use in medicaments - Google Patents

Abstract

New quinoxalindone derivatives are disclosed having formula (I), in which R?1, R5, R6 and R7¿ have the meanings given in the description, as well as their preparation and use in medicaments.

Description

 New quinoxalinedione derivatives, their production and use in medicinal products

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

It is known from numerous publications that quinoxaline derivatives have affinity for the quisqualate receptors and, because of the affinity, are suitable as medicaments for the treatment of diseases of the central nervous system. For example, in WO9308173 6-methyl-1-alkyl-substituted chionoxaline-2,3-dionondvate and in EPA-03771 12 6-methyl- and 7-ethyl] -l-hydroxy-chionoxaline-2,3-dione are described. These compounds have the disadvantage that they do not have the good solubility required for drugs and, at the same time, good affinity for the quisqualate receptor

It was therefore the task of synthesizing new compounds which are very soluble, have a specific antagonistic effect on the AMPA receptor and are therefore suitable as medicaments for the treatment of the diseases which are mediated by the hyperactivity of the excitative amino acids

The compounds according to the invention have the formula I.

wherein

R ¹ - (CH ₂ ) _n -CR ² H- (CH2) mZ and

R ⁵ Cι _ ₆ alkyl, which may be substituted with halogen, -OR ⁸ , -NR ⁹ R ¹⁰ , SO _Q -R ^1] , COR ¹² , optionally substituted aryl or optionally substituted hetaryl, C2-6 "alkenyl, the may be substituted with halogen, -OR ⁸ , -NR ⁹ R ¹⁰ , SO _Q -R ^{1 J} , COR ¹² , optionally substituted aryl or optionally substituted hetaryl, SO _p -R 3 _OCjer -CH = R ^ ₎ 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. ^ - Alkyl, which can be substituted with halogen, -OR ⁸ , -NR ⁹ R ¹⁰ , SO ^ R ^{1 J} , COR ¹² , optionally substituted aryl or optionally substituted hetaryl, C2-6 "alkenyl, which with halogen, -OR ⁸ , -NR ⁹ R ¹⁰ , SOo-R ^{1 1} , COR ¹² , optionally substituted aryl or optionally substituted hetaryl may be substituted, SO _p -R ¹³ or -CH = R ¹ ^

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

Z POXY, OPOXY, S0 ₂ R ²¹ , CO ₂ R ²² , cyano or tetrazole,

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, Cι_ ₆ alkoxy or NR ²³ R ²⁴ ,

R ^{1 5} oxygen, = NOH or

_/ C _1.6 alkyl

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 ^Ö 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.

If 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, tπazine, 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

If R ⁹ and R ¹⁰ > R ¹⁶ and R ¹⁷ , R ¹⁹ and R ²⁰ , R ²³ and R ²⁴ or R ²⁵ and R ²⁶ together with the nitrogen atom form a saturated heterocycle, piperidine, pyrrolidine, morpholine, thiornorphohn, hexahydroazepine, for example or piperazine. 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) -pιperidin. Form R ⁹ and R ¹⁰ - R ¹⁶ and R ¹⁷ , R ¹⁹ and R ²⁰ , R ²³ and R ²⁴ or R ²⁵ and R ²⁶ , together with the nitrogen atom, an unsaturated heterocycle, for example imidazole, pyrazole, pyrrole and triazole , which can be substituted once or twice with cyano, C 1.4 alkyl, phenyl or CO 2 -C 6 alkyl.

Compounds in which R5 is alkyl are preferred, which may be substituted by -OR ⁸ , - NR ⁹ R ¹⁰ , SOQ-R '1, COR ¹² , optionally substituted aryl or optionally substituted hetaryl

If an acidic function is included, 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, Seπnoi, Tns-hydroxy-methyl-amino-methane, ammopropanediol, Sovak base, l-Amιno-2,3,4-butantπol

If a basic function is included, the 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. Because 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) a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) displaced the AMPA receptors, they are particularly suitable for the treatment of diseases which are influenced by the receptors of excitatory amino acids, in particular the AMPA receptor

According to the invention, 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 According to the invention, 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. 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. Furthermore, the compounds can be used as anesthetics (anesthetic ), Pain relievers or anti-emetics are used

The pharmacological activity of the compounds of the formula I was determined by means of the tests described below

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 results of these experiments show that the compound of the formula I and its acid addition salts influence functional disorders of the AMPA receptor. They are therefore suitable for the production of medicaments for the symptomatic and preventive treatment of diseases which are triggered by changes in the function of the AMPA receptor complex become Treatment with the compounds according to the invention prevents or delays the cell damage and functional disorders which occur as a result of the disease and reduces the symptoms which arise as a result.

The indications can be shown by conventional pharmacological tests.

To use the compounds according to the invention as pharmaceuticals, they are brought into the form of a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains. The pharmaceutical preparations can be in solid form, for example as tablets, 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

a compound of formula II

wherein 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

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

wherein 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 dimethylaminopyπdin, 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 alcohol or acetonitrile can be added to the reaction mixture

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

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

The nucleophilic substitution 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

The substitution by alkenyl compounds is carried out with the catalysis of transition metal complexes such as Pd (0), for example palladium tetrakistπphenylphosphine or Pd ( ²⁺ \ such as Palladιum-bιsTπ-o-tolylphosphιn-dιchloπd or Nιckel (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

Suitable nucleophiles are, for example, the corresponding boronic acids or boranes or organotin compounds, organozinc compounds, Gπgnard 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, Tπalkylphosphiten or preferably with Tπarylphosphinen

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. For this purpose, 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. As bases are e.g. Alkali hydrides, alkali amides, alkali alcoholates such as potassium tert-butylate, alkali or alkaline earth carbonates or hydroxides, optionally in the presence of phase transfer catalysts such as e.g. Crown breath or organic bases such as triethylamine, diisopropylethylamine or diazabicycloundecane, if appropriate in the presence of salts such as lithium bromide

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

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 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

The oxidation of thioethers to sulfoxides or sulfones is carried out by methods known from the literature. For example, 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 Natπumperjodat 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. 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

The 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. In the case of the phosphonic acids, the esterification can be achieved by reaction with orthoesters, if appropriate with the addition of catalysts such as p-toluenesulfonic acid

The 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 nitπles mιt_eιnem azide such as, for example, tπmethylsilylazide, hydrochloric acid or sodium azide, if appropriate with the addition of a proton source such as, for example, ammonium chloride or tπethylammonium 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

If the preparation of the starting compounds is not described, they are known or can be prepared analogously to known compounds, for example according to WO93 / 08173, WO94 / 25469 or the processes described here

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

Production of the starting materials

A.) 3.3 g (30 mmol) aminomethanephosphonic acid are placed in 120 ml water and 120 ml acetonitrile together with 3.37 g (31.8 mmol) soda and 7.8 g (97% ιg, 30 mmol) 3 - Tπfluormethyl-4,6-dιchlornιtrobenzol added and stirred for 4 h at 120 ^ C bath temperature at reflux After removal of the Acetomtπls on a rotary evaporator is extracted three times with 100 ml of ethyl acetate. The organic phase is washed with a little water. It contains starting material and is discarded. 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 - Nιtro-4-tπfluormethyl-5-chlorophenyl) -amιnomethanphosphonsaure of melting point 207.3 ^ C

B.), 67 g of N- (2-nitro-4-tπfluoromethyl-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. -amιnomethanphosphonsauredιethylester

Are produced in an analogous manner. N- (2-Nιtro-4-tπfluormethyI-5-phenylthιo) -phenyl-amιnomethanphosphonsauredιethylester

C.) 8.5 g of N- (2-nitro-4-trifluoromethyl-5-chlorophenyl) aminomethanephosphonate in 250 ml of toluene with 60 ml of ethanol, 50 ml of 2M soda solution, 0.9 g

Palladium tetrakistπphenylphosphine and 3.7 g of styrylboronic acid are added and the mixture is heated to a bath temperature of 110 ° C. for 7 hours under argon. After concentration, the mixture is distributed in ethyl acetate and water and the ethyl acetate phase is dried, filtered and concentrated. The residue is chromatographed twice over silica gel, initially with the eluent toluene / ethyl acetate = 1 1 and then the correspondingly combined fractions first with cyclohexane to separate Tπphenylphosphin and later with ethyl acetate. 5.8 g (58% d Th) of N- (4-Nιtro-2- tπfluormethyl-5-styryl) -phenyl-amιnomethanphosphonsauredιethylester

D.) 1 g of 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-tπfluoromethyl-5-phenethyl) phenyl are obtained aminomethanephosphonate, which are used in the next step without further purification

Are produced in an analogous manner

N- (2-Amιno-4-tπfluormethyl-5- (4-chlθφhenylethyl) phenyl) - aminomethanephosphonic acid diethyl ester

N- (2-Amιno-4-tπfiuormethyl-5- (4-methoxyphenylethyi) -phenyl) -amιnomethanphosphonsaure- diethyl ester

N- (2-Aιmno-4-tπfluormethyl-5- (4-fluorophenylethyl) phenyl) - ammomethanephosphonic acid diethyl ester

N- (2-Amιno-4-tπfluormethyl-5- (pyπd-2-ylethyl) -phenyl) -amιnomethanphosphonsauredιethylester

E.) 2.96 g of N- (2-nitro-4-trifluoromethyl-5-styryl) phenyl-aminomethanephosphonic acid ester are dissolved in 140 ml of methanol and 140 ml of methylene chloride and cooled to -78 ° C. Ozone is then passed into the solution for 15 min. After the starting material has disappeared by means of TLC monitoring, 2.8 g of tπphenylphosphine are added. The mixture is allowed to come to room temperature and is concentrated. The residue is chromatographed on silica gel with acetone: hexane = l 1 , 8g N- (2-Nιtro-4-tπfluormethyl-5-formyl) - phenyl-aminomethanephosphonic acid diethyl ester

F.) 2.56 g of N- (2-nitro-4-trifluoromethyl-5-formyl) phenyl) aminomethanephosphonate are dissolved in 130 ml of methanol and slowly added with 260 mg of sodium boronate in portions. After the addition has ended, the mixture is stirred at room temperature for 2 hours. It is then concentrated and distributed in ethyl acetate and 1N hydrochloric acid. The ethyl acetate phase is washed with water, dried, filtered and concentrated. The residue is chromatographed on silica gel with acetone hexane = l 1. 2.2 g of diethyl N- (2-nitro-4-tifluoromethyl-5-hydroxymethyl) phenylaminomethanephosphonate are obtained

G.) 0.76g of N- (2-nitro-4-trifluoromethyl-5-hydroxymethyl) phenyl-aminomethanephosphonic acid diethyl ester are hydrogenated in 75 ml of ethanol with 0.24 g of palladium / carbon (10%) under normal hydrogen pressure at room temperature. After the catalyst has been suctioned off through diatomaceous earth, the filtrate is concentrated. The residue of 0.73 g of N- (2-amino-4-tifluoromethyl-5-hydroxymethyl) phenyl-aminomethanephosphonic acid ethyl ester is used in the next step without further purification

The following are produced in an analogous manner: N- (2-Amιno-4-trifluoromethyl-5-N-moφholιnomethyl) -phenyl-amιnomethanphosphonsaure- diethyl ester.

Diethyl N- (2-amino-4-trifluoromethyl-5- (2-carbethoxyeth-l -yl) -phenyl-aminomethanephosphonate (from N- (2-nitro-4-tetrofluoromethyl-5- (2-carbethoxyethen-1 - yl) -phenyl-aminomethane-phosphonic acid diethyl ester).

H.) 1.75 g of N- (2-nitro-4-tifluoromethyl-5-hydroxymethyl) phenyl-aminomethanephosphonic acid diethyiester are dissolved in 60 ml of methylene chloride and successively mixed with 634 mg of dimethylamino pyridine and 980 mg of tosyl chloride, it is overnight at room temperature touched. Then another 266 mg of dimethylaminopyridine and 400 mg of tosyl chloride are added and the mixture is stirred at room temperature for a further 7 hours. It is diluted with methylene chloride, washed once with 1 N hydrochloric acid and with saturated sodium chloride solution. The organic phase is dried, filtered and concentrated. The residue is chromatographed on silica gel using ethyl acetate as the eluent. 1.4 g of N- (2-nitro-4-trifluoπτιethyl-5-chloromethyl) -phenyl-aminomethanephosphonic acid diethyl ester are obtained.

I.) 550 mg of 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-ethylthιomethyl) -phenylaminomethanephosphonate are obtained.

K.) 356 mg of N- (2-nitro-4-tifluoromethyl-5-ethylthiomethyl) phenyl-aminomethanephosphonic acid diethyl ester are dissolved in 14 ml of methanol and added dropwise to a solution of 212 mg of ammonium chloride in 14 ml of water which has been mixed with 140 mg of iron powder. When the addition is complete, the mixture is heated to 80 ° C. for 1 hour. After suction filtration over diatomaceous earth, the filtrate is concentrated. The residue is used in the next step without further purification.

The following is prepared in an analogous manner: N- (2-amino-4-tifluoromethyl-5-phenylthio) -phenyl-aminomethanephosphonic acid ethyl ester.

L.) To a suspension of 60 mg of sodium hydride (80% in oil) in 1 ml of dimethoxyethane, 0.5 ml of phosphonoacetate in 1 ml of dimethoxyethane is added dropwise. After stirring at room temperature, 384 mg of N- (2-amino-4-trifluoromethyl-5-formylphenyl) aminomethane Phosphonic acid diethyl ester in 8 ml of dimethoxyethane was added dropwise to the batch and, after the addition had ended, the mixture was heated at a bath temperature of 80 ° C. for 4 hours. Then it was poured onto ice, dimethoxyethane was distilled off and extracted with ethyl acetate. The organic phase was dried, filtered and concentrated, and the residue was eluted over silica gel with acetoneexane = M Separately, 350 mg of N- (2-amino-4-tπfluoπτιethyl-5- (2-carbethoxyethen-ly]) - phenyl-amomomethanephosphonic acid diethyl ester are obtained

M.) 1.6 g of N- (2-nitro-4-trifluoromethyl-5-fluorophene-aminomethanephosphonic acid) are dissolved in 20 ml of water and mixed with 1.6 g of sodium carbonate. 660 mg of thiophenol are then added and the mixture is stirred for 1, 25 hours at 120 ° C heated bath temperature. After cooling, it is first extracted with ethyl acetate. This extract is discarded. The aqueous phase is acidified with 4N hydrochloric acid and extracted three times with ethyl acetate. This collected Essigesteφhase is dried, filtered and concentrated and used without further purification in the esterification B.)

N.) 1, 1g of N- (2-Nιtro-4-tπfluormethyl-5-chloromethyl) -phenylamιnomethanphosphonsaureethy lester are warmed to 25 ° C in 25ml Moφhohn for 2h. It is concentrated, the residue is taken up in ethyl acetate and extracted with 1N sodium hydroxide solution . The Essigesteφhase washed with water, dried, filtered and concentrated. The residue is over silica gel with acetone. Hexane = I 1 as the eluent, chromatographed. 600 mg of N- (2-nitro-4-tifluoromethyl-5- (N-moφhohno-methyl) -phenyl-aminomethanephosphonic acid methyl ester are obtained

O.) 1, 58 N- (2-Nιtro-4-tπfluormethyl-5-foπnyl) -phenyamιnomethanphosphonsauredιethylester are placed in 160 ml of absolute toluene under argon and mixed with 4.65 g of a mixture of 2-Picolyltnphenylphosphomumchloπd and Natπumamid The approach stirred 2 hours at room temperature After dilution with ethyl acetate, the mixture is extracted twice with water. The ethyl acetate phase is concentrated. The residue is chromatographed on silica gel with acetone: hexane = 1 as the eluent. 915 mg of N- (2-nitro-4-tπfluoromethyl-5- (pyπd- 2-yl-vιnyl) -phenyl) -amιnomethanphosphonsauredιethylester.

P.) 500 mg of N- (2-nitro-4-trifluoromethyl-5-formyl) -phenylmomnomethanphosphonsauredιethylester are placed in 50 ml of absolute toluene, mixed with 1.36 g of 4-methoxybenzyltπphenylphosphonιum- chlorine, cooled to 0 ° C and 370 mg of potassium tertiarbutylate added. The mixture is then stirred at room temperature for 3 hours. Water is added and the mixture is extracted. The combined organic phases are washed with saturated sodium chloride solution, filtered and concentrated. The residue is washed over silica gel with acetone: hexane = 1 ^• 1 as Chromatographing the eluent gives 370 mg of N- (2-nitro-4-tifluoromethyl-5- (4-methoxy (styryl) phenyl) aminomethanephosphonate ethyl ester

Analog are manufactured

N- (2-Nιtro-4-tπfluormethyl-5- (4-fluoro (styryl) phenyl) -amιnomethanphoshponsauredιethylester N- (2-Nιtro-4-tπfluormethyl-5- (4-chloro (styryl) phenyl) -amιnomethanphoshponsauredιethylester

example 1

870 mg of N - [(2-amino-4-tπfluoromethyl-5-phenethyl) phenyl] - diethyl aminomethanephosphonate are dissolved in 50 ml of absolute tetrahydrofuran and mixed with 0.57 g of triethylamine. A solution of 0.6 g of ethyl oxalate chloride in 12 ml of absolute tetrahydrofuran is added dropwise to this solution at room temperature. After the addition is complete, stirring is continued for 4 hours at room temperature. The precipitate is then filtered off and the filtrate is concentrated. The residue is taken up in 50 ml of IN hydrochloric acid and 50 ml of ethanol and stirred for 3 hours at a bath temperature of 120 ° C. The precipitate is filtered off and the filtrate is discarded. After recrystallization from ethanol, 230 mg (60% of theory) of N - [(6-trifluoromethyl-7-phenylethyl-l, 2,3,4-tetrahydrochnoxahn-2,3-dione) -lyl] - methanephosphonic acid diethyl ester are obtained

The following are produced in an analogous manner:

[(6-Trifluoromethyl-7- (4- (chlorophenylethyl) -1, 2,3,4-tetrahydroquinoxalion-2,3-dion) -lyl] methanephosphonic acid diethyl ester.

[(6-Tπfluormethyl-7- (4-fluorophenylethyl) -l, 2,3,4-tetrahydroquinoxahn-2,3-dione) -lyl] - diethyl methanephosphonate.

[(6-Tπfluormethyl-7- (4-methoxyphenylethyl) -l, 2,3,4-tetrahydroquinoxahn-2,3-dione) -lyl] - diethyl methanephosphonate

[(6-Tπfluoιmethyl-7-hydroxymethyl-1, 2,3,4-tetrahydrochιnoxalιn-2,3-dιon) - 1 yl] - diethyl methanephosphonate.

[(6-Trιfluormethyl-7-ethylthιomethyl-l, 2,3,4-tetrahydrochιnoxalιn-2,3-dιon) -l yl] - diethyl methanephosphonate.

[(6-Tπfluormethyl-7-phenylthio-l, 2,3,4-tetrahydrochιnoxalιn-2,3-dιon) -lyl] - diethyl methanephosphonate

[(6-Tπfluoπnethyl-7- (N-Moφholιnomethyl-l, 2,3,4-tetrahydrochιnoxalιn-2,3-dιon) -lyl] - methanephosphonic acid diethyl ester [(6-Trifluoromethyl-7- (2-hydroxycarbonyleth-l-yl) -1, 2,3,4-tetrahydroquinoxaline-2,3-dione) -lyl] - methanephosphonic acid diethyl ester. (The carboxylic ester originally present is among the

Reaction conditions saponified).

[(6-Trifluoromethyl-7- (2-pyridylethy 1) - 1, 2,3,4-tetrahydroquinoxaline-2,3-dione) - 1 y 1] - methanephosphonic acid diethyl ester.

Example 2

150mg [(6-trifluoromethyl-7-phenylthio-l, 2,3,4-tetrahydroquinoxaline-2,3-dione) lyl] methanephosphonic acid diethyl ester are dissolved in 10 ml of methanol and a solution of 1 10 mg of sodium periodate in 3 ml of water is added and stirred for 10 hours at room temperature. It is then diluted with water and shaken three times with ethyl acetate. The organic phase is concentrated and chromatographed twice over silica gel first with the eluent toluene: glacial acetic acid: water = 1 0:10: 1 and the second time with methylene chloride :: ethanol = 10: 1. 121 mg of 6-trifluoromethyl-7-sulfoxyphenyl-1, 2,3,4-tetrahydroquinoxaline-2,3-dione) -l yl] -methanephosphonic acid diethyl ester are obtained.

The following is produced in an analogous manner:

6-Trifluoromethyl-7- (ethylsulfoxymethyl) - 1, 2,3,4-tetrahydroquinoxaline-2,3-dione) - 1 yl] - methanephosphonic acid diethyl ester

Example 3

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

The following is produced in an analogous manner:

6-trifluoromethyl-7- (ethylsulfonylmethyl) -l, 2,3,4-tetrahydroquinoxaline-2,3-dione) -l yl] - methanephosphonic acid diethyl ester Example 4

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-Tπfluormethyl-7-phenylethyl-l, 2,3,4-tetrahydrochionoxane-2,3-dion) -lyl] methanephosphonic acid with a melting point of 260 ° C.

Are produced in an analogous manner

[(6-Tπfluormethyl-7-hydroxycarbonylethyl-1, 2,3,4-tetrahydrochιnoxahn-2,3-dione) - 1 yl] - methanephosphonic acid

[(6-Tπfluormethyl-7-phensulfonyl-1, 2,3,4-tetrahydrochιnoxalιn-2,3-dιon) - 1 y I] - methanephosphonic acid

[(6-Tπfluormethyl-7-phenylthιo-l, 2,3,4-tetrahydrochιnoxalιn-2,3-dιon) -lyl] - methanephosphonic acid

[(6-Trifluoromethyl-7-formyl-1, 2,3,4-tetrahydrochnoxahn-2,3-dionon) lyl] methanephosphonic acid [(6-trifluoromethyl-7- (4-chloro-phenyl) -ethyl) 2, 3,4-tetrahydroquinoxahn-2,3-dione) - lylj- methanephosphonic acid

[(6-Tπfluormethy l-7- (4-fluoφhenyl) ethyl-1, 2,3,4-tetrahydrochionoxalion-2,3-dion) - 1 y 1] - methanephosphonic acid

Example 5

200mg [(6-Tπfluormethyi-7-hydroxymethyl-l, 2,3,4-tetrahydrochιnoxalιn-2,3-dione) -lyl] - methanephosphonic acid diethyl ester are placed in 9 ml of acetonitrile and mixed with 0.44 ml of methyl bromosilane. The mixture is stirred for 8 hours at room temperature , then mixed with water and concentrated. The residue is extracted with water and suction filtered. 80 mg are obtained [(6-trifluoromethyl-7-hydroxymethyl-1, 2,3,4-tetrahydroquinoxahn-2,3-dione) - 1 y 1] - methanephosphonic acid

Are produced in an analogous manner.

[(6-Tπfluormethyl-7-ethylthιomethyl-1, 2,3,4-tetrahydrochιnoxahn-2,3-dιon) - 1 yl] - methanephosphonic acid

[(6-Tπfluormethyl-7-ethysulfonylmethyl-1, 2,3,4-tetrahydrochιnoxalιn-2,3-dιon) - 1 yl] - methanephosphonic acid

[(6-Tπfluormethyl-7-Moφholιnomethyl-1, 2,3,4-tetrahydrochιnoxahn-2,3-dιon) - 1 yl] - methanephosphonic acid [(6-Trifluoromethyl-7- (2-pyridylethyl) -1, 2,3,4-tetrahydroquinoxaline-2,3-dione) -lyl] -methane-phosphonic acid.

[(6-Trifluoromethyl-7- (4-methoxyphenyl) -ethyl-1, 2,3,4-tetrahydroquinoxaline-2,3-dione) - 1 yl] - methylphosphonic acid.

Example 6

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. The residue is chromatographed on silica gel with toluene: glacial acetic acid: water = 10: 10: 1. 160 mg of diethyl [(6-trifluoromethyl-7-formyl-l, 2,3,4-tetrahydroquinoxaline-2,3-dione) -lyl] -methanephosphonate are obtained in addition to the 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] - methanephosphonic acid diethyl ester are placed in 10 ml of benzene and successively with 0.1 ml of triethylamine and 63 mg of N- Isopropylhydroxylamine hydrochloride added. The mixture is stirred at room temperature for 8 hours. The solid is then suctioned off. The solid is chromatographed on silica gel using toluene: glacial acetic acid: water = 10: 10: 1. 120 mg of [6- trifluoromethyl l-7- [N-oxy- (N-isopropylformylimino)] - 1, 2,3,4-tetrahydroquinoxaline-2,3-dione) - 1 yl] - methanephosphonic acid diethyl ester are obtained.

The following is produced in an analogous manner:

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

Claims

claims

1) Compounds of formula I.

woπn R ¹ - (CH ₂ ) _n -CR ² H- (CH2) mZ and

R ⁵ Cι_6- alkyl, which may be substituted with halogen, -OR ⁸ , -NR ⁹ R ¹⁰ , SO ₀ -R ^J] , COR ¹² , optionally substituted aryl or optionally substituted hetaryl, C ₉ .5-alkenyl, which with Halogen, -OR ⁸ , -NR ⁹ R ¹⁰ , SOo-R ¹ 1, COR ¹² , optionally substituted aryl or optionally substituted hetaryl may be substituted, SO _p -R ¹³ or -CH = R ¹⁵ ,

R ^Ö and R ^{7 are the} same or different and are hydrogen, halogen, NO2, cyano, NR ^ RI ⁷ , -COR ¹⁴ , OR ¹⁸ , optionally substituted aryl, optionally substituted hetaryl, Cj.g- alkyl, which with halogen, - OR ⁸ , -NR ⁹ R ¹⁰ , SO _Q -R ^{1 l} , COR ¹² , optionally substituted aryl or optionally substituted hetaryl, C2-ό-alkenyl which can be substituted with halogen, -OR ⁸ , -NR ⁹ R ¹⁰ , SO _Q -R ^{1 l} , COR ¹² , optionally substituted aryl or optionally substituted hetaryl may be substituted, SO _p -R ¹³ or -CH = R ¹ ^,

R ^{2 is} hydrogen or - (CH ₂ ) _q -R ³

R ^{3 is} hydrogen, hydroxy, C ₆ _ alkoxy or NR ¹⁹ R ²⁰ ,

n, m and q each 0, 1, 2 or 3

Z POXY, OPOXY, SO ₂ R ²¹ , CO ₂ R ²² , cyano or tetrazole,

R ⁸ and R ^{18 are} hydrogen, optionally substituted by halogen C 1-6 alkyl,

o and p each 0, 1 or 2, R ^{1 1} and R ^{13 are} hydrogen, Cμö-alkyl ^or optionally substituted aryl,

R ¹² , R ¹⁴ , R ²¹ and R ²² OH, C \ _ ₆ - alkoxy or NR ²³ R ²⁴ ,

R ¹⁵ oxygen, = NOH or

C ^ alkyl

= \

X and Y are the same or different and are hydroxy, C _] _6-alkoxy, C _j ^ alkyl or NR ² R26,

R ⁹ and R ^{1 0} , R ¹⁶ and R ¹⁷ , R ¹⁹ and R ²⁰ , R ²³ and R ²⁴ , R ²⁵ and R ² 6 are the same or different and are hydrogen, C] _4-alkyl, aryl or together with the nitrogen atom form a 5-7-saturated 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

) N - [(6-Trifluoromethyl-7-phenylethyl-l, 2,3,4-tetrahydroquinoxalion-2,3-dione) -lyl] - methanephosphonic acid diethyl ester

[(6 Tπfluormethyl-7-phenylthιo- 1, 2,3,4-tetrahydrochιnoxalιn-2,3-dιon) - 1 yl] - diethyl methanephosphonate

[(6-Tπfluormethyl-7- (2-pyrιdylethyl) - 1, 2,3,4-tetrahydrochιnoxahn-2,3-dιon) - 1 yl] - methanephosphonic acid diethyl ester

[(6-Tπfluormethyl-7-phenylethyl-1, 2,3,4-tetrahydrochιnoxahn-2,3-dione) - 1 yl] - methanephosphonic acid

[(6-Tπfluormethyl-7-ethylthιomethyl-1, 2, 3,4-tetrahydrochιnoxahn-2,3-dιon) - lylj- methanephosphonic acid [(6-trifluoromethyl-7-moφholιnomethyl-1,

2,3,4-tetrahydroquinoxahn-2,3-dione) - 1 yl] - methanephosphonic acid.

3.) Medicament containing a compound of formula I according to claim 1.

4.) Process for the preparation of the compounds of formula I, characterized in that a compound of formula II

where R! , R ⁵ , R ⁶ and R ^{7 have} the meaning given above, cyclize with oxalic acid or reactive oxalic acid derivatives and, if desired, then saponify the ester group or esterify or amidate the acid group or introduce a tetrazole group or add alcohols to aldehydes or thioethers to sulfoxides or sulfones or sulfoxides Sulfones are oxidized, or aldehydes are converted into oximes or nitrones, or the isomers are separated or the salts are formed.